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BackgroundObesity and consumption of high-fat diets (HFD) are associated with intestinal permeabilization and increased paracellular transport of endotoxins, which can promote neuroinflammation. Inflammation can affect the hypothalamic pituitary adrenal (HPA) axis, which controls responses to stress and downregulates the brain-derived neurotrophic factor (BDNF), which can promote anxiety and depression, conditions frequently found in obesity. We previously showed that consumption of anthocyanins (AC) mitigate HFD-induced insulin resistance, intestinal permeability, and inflammation.ObjectivesThis study investigated if a dietary supplementation with a cyanidin- and delphinidin-rich extract (CDRE) could counteract HFD/obesity-induced hippocampal inflammation in mice.MethodsC57BL/6J male mice were fed for 14 wk on one of the following diets: 1) a control diet containing 10% total calories from fat (C), 2) a control diet supplemented with 40 mg AC/kg body weight (BW) (CAC), 3) a HFD containing 60% total calories from fat (lard) (HF), or 4) the HFD supplemented with 2, 20, or 40 mg AC/kg BW (HFA2, HFA20, and HFA40, respectively). In plasma and in the hippocampus, parameters of neuroinflammation and the underlying cause (endotoxemia) and consequences (alterations to the HPA and BDNF downregulation) were measured.ResultsConsumption of the HFD caused endotoxemia. Accordingly, hippocampal Tlr4 mRNA levels were 110% higher in the HF group, which were both prevented by CDRE supplementation. Consumption of the HFD also caused: 1) microgliosis and increased expression of genes involved in neuroinflammation, that is, Iba-1, Nox4, Tnfα, and Il-1β, 2) alterations of HPA axis regulation, that is, with low expression of mineralocorticoid (MR) and glucocorticoid (GR) receptors; and 3) decreased Bdnf expression. Supplementation of HFD-fed mice with CDRE mitigated neuroinflammation, microgliosis, and MR and BDNF decreases.ConclusionsCDRE supplementation mitigates the negative effects associated with HFD consumption and obesity in mouse hippocampus, in part by decreasing inflammation, improving glucocorticoid metabolism, and upregulating BDNF.

Hypertriglyceridemia is a risk factor for type 2 diabetes and cardiovascular disease (CVD). Plasma triglycerides (TGs) are a key factor for assessing the risk of diabetes or CVD. However, previous lipidomics studies have demonstrated that not all TG molecules behave the same way. Individual TGs with different fatty acid compositions are regulated differentially under various conditions. In addition, distinct groups of TGs were identified to be associated with increased diabetes risk (TGs with lower carbon number [C#] and double-bond number [DB#]), or with decreased risk (TGs with higher C# and DB#). In this study, we examined the effects of high-fat feeding in rats on plasma lipid profiles with special attention to TG profiles. Wistar rats were maintained on either a low-fat (control) or high-fat diet (HFD) for 2 weeks. Plasma samples were obtained before and 2.5 h after a meal (n = 10 each) and subjected to lipidomics analyses. High-fat feeding significantly impacted circulating lipid profiles, with the most significant effects observed on TG profile. The effects of an HFD on individual TG species depended on DB# in their fatty acid chains; an HFD increased TGs with low DB#, associated with increased diabetes risk, but decreased TGs with high DB#, associated with decreased risk. These changes in TGs with an HFD were associated with decreased indices of hepatic stearoyl-CoA desaturase (SCD) activity, assessed from hepatic fatty acid profiles. Decreased SCD activity would reduce the conversion of saturated to monounsaturated fatty acids, contributing to the increases in saturated TGs or TGs with low DB#. In addition, an HFD selectively depleted ω-3 polyunsaturated fatty acids (PUFAs), contributing to the decreases in TGs with high DB#. Thus, an HFD had profound impacts on circulating TG profiles. Some of these changes were at least partly explained by decreased hepatic SCD activity and depleted ω-3 PUFA.

Trans vaccenic acid (TVA, trans11-18 : 1) and cis9, trans11-CLA (also known as rumenic acid; RA) have received widespread attention as potentially beneficial trans-FA due to their putative health benefits, including anti-diabetic properties. The objective of this study was to determine the effects of beef fat naturally enriched with TVA and RA on parameters related to glucose homoeostasis and associated metabolic markers in diet-induced obese (DIO) mice. Thirty-six male C57BL/6J mice (8 weeks old) were fed for 19 weeks with either a control low-fat diet (CLF), a control high-fat diet (CHF), or a TVA+RA-enriched high-fat diet (EHF). Compared with CLF, feeding either CHF or EHF resulted in adverse metabolic outcomes associated with high-fat diets, including adiposity, impaired glucose control and hepatic steatosis. However, the EHF diet induced a significantly higher liver weight TAG content and elevated plasma alanine transaminase levels compared with the CHF diet. Collectively, the findings from this study suggest that EHF does not improve glucose tolerance and worsens liver steatosis in DIO mice. However, the adverse effects of EHF on the liver could be in part related to the presence of other trans-FA in the enriched beef fat.

The brain bidirectionally communicates with the gut to control food intake and energy balance, which becomes dysregulated in obesity. For example, endocannabinoid (eCB) signaling in the small-intestinal (SI) epithelium is upregulated in diet-induced obese (DIO) mice and promotes overeating by a mechanism that includes inhibiting gut-brain satiation signaling. Upstream neural and molecular mechanism(s) involved in overproduction of orexigenic gut eCBs in DIO, however, are unknown. We tested the hypothesis that overactive parasympathetic signaling at the muscarinic acetylcholine receptors (mAChRs) in the SI increases biosynthesis of the eCB, 2-arachidonoyl-sn-glycerol (2-AG), which drives hyperphagia via local CB1Rs in DIO. Male mice were maintained on a high-fat/high-sucrose Western-style diet for 60 d, then administered several mAChR antagonists 30 min prior to tissue harvest or a food intake test. Levels of 2-AG and the activity of its metabolic enzymes in the SI were quantitated. DIO mice, when compared to those fed a low-fat/no-sucrose diet, displayed increased expression of cFos protein in the dorsal motor nucleus of the vagus, which suggests an increased activity of efferent cholinergic neurotransmission. These mice exhibited elevated levels of 2-AG biosynthesis in the SI, that was reduced to control levels by mAChR antagonists. Moreover, the peripherally restricted mAChR antagonist, methylhomatropine bromide, and the peripherally restricted CB1R antagonist, AM6545, reduced food intake in DIO mice for up to 24 h but had no effect in mice conditionally deficient in SI CB1Rs. These results suggest that hyperactivity at mAChRs in the periphery increases formation of 2-AG in the SI and activates local CB1Rs, which drives hyperphagia in DIO.

Exercise promotes pulsatile shear stress in the arterial circulation and ameliorates cardiometabolic diseases. However, exercise-mediated metabolic transducers for vascular protection remain under-investigated. Untargeted metabolomic analysis demonstrated that wild-type mice undergoing voluntary wheel running exercise expressed increased endothelial stearoyl-CoA desaturase 1 (SCD1) that catalyzes anti-inflammatory lipid metabolites, namely, oleic (OA) and palmitoleic acids (PA), to mitigate NF-κB-mediated inflammatory responses. In silico analysis revealed that exercise augmented time-averaged wall shear stress but mitigated flow recirculation and oscillatory shear index in the lesser curvature of the mouse aortic arch. Following exercise, endothelial Scd1-deleted mice (Ldlr-/- Scd1EC-/-) on high-fat diet developed persistent VCAM1-positive endothelium in the lesser curvature and the descending aorta, whereas SCD1 overexpression via adenovirus transfection mitigated endoplasmic reticulum stress and inflammatory biomarkers. Single-cell transcriptomics of the aorta identified Scd1-positive and Vcam1-negative endothelial subclusters interacting with other candidate genes. Thus, exercise mitigates flow recirculation and activates endothelial SCD1 to catalyze OA and PA for vascular endothelial protection.

Previous studies indicate that CNS administration of oxytocin (OT) reduces body weight in high fat diet-induced obese (DIO) rodents by reducing food intake and increasing energy expenditure (EE). We recently demonstrated that hindbrain (fourth ventricular [4V]) administration of OT elicits weight loss and elevates interscapular brown adipose tissue temperature (TIBAT, a surrogate measure of increased EE) in DIO mice. What remains unclear is whether OT-elicited weight loss requires increased sympathetic nervous system (SNS) outflow to IBAT. We hypothesized that OT-induced stimulation of SNS outflow to IBAT contributes to its ability to activate BAT and elicit weight loss in DIO mice. To test this hypothesis, we determined the effect of disrupting SNS activation of IBAT on the ability of 4V OT administration to increase TIBAT and elicit weight loss in DIO mice. We first determined whether bilateral surgical SNS denervation to IBAT was successful as noted by ≥ 60% reduction in IBAT norepinephrine (NE) content in DIO mice. NE content was selectively reduced in IBAT at 1-, 6- and 7-weeks post-denervation by 95.9 ± 2.0, 77.4 ± 12.7 and 93.6 ± 4.6% (P

Glucose is the primary energy source for most mammalian cells and its transport is affected by a family of facilitative glucose transporters (GLUTs) encoded by the SLC2 gene. GLUT1 and GLUT3, highly expressed isoforms in the blood-brain barrier and neuronal membranes, respectively, are associated with multiple neurodevelopmental disorders including epilepsy, dyslexia, ADHD, and autism spectrum disorder (ASD). Dietary therapies, such as the ketogenic diet, are widely accepted treatments for patients with the GLUT1 deficiency syndrome, while ameliorating certain symptoms associated with GLUT3 deficiency in animal models. A ketogenic diet, high-fat diet, and calorie/energy restriction during prenatal and postnatal stages can also alter the placental and brain GLUTs expression with long-term consequences on neurobehavior. This review focuses primarily on the role of diet/energy perturbations upon GLUT isoform-mediated emergence of neurodevelopmental and neurodegenerative disorders.

Our research used glucocorticoids as a medically relevant molecular probe to identify a previously unrecognized ADAMTS1-PTN-Wnt pathway. We elucidated the role of this pathway in regulating adipose precursor cell (APC) behavior to either proliferate or differentiate in response to systemic cues, such as elevated caloric intake. Further, our studies identified the non-muscle myosin protein MYH9 as a key target of this pathway to modulate adipogenesis in vivo. These findings enable strategies toward developing novel therapeutics for obesity and related metabolic disorders.

• Two-thirds of children who responded to KDT maintained response post-diet. • One third of children maintained response without further treatments added. • Children who were seizure-free on diet were more likely to maintain response. There is limited research on the proportion of individuals with epilepsy who maintain response to ketogenic diet therapy (KDT) after discontinuing treatment. We aimed to determine the proportion of individuals who did / did not maintain response post KDT and explore factors that may influence the likelihood of maintaining response. Retrospective data were collected from 97 individuals from 9 KDT centres. Individuals had achieved ≥50 % seizure reduction on KDT for at least 12 months, with seizure frequency data available at 3 months+ post diet. Outcome 1 was: recurrence of seizures or increase in seizure frequency post diet; outcome 2: recurrence of seizures, increase in seizure frequency or an additional anti-seizure treatment started post diet. 61/97 (62.9 %) individuals maintained response at latest follow-up (mean 2.5[2.0] years since stopping KDT). Approximately one third maintained response without further anti-seizure treatments. One quarter of individuals had an increase in frequency or recurrence of seizures within 6 months (95 %CI 4, 12) for outcome 1 and within 3 months (3, 6) for outcome 2. Individuals who did not achieve seizure freedom on diet were significantly more likely to have an increase in seizures or to require additional anti-seizure treatments post diet compared to those who were seizure-free on diet (hazard ratio 4.02, 95 %CI (1.46, 11.16) p < 0.01). Our findings should help guide clinical teams with the information they provide patients and their families regarding likelihood of long-term seizure response to KDT. Realistic costings for KDT services may need to be considered. [ABSTRACT FROM AUTHOR]

High-fat, low-carbohydrate enteral nutrition has gained attention, with expectations of an improved respiratory condition, fewer complications, and lower mortality. The present study performed a systematic review and meta-analysis of randomized controlled trials to examine the effects of high-fat, low-carbohydrate enteral nutrition in critically ill adult patients. We searched MEDLINE via Pubmed, Cochrane Central Register of Controlled Trials (CENTRAL), and ICHUSHI for randomized controlled trials comparing high-fat, low-carbohydrate enteral nutrition to standard enteral nutrition in critically ill adult patients who received enteral nutrition. The primary outcome was mortality. Secondary outcomes included intensive care unit (ICU) mortality, length of ICU stay, length of mechanical ventilation, and adverse events of diarrhea and gastric residual volume. We examined the risk of bias using the Cochrane risk-of-bias tool for randomized trials version 2. We assessed the overall certainty of evidence based on the Grading of Recommendations Assessment, Development, and Evaluation methodology. Synthesis results were calculated with risk ratios and 95% confidence intervals using a Mantel-Haenszel random-effects model. Eight trials with 607 patients were included. The effects of high-fat, low-carbohydrate enteral nutrition on mortality did not significantly differ from those of standard enteral nutrition (62/280 [22.1%] vs. 39/207 [18.8%], risk ratios = 1.14, 95% confidence intervals 0.80 to 1.62, P = 0.47). No significant differences were observed in ICU mortality, ICU length of stay, diarrhea, or gastric residual volume between the two groups. However, high-fat, low-carbohydrate enteral nutrition was associated with a significantly shorter duration of mechanical ventilation (mean difference −1.72 days, 95% confidence intervals −2.93 to −0.50, P = 0.005). High-fat, low-carbohydrate enteral nutrition may not affect mortality, but may decrease the duration of mechanical ventilation in critically ill adult patients. Limitations include the small number of studies and potential for bias. Further research is needed to confirm these results and investigate effects on other outcomes and in a subgroup of patients requiring mechanical ventilation. [ABSTRACT FROM AUTHOR]

Diet-related metabolic syndrome is the largest contributor to adverse health in the United States. However, the study of gene-environment interactions and their epigenomic and transcriptomic integration is complicated by the lack of environmental and genetic control in humans that is possible in mouse models. Here we exposed three mouse strains, C57BL/6J (BL6), A/J, and NOD/ShiLtJ (NOD), to a high-fat, high-carbohydrate diet, leading to varying degrees of metabolic syndrome. We then performed transcriptomic and genome-wide DNA methylation analyses for each strain and found overlapping but also highly divergent changes in gene expression and methylation upstream of the discordant metabolic phenotypes. Strain-specific pathway analysis of dietary effects revealed a dysregulation of cholesterol biosynthesis common to all three strains but distinct regulatory networks driving this dysregulation. This suggests a strategy for strain-specific targeted pharmacologic intervention of these upstream regulators informed by epigenetic and transcriptional regulation. As a pilot study, we administered the drug GW4064 to target one of these genotype-dependent networks, the farnesoid X receptor pathway, and found that GW4064 exerts strain-specific protection against dietary effects in BL6, as predicted by our transcriptomic analysis. Furthermore, GW4064 treatment induced inflammatory-related gene expression changes in NOD, indicating a strain-specific effect in its associated toxicities as well as its therapeutic efficacy. This pilot study demonstrates the potential efficacy of precision therapeutics for genotype-informed dietary metabolic intervention and a mouse platform for guiding this approach.

Hypothalamic gliosis associated with high-fat diet (HFD) feeding increases susceptibility to hyperphagia and weight gain. However, the body-weight-independent contribution of microglia to glucose regulation has not been determined. Here, we show that reducing microglial nuclear factor κB (NF-κB) signaling via cell-specific IKKβ deletion exacerbates HFD-induced glucose intolerance despite reducing body weight and adiposity. Conversely, two genetic approaches to increase microglial pro-inflammatory signaling (deletion of an NF-κB pathway inhibitor and chemogenetic activation through a modified Gq-coupled muscarinic receptor) improved glucose tolerance independently of diet in both lean and obese rodents. Microglial regulation of glucose homeostasis involves a tumor necrosis factor alpha (TNF-α)-dependent mechanism that increases activation of pro-opiomelanocortin (POMC) and other hypothalamic glucose-sensing neurons, ultimately leading to a marked amplification of first-phase insulin secretion via a parasympathetic pathway. Overall, these data indicate that microglia regulate glucose homeostasis in a body-weight-independent manner, an unexpected mechanism that limits the deterioration of glucose tolerance associated with obesity.

Pregnane X receptor (PXR) is a xenobiotic receptor that can be activated by numerous chemicals including endogenous hormones, dietary steroids, pharmaceutical agents, and environmental chemicals. PXR has been established to function as a xenobiotic sensor to coordinately regulate xenobiotic metabolism by regulating the expression of many enzymes and transporters required for xenobiotic metabolism. Recent studies have implicated a potentially important role for PXR in obesity and metabolic disease beyond xenobiotic metabolism, but how PXR action in different tissues or cell types contributes to obesity and metabolic disorders remains elusive. To investigate the role of adipocyte PXR in obesity, we generated a novel adipocyte-specific PXR deficient mouse model (PXRΔAd). Notably, we found that loss of adipocyte PXR did not affect food intake, energy expenditure, and obesity in high-fat diet-fed male mice. PXRΔAd mice also had similar obesity-associated metabolic disorders including insulin resistance and hepatic steatosis as control littermates. PXR deficiency in adipocytes did not affect expression of key adipose genes in PXRΔAd mice. Our findings suggest that adipocyte PXR signaling may be dispensable in diet-induced obesity and metabolic disorders in mice. Further studies are needed to understand the role of PXR signaling in obesity and metabolic disorders in the future. SIGNIFICANCE STATEMENT: The authors demonstrate that deficiency of adipocyte pregnane X receptor (PXR) does not affect diet-induced obesity or metabolic disorders in mice and infers that adipocyte PXR signaling may not play a key role in diet-induced obesity. More studies are needed to understand the tissue-specific role of PXR in obesity.

In obesity, CD11c+ innate immune cells are recruited to adipose tissue and create an inflammatory state that causes both insulin and catecholamine resistance. We found that ablation of Gnas, the gene that encodes Gαs, in CD11c expressing cells protects mice from obesity, glucose intolerance, and insulin resistance. Transplantation studies showed that the lean phenotype was conferred by bone marrow-derived cells and did not require adaptive immunity. Loss of cAMP signaling was associated with increased adipose tissue norepinephrine and cAMP signaling, and prevention of catecholamine resistance. The adipose tissue had reduced expression of catecholamine transport and degradation enzymes, suggesting that the elevated norepinephrine resulted from decreased catabolism. Collectively, our results identified an important role for cAMP signaling in CD11c+ innate immune cells in whole-body metabolism by controlling norepinephrine levels in white adipose tissue, modulating catecholamine-induced lipolysis and increasing thermogenesis, which, together, created a lean phenotype.Article highlightsWe undertook this study to understand how immune cells communicate with adipocytes, specifically, whether cAMP signaling in the immune cell and the adipocyte are connected. We identified a reciprocal interaction between CD11c+ innate immune cells and adipocytes in which high cAMP signaling in the immune cell compartment induces low cAMP signaling in adipocytes and vice versa. This interaction regulates lipolysis in adipocytes and inflammation in immune cells, resulting in either a lean, obesity-resistant, and insulin-sensitive phenotype, or an obese, insulin-resistant phenotype.

Non-alcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome, and is estimated to affect one billion individuals worldwide. An increased intake of a high-fat diet (HFD) and sugar-sweetened beverages are risk-factors for NAFLD development, but how their combined intake promotes progression to a more severe form of liver injury is unknown. Here we show that fructose metabolism via ketohexokinase (KHK) C isoform leads to unresolved endoplasmic reticulum (ER) stress when coupled with a HFD intake. Conversely, a liver-specific knockdown of KHK in mice consuming fructose on a HFD is adequate to improve the NAFLD activity score and exert a profound effect on the hepatic transcriptome. Overexpression of KHK-C in cultured hepatocytes is sufficient to induce ER stress in fructose free media. Upregulation of KHK-C is also observed in mice with genetically induced obesity or metabolic dysfunction, whereas KHK knockdown in these mice improves metabolic function. Additionally, in over 100 inbred strains of male or female mice hepatic KHK expression correlates positively with adiposity, insulin resistance, and liver triglycerides. Similarly, in 241 human subjects and their controls, hepatic Khk expression is upregulated in early, but not late stages of NAFLD. In summary, we describe a novel role of KHK-C in triggering ER stress, which offers a mechanistic understanding of how the combined intake of fructose and a HFD propagates the development of metabolic complications.

Oats are recognized to provide many health benefits that are mainly associated with its dietary fibre, β-glucan. However, the protein derived from oats is largely understudied with respect to its ability to maintain health and attenuate risk factors of chronic diseases. The goal of the current study was to investigate the metabolic effects of oat protein consumption in lieu of casein as the protein source in high fat, high sucrose (HF/HS) fed Wistar rats. Four-week-old rats were divided into three groups and were fed three different experimental diets: a control diet with casein as the protein source, an HF/HS diet with casein, or an HF/HS diet with oat protein for 16 weeks. Heart structure and function were determined by echocardiography. Blood pressure measurements, an oral glucose tolerance test, and markers of cholesterol metabolism, oxidative stress, inflammation, and liver and kidney damage were also performed. Our study results show that incorporation of oat protein in the diet was effective in preserving systolic heart function in HF/HS fed rats. Oat protein significantly reduced serum total and low-density lipoprotein cholesterol levels. Furthermore, oat protein normalized liver HMG-CoAR activity, which, to our knowledge, is the first time this has been reported in the literature. Therefore, our research suggests that oat protein can provide hypocholesterolemic and cardioprotective benefits in a diet-induced model of metabolic syndrome. [ABSTRACT FROM AUTHOR]

We compared the effects of two different high-caloric diets administered to 4-week-old rats for 12 weeks: a diet rich in sugar (30% sucrose) and a cafeteria diet rich in sugar and high-fat foods. We focused on the hippocampus, particularly on the gamma-aminobutyric acid (GABA)ergic system, including the Ca2+-binding proteins parvalbumin (PV), calretinin (CR), calbindin (CB), and the neuropeptides somatostatin (SST) and neuropeptide Y (NPY). We also analyzed the density of cholinergic varicosities, brain-derived neurotrophic factor (BDNF), reelin (RELN), and cyclin-dependent kinase-5 (CDK-5) mRNA levels, and glial fibrillary acidic protein (GFAP) expression. The cafeteria diet reduced PV-positive neurons in the granular layer, hilus, and CA1, as well as NPY-positive neurons in the hilus, without altering other GABAergic populations or overall GABA levels. The high-sugar diet induced a decrease in the number of PV-positive cells in CA3 and an increase in CB-positive cells in the hilus and CA1. No alterations were observed in the cholinergic varicosities. The cafeteria diet also reduced the relative mRNA expression of RELN without significant changes in BDNF and CDK5 levels. The cafeteria diet increased the number but reduced the length of the astrocyte processes. These data highlight the significance of determining the mechanisms mediating the observed effects of these diets and imply that the cognitive impairments previously found might be related to both the neuroinflammation process and the reduction in PV, NPY, and RELN expression in the hippocampal formation. [ABSTRACT FROM AUTHOR]

Despite the fact that genes and the environment are known to play a central role in islet function, our knowledge of how these parameters interact to modulate insulin secretory function remains relatively poor. Presently, we performed ex vivo glucose-stimulated insulin secretion and insulin content assays in islets of 213 mice from 13 inbred mouse strains on chow, Western diet (WD), and a high-fat, carbohydrate-free (KETO) diet. Strikingly, among these 13 strains, islets from the commonly used C57BL/6J mouse strain were the least glucose responsive. Using matched metabolic phenotyping data, we performed correlation analyses of isolated islet parameters and found a positive correlation between basal and glucose-stimulated insulin secretion, but no relationship between insulin secretion and insulin content. Using in vivo metabolic measures, we found that glucose tolerance determines the relationship between ex vivo islet insulin secretion and plasma insulin levels. Finally, we showed that islet glucose-stimulated insulin secretion decreased with KETO in almost all strains, concomitant with broader phenotypic changes, such as increased adiposity and glucose intolerance. This is an important finding as it should caution against the application of KETO diet for beta-cell health. Together these data offer key insights into the intersection of diet and genetic background on islet function and whole body glucose metabolism. NEW & NOTEWORTHY: Thirteen strains of mice on chow, Western diet, and high-fat, carbohydrate-free (KETO), correlating whole body phenotypes to ex vivo pancreatic islet functional measurements, were used. The study finds a huge spectrum of functional islet responses and insulin phenotypes across all strains and diets, with the ubiquitous C57Bl/6J mouse exhibiting the lowest secretory response of all strains, highlighting the overall importance of considering genetic background when investigating islet function. Ex vivo basal and stimulated insulin secretion are correlated in the islet, and KETO imparts widescale downregulation of islet insulin secretion. [ABSTRACT FROM AUTHOR]

Objective To investigate the effect of NOD-like receptor family pyrin domain containing 3（NLRP3) knockdown on a mouse model of nonalcoholic steatohepatitis (NASH) induced by high-fat high-carbohydrate (HFHC) diet. Methods A total of 44 mice were randomly divided into normal diet group (CON group) with 20 mice and HFHC group with 24 mice. At the end of week 14 of modeling，4 mice were randomly selected from the HFHC group for the pre-experiment of adeno-associated virus (AAV) by tail vein injection, and NLRP3 knockdown was verified after 4 weeks. After NLRP3 knockdown was verified at the end of week 18, the remaining 40 mice were given a single tail vein injection of AAV, and then they were divided into CON+NLRP3 knockdown negative control group (CON+NLRP3-NC group), CON+NLRP3 knockdown group (CON+NLRP3-KD group), HFHC+NLRP3- NC group, and HFHC+NLRP3-KD group, with 10 mice in each group. At the end of week 24, the activation of NLRP3 inflammasome was observed； related indicators were measured, including body weight, liver weight, liver index, and glucose metabolism (fasting blood glucose, fasting insulin, and Homeostasis Model Assessment of Insulin Resistance [HOMA-IR] index)；the indicators of liver lipid content (liver triglyceride [TG] and oil red O staining), liver inflammation (serum alanine aminotransferase [ALT] activity, HE staining, and inflammation-related genes), and liver fibrosis (Sirius Red staining and fibrosis-related genes) were measured. A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the least significant difference t-test was used for further comparison between two groups. Results Compared with the CON+NLRP3-NC group based on the results of Western Blot, the HFHC+NLRP3-NC group had significant increases in the protein expression levels of NLRP3, pro-Caspase1, Caspase1, ASC, and IL-1β, while the HFHC+NLRP3-KD group had significant reductions in these levels (all P<0.05). The HFHC+NLRP3-NC group showed varying degrees of increase in body weight, liver weight, liver index, and glucose metabolism indicators, while the HFHC+NLRP3-KD group showed significant improvements in these indicators (all P<0.05). As for hepatic fat deposition, compared with the CON+NLRP3-NC group, the HFHC+NLRP3-NC group had a significant increase in liver TG, with a large number of red lipid droplets shown by oil red O staining, and the HFHC+ NLRP3-KD group had significant reductions in liver TG and the number of lipid droplets in the liver (all P<0.01). In terms of liver inflammation, compared with the CON+NLRP3-NC group, the HFHC+NLRP3-NC group had significant increases in serum ALT, NAFLD activity score, and inflammation-related genes, while the HFHC+NLRP3-KD group had significant reductions in these indicators (all P<0.01). As for liver fibrosis, compared with the CON+NLRP3-NC group, the HFHC+NLRP3-NC group had significant increases in collagen fiber area and fibrosis-related genes, and the HFHC+NLRP3-KD group had significant reductions in fibrosis-related genes (all P<0.05) and a tendency of reduction in collagen fiber area (P>0.05). Conclusion NLRP3 knockdown can significantly improve hepatic fat deposition and inflammation in a mouse model of HFHC-induced NASH. [ABSTRACT FROM AUTHOR]

Chitinase-3-like 1 protein (CHI3L1) is a secreted glycoprotein, strongly correlated with fibrosis severity in chronic liver diseases including non-alcoholic steatohepatitis (NASH). However, the mechanisms by which CHI3L1 contributes to fibrogenesis remain undefined. Here, we showed that infiltrating monocyte-derived liver macrophages represent the main source of CHI3L1 in murine NASH. We developed a floxed CHI3L1 knock-out (KO) mouse to further study the cell-specific role of CHI3L1 ablation. Wildtype (WT) and myeloid cell-specific CHI3L1 KO mice (CreLyz) were challenged with a highly inflammatory and fibrotic dietary model of NASH by administering choline-deficient high-fat diet for 10 weeks. Macrophage accumulation and inflammatory cell recruitment were significantly ameliorated in the CreLyz group compared to WT (F4/80 IHC p

Sustained hyperglycemia results in excess protein O-GlcNAcylation, leading to vascular complications in diabetes. This study aims to investigate the role of O-GlcNAcylation in the progression of coronary microvascular disease (CMD) in inducible type 2 diabetic (T2D) mice generated by a high-fat diet with a single injection of low-dose streptozotocin. Inducible T2D mice exhibited an increase in protein O-GlcNAcylation in cardiac endothelial cells (CECs) and decreases in coronary flow velocity reserve (CFVR, an indicator of coronary microvascular function) and capillary density accompanied by increased endothelial apoptosis in the heart. Endothelial-specific O-GlcNAcase (OGA) overexpression significantly lowered protein O-GlcNAcylation in CECs, increased CFVR and capillary density, and decreased endothelial apoptosis in T2D mice. OGA overexpression also improved cardiac contractility in T2D mice. OGA gene transduction augmented angiogenic capacity in high-glucose treated CECs. PCR array analysis revealed that seven out of 92 genes show significant differences among control, T2D, and T2D + OGA mice, and Sp1 might be a great target for future study, the level of which was significantly increased by OGA in T2D mice. Our data suggest that reducing protein O-GlcNAcylation in CECs has a beneficial effect on coronary microvascular function, and OGA is a promising therapeutic target for CMD in diabetic patients.

Obesity incidence is increasing worldwide with the urgent need to identify new therapeutics. Sex differences in immune cell activation drive obesity-mediated pathologies where males are more susceptible to obesity comorbidities and exacerbated inflammation. Here, we demonstrate that the macrophage-secreted protein RELMα critically protects females against high-fat diet (HFD)-induced obesity. Compared to male mice, serum RELMα levels were higher in both control and HFD-fed females and correlated with frequency of adipose macrophages and eosinophils. RELMα-deficient females gained more weight and had proinflammatory macrophage accumulation and eosinophil loss in the adipose stromal vascular fraction (SVF), while RELMα treatment or eosinophil transfer rescued this phenotype. Single-cell RNA-sequencing of the adipose SVF was performed and identified sex and RELMα-dependent changes. Genes involved in oxygen sensing and iron homeostasis, including hemoglobin and lncRNA Gm47283/Gm21887, correlated with increased obesity, while eosinophil chemotaxis and response to amyloid-beta were protective. Monocyte-to-macrophage transition was also dysregulated in RELMα-deficient animals. Collectively, these studies implicate a RELMα-macrophage-eosinophil axis in sex-specific protection against obesity and uncover new therapeutic targets for obesity.

Background Many infancy-onset epilepsies have a poor prognosis for seizure control and neurodevelopmental outcome. Ketogenic diets can improve seizures in older children and adults unresponsive to antiseizure medicines. We aimed to determine the effectiveness of the ketogenic diet in reducing seizure frequency compared to further antiseizure medicine in infants with drug-resistant epilepsy. Methods In this randomised, open-label trial, 136 infants with epilepsy, aged 1–24 months, with > 4 seizures/week and a previous trial of ≥ 2 antiseizure medicines were recruited from 19 hospitals in the United Kingdom. Following a 1- or 2-week observation period, participants were randomised to receive the classical ketogenic diet or a further antiseizure medicine for 8 weeks, using a computer-generated schedule without stratification. Treatment allocation was concealed from research nurses involved in patient care, but not from participants. The primary outcome was the number of seizures/day recorded during weeks 6–8. All analyses were intention to treat. The trial is registered with the European Union Drug Regulating Authorities Clinical Trials Database (2013-002195-40). Findings Between 1 January 2015 and 30 September 2021, 136 eligible infants were randomised. Sixty-one (78%) of 78 assigned to a ketogenic diet and 47 (81%) of 58 assigned to antiseizure medicine had primary outcome data. At 8 weeks, the number of seizures per day, accounting for the baseline rate and randomised group, was not significantly different between groups [median (interquartile range) ketogenic diet 5 (1, 16); antiseizure medicine 3 (2, 11), incidence rate ratio 1.33, 95%, confidence internal 0.84 to 2.11; p = 0.22]. A similar number of infants reported at least one serious adverse event in both groups [antiseizure medicine: 24/56 (43%), ketogenic diet: 40/78 (51%)]. The most common serious adverse events were seizures in both groups. Three infants died during the course of the trial, all of whom were randomised to the ketogenic diet arm; deaths were considered to be unrelated to treatment. Interpretation There was no evidence that a ketogenic diet was better than further antiseizure medicine in achieving seizure control in infants with epilepsy. The two treatments were similarly tolerated and a ketogenic diet appears safe to use in infants with epilepsy. A ketogenic diet could be a treatment option in infants whose seizures continue despite trial of two standard antiseizure medicines. Study registration This study was registered as EudraCT 2013-002195-40. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/10/18) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 16. See the NIHR Funding and Awards website for further award information. Plain language summary Many babies with epilepsy continue to have seizures (‘fits’), despite taking medicines. These babies are unlikely to make the same developmental progress as babies without epilepsy. Ketogenic diets are high in fat and low in carbohydrate and have been shown to reduce seizures in older children and adults. Babies (age 1–24 months) with epilepsy, who still had seizures despite having tried medicines, either started a ketogenic diet or another medicine. They then stayed on this treatment for 8 weeks. We wanted to know whether there was a difference in the number of seizures in the last 2 weeks of treatments compared to before. Seventy-eight babies started a ketogenic diet and 58 started another medicine. Overall, the number of seizures babies had every day was similar in both groups. A similar number of babies in both groups either had to go to hospital for some reason or stay in hospital for longer. This was mostly because of seizures. Two babies suffered ‘sudden unexpected death in epilepsy’ and another died during a planned surgery. These deaths were not thought to be related to the ketogenic diet. Both the ketogenic diet and the medicines helped to reduce the number of seizures in the babies. Babies in both groups had similar side effects. Doctors could consider starting a ketogenic diet in babies who continue to have seizures even though they have tried medicines to stop their seizures. Scientific summary Background Many infancy-onset epilepsies are poorly responsive to antiseizure medicines (ASMs) with poor prognosis for neurodevelopmental outcome. Ketogenic diets (KDs), which are high-fat, low-carbohydrate diets, have been shown to reduce seizures in older children with drug-resistant epilepsy. No high-quality evidence is available for infants. Objectives In this open-label randomised controlled trial, we compared the efficacy of the classical KD to a further appropriate ASM in infants with drug-resistant epilepsy. The primary outcome was the number of seizures recorded during weeks 6–8, accounting for the baseline rate and randomised group. Secondary outcomes at 8 weeks were the number of infants seizure-free in weeks 6–8 of the intervention period, responder rate (defined as the number showing more than a 50% improvement in seizure frequency compared to baseline), tolerance to KD and relationship between medium-chain fatty acids and seizure control. Secondary outcomes at 12 months were retention on treatment, quality of life and neurodevelopmental outcome. Adverse events were recorded throughout the trial. Serious adverse events were reported to the study sponsor. Methods Infants (age 1–24 months) with epilepsy, with an average ≥ 4 seizures/week and previous trials of ≥ 2 ASMs were recruited from 19 hospitals in the UK. Following a 1- or 2-week observation period, during which there were no changes to regular ASMs (emergency seizure treatments continued as required), participants were randomised to receive a classical KD or a further ASM for 8 weeks, using a computer-generated schedule without stratification. An allocation ratio of 1 : 1.35 was used to account for the therapist effect in the KD group only. Treatment allocation was concealed from research nurses involved in patient care, but not from participants. The primary outcome was the number of seizures/day recorded during weeks 6–8. All analyses were intention to treat. The following assessments were performed in all infants prior to randomisation: medical history, physical examination, administration of the Infant Toddler Quality of Life Questionnaire™ (ITQOL-97; © HealthActCHQ Inc. 2013) and Vineland Adaptive Behaviour Scales (Vineland™-II), and clinical laboratory assessments. Food diaries required for diet calculation were returned from parents/guardians of all participants a maximum of 1 week into the observation period. Parents/carers were asked to keep daily seizure diaries throughout the 8-week treatment periods for participants in both arms. Thereafter, they were requested to reduce seizure recording to at least 1–2 days per week, as clinically indicated, until 28 days before the final 12-month visit, when daily seizure recording recommenced. Follow-up visits were arranged at 4 weeks, 8 weeks, and 6, 9 and 12 months. Assessments included clinical review, physical examination, documentation of seizure frequency from seizure diaries, review of adverse events and concomitant medication, clinical laboratory assessments (8 weeks, and 6 and 12 months) and completion of tolerability questionnaire by parents/carers together with research nurses, the ITQOL-97 (8 weeks and 12 months) and Vineland-II (12 months). After the 8-week assessment, according to the infant’s clinical response to treatment (seizure outcome and tolerability), KD or ASM was then continued or changed; those randomised to the ASM arm then had the opportunity to start KD. Results Of 136 eligible infants, 78 were randomised to KD and 58 to ASM. Of 78 infants who started KD, 67 (86%) continued to 8 weeks, of which 61 (78%) had primary outcome data available; 53 (91% of those randomised to ASM group) started a further ASM, 49 (84%) continued to 8 weeks and 47 (81%) had primary outcome data available. The median number of daily seizures was not significantly different in both groups at 8 weeks [KD 5 (1, 16); ASM 3 (2, 11), incidence rate ratio (IRR) 1.33, 95% confidence interval (CI) 0.84 to 2.11; p = 0.22]. The odds ratio (OR) of achieving ≥ 50% seizure reduction was 1.21 (95% CI 0.55 to 2.65) and 0.88 (0.27 to 2.80) for seizure freedom. A total of 7/63 infants (11%) in the KD group were seizure-free, compared with 6/48 (13%) in the ASM group (OR 0.88, 95% CI 0.27 to 2.80). A higher proportion of infants in the ASM group changed the number or dose of concurrent ASMs during the intervention period [24/48 (50%)] compared to KD [9/66 (14%)]. The side-effect score at 8 weeks was similar in both groups [KD median 40; interquartile range (IQR) 38–42; ASM median 41 IQR 39‒44) and there were no clinically significant differences other than those expected in clinical or laboratory parameters between groups. At 8 weeks, median scores within the ITQOL-97 were numerically higher (suggesting better health) in the KD group for 7 of the 12 concepts. The infant’s pain, its global behaviour, impact on parental time and family cohesion were equal between the two groups, although general perceptions of the infant’s health were numerically higher in the ASM arm. A numerically larger proportion of parents/guardians of infants in the KD group perceived their child’s health to be ‘much better than a year ago’ (10/40, 25%) compared to those in the ASM group (3/32, 9%); numerically more parents/guardians of infants in the ASM group perceived their child’s health to be ‘much worse than a year ago’ (8/32, 25%) compared to those in the KD group (2/40, 5%). Of 66 infants randomised to KD > 12 months before the study end date, 31 (47%) continued the diet to 12 months; of 47 randomised to further ASM > 12 months before the study end date, 21 (45%) continued the ASM to 12 months. For those who reported data, there were no differences between groups for any concept within the ITQOL-97 at 12 months, except for the infant’s temperament and mood (coefficient −6.09, 95% CI −11.63 to −0.54) and the infant getting along with others (coefficient −6.79, 95% CI −12.97 to −0.60), which favoured the ASM group. A similar proportion of parents/guardians of infants in both groups perceived their child’s health to be ‘much better than a year ago’ (12/24 50% ASM; 11/30 37% KD) or ‘much worse than a year ago’ (0/24, 0% ASM; 1/30, 3% KD). Within the Vineland-II there were neither significant differences between groups in the overall standardised score nor domain standard scores at 12 months. The Daily living domain sum of v-scale scores was nominally improved in the ASM group (coefficient 2.23, 95% CI −4.22 to −0.25). A total of 73 serious adverse events (SAEs) were reported in the ASM group and 161 in the KD group. A similar proportion of infants in both groups reported at least 1 SAE (43% ASM; 51% KD) – most commonly seizures. Three infants died in the KD arm, all considered unrelated to treatment. Conclusions There was no evidence that KD was better than further ASM in achieving seizure control in infants with epilepsy. The two treatments were similarly tolerated and KD appeared safe to use in infants with epilepsy. KD could be a treatment option in infants whose seizures continue despite trial of two standard ASMs. Further trials are needed with larger cohorts at 12-month follow-up and beyond, particularly to look at quality of life and neurodevelopment, perhaps with alternative study design. Study registration This study was registered as EudraCT 2013-002195-40. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/10/18) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 16. See the NIHR Funding and Awards website for further award information.

Extracellular matrix proteins are associated with metabolically healthy adipose tissue and regulate inflammation, fibrosis, angiogenesis, and subsequent metabolic deterioration. In this study, we demonstrated that transforming growth factor-beta (TGFBI), an extracellular matrix (ECM) component, plays an important role in adipose metabolism and browning during high-fat diet-induced obesity. TGFBI KO mice were resistant to adipose tissue hypertrophy, liver steatosis, and insulin resistance. Furthermore, adipose tissue from TGFBI KO mice contained a large population of CD11b+ and CD206+ M2 macrophages, which possibly control adipokine secretion through paracrine mechanisms. Mechanistically, we showed that inhibiting TGFBI-stimulated release of adipsin by Notch-1-dependent signaling resulted in adipocyte browning. TGFBI was physiologically bound to Notch-1 and stimulated its activation in adipocytes. Our findings revealed a novel protective effect of TGFBI deficiency in obesity that is realized via the activation of the Notch-1 signaling pathway.

Diabetes represents a spectrum of disease in which metabolic dysfunction damages multiple organ systems including liver, kidneys and peripheral nerves1,2. Although the onset and progression of these co-morbidities are linked with insulin resistance, hyperglycaemia and dyslipidaemia3-7, aberrant non-essential amino acid (NEAA) metabolism also contributes to the pathogenesis of diabetes8-10. Serine and glycine are closely related NEAAs whose levels are consistently reduced in patients with metabolic syndrome10-14, but the mechanistic drivers and downstream consequences of this metabotype remain unclear. Low systemic serine and glycine are also emerging as a hallmark of macular and peripheral nerve disorders, correlating with impaired visual acuity and peripheral neuropathy15,16. Here we demonstrate that aberrant serine homeostasis drives serine and glycine deficiencies in diabetic mice, which can be diagnosed with a serine tolerance test that quantifies serine uptake and disposal. Mimicking these metabolic alterations in young mice by dietary serine or glycine restriction together with high fat intake markedly accelerates the onset of small fibre neuropathy while reducing adiposity. Normalization of serine by dietary supplementation and mitigation of dyslipidaemia with myriocin both alleviate neuropathy in diabetic mice, linking serine-associated peripheral neuropathy to sphingolipid metabolism. These findings identify systemic serine deficiency and dyslipidaemia as novel risk factors for peripheral neuropathy that may be exploited therapeutically.

Analogues of the hepatokine fibroblast growth factor 21 (FGF21) are in clinical development for type 2 diabetes and nonalcoholic steatohepatitis (NASH) treatment. Although their glucose-lowering and insulin-sensitizing effects have been largely unraveled, the mechanisms by which they alleviate liver injury have only been scarcely addressed. Here, we aimed to unveil the mechanisms underlying the protective effects of FGF21 on NASH using APOE*3-Leiden.CETP mice, a well-established model for human-like metabolic diseases. Liver-specific FGF21 overexpression was achieved in mice, followed by administration of a high-fat high-cholesterol diet for 23 weeks. FGF21 prevented hepatic lipotoxicity, accompanied by activation of thermogenic tissues and attenuation of adipose tissue inflammation, improvement of hyperglycemia and hypertriglyceridemia, and upregulation of hepatic programs involved in fatty acid oxidation and cholesterol removal. Furthermore, FGF21 inhibited hepatic inflammation, as evidenced by reduced Kupffer cell (KC) activation, diminished monocyte infiltration, and lowered accumulation of monocyte-derived macrophages. Moreover, FGF21 decreased lipid- and scar-associated macrophages, which correlated with less hepatic fibrosis as demonstrated by reduced collagen accumulation. Collectively, hepatic FGF21 overexpression limits hepatic lipotoxicity, inflammation, and fibrogenesis. Mechanistically, FGF21 blocks hepatic lipid influx and accumulation through combined endocrine and autocrine signaling, respectively, which prevents KC activation and lowers the presence of lipid- and scar-associated macrophages to inhibit fibrogenesis.

High fat diets (HFDs) have been linked to several diseases including obesity, diabetes, fatty liver, inflammatory bowel disease (IBD) and colon cancer. In this study, we examined the impact on intestinal gene expression of three isocaloric HFDs that differed only in their fatty acid composition-coconut oil (saturated fats), conventional soybean oil (polyunsaturated fats) and a genetically modified soybean oil (monounsaturated fats). Four functionally distinct segments of the mouse intestinal tract were analyzed using RNA-seq-duodenum, jejunum, terminal ileum and proximal colon. We found considerable dysregulation of genes in multiple tissues with the different diets, including those encoding nuclear receptors and genes involved in xenobiotic and drug metabolism, epithelial barrier function, IBD and colon cancer as well as genes associated with the microbiome and COVID-19. Network analysis shows that genes involved in metabolism tend to be upregulated by the HFDs while genes related to the immune system are downregulated; neurotransmitter signaling was also dysregulated by the HFDs. Genomic sequencing also revealed a microbiome altered by the HFDs. This study highlights the potential impact of different HFDs on gut health with implications for the organism as a whole and will serve as a reference for gene expression along the length of the intestines.

Bitter taste receptors (Tas2rs in mice) detect bitterness, a warning signal for toxins and poisons, and are expressed in enteroendocrine cells. We tested the hypothesis that Tas2r138 and Tas2r116 mRNAs are modulated by microbiota alterations induced by a long-term high-fat diet (HFD) and antibiotics (ABX) (ampicillin and neomycin) administered in drinking water. Cecum and colon specimens and luminal contents were collected from C57BL/6 female and male mice for qRT-PCR and microbial luminal 16S sequencing. HFD with/without ABX significantly increased body weight and fat mass at 4, 6, and 8 weeks. Tas2r138 and Tas2r116 mRNAs were significantly increased in mice fed HFD for 8 weeks vs. normal diet, and this increase was prevented by ABX. There was a distinct microbiota separation in each experimental group and significant changes in the composition and diversity of microbiome in mice fed a HFD with/without ABX. Tas2r mRNA expression in HFD was associated with several genera, particularly with Akkermansia, a Gram-negative mucus-resident bacterium. These studies indicate that luminal bacterial composition is affected by sex, diet, and ABX and support a microbial dependent upregulation of Tas2rs in HFD-induced obesity, suggesting an adaptive host response to specific diet-induced dysbiosis.

Inflammatory bowel disease (IBD) is a multifactorial disease with increasing incidence in the U.S. suggesting that environmental factors, including diet, are involved. It has been suggested that excessive consumption of linoleic acid (LA, C18:2 omega-6), which must be obtained from the diet, may promote the development of IBD in humans. To demonstrate a causal link between LA and IBD, we show that a high fat diet (HFD) based on soybean oil (SO), which is comprised of ~55% LA, increases susceptibility to colitis in several models, including IBD-susceptible IL10 knockout mice. This effect was not observed with low-LA HFDs derived from genetically modified soybean oil or olive oil. The conventional SO HFD causes classical IBD symptoms including immune dysfunction, increased intestinal epithelial barrier permeability, and disruption of the balance of isoforms from the IBD susceptibility gene Hepatocyte Nuclear Factor 4α (HNF4α). The SO HFD causes gut dysbiosis, including increased abundance of an endogenous adherent invasive Escherichia coli (AIEC), which can use LA as a carbon source. Metabolomic analysis shows that in the mouse gut, even in the absence of bacteria, the presence of soybean oil increases levels of LA, oxylipins and prostaglandins. Many compounds in the endocannabinoid system, which are protective against IBD, are decreased by SO both in vivo and in vitro. These results indicate that a high LA diet increases susceptibility to colitis via microbial and host-initiated pathways involving alterations in the balance of bioactive metabolites of omega-6 and omega-3 polyunsaturated fatty acids, as well as HNF4α isoforms.

Intra-Uterine Growth Restriction (IUGR) is a risk factor for many adult-onset chronic diseases, such as diabetes and obesity. These diseases are associated with intestinal microbiome perturbations (dysbiosis). The establishment of an intestinal microbiome begins in utero and continues postnatally (PN). Hypercaloric diet-induced dysbiosis is a major driver of childhood obesity. We hypothesized that different postnatal diets superimposed on IUGR will alter the postnatal intestinal microbiome. We compared four experimental rat groups: (1) Ad lib fed regular chow diet pre- and postnatally (CON), (2-3) IUGR induced by maternal caloric restriction prenatally followed postnatally (PN) by either (2) the control diet (IUGR-RC) or (3) High-Fat-high-fructose (IUGR-HFhf) diet, and lastly (4) HFhf ad lib pre- and postnatally (HFhf). Fecal samples were collected from dams and male and female rat offspring at postnatal day 2, 21, and adult day 180 for 16S rRNA gene sequencing. Maternal diet induced IUGR led to dysbiosis of the intestinal microbiome at PN21. Postnatal HFhf diet significantly reduced microbial diversity and worsened dysbiosis reflected by an increased Gammaproteobacteria/Clostridia ratio. Dysbiosis arising from a mismatch between IUGR and a postnatal HFhf diet may contribute to increased risk of the IUGR offspring for subsequent detrimental health problems.

Inhibition of AMPK is tightly associated with metabolic perturbations upon over nutrition, yet the molecular mechanisms underlying are not clear. Here, we demonstrate the serine/threonine-protein phosphatase 6 regulatory subunit 3, SAPS3, is a negative regulator of AMPK. SAPS3 is induced under high fat diet (HFD) and recruits the PP6 catalytic subunit to deactivate phosphorylated-AMPK, thereby inhibiting AMPK-controlled metabolic pathways. Either whole-body or liver-specific deletion of SAPS3 protects male mice against HFD-induced detrimental consequences and reverses HFD-induced metabolic and transcriptional alterations while loss of SAPS3 has no effects on mice under balanced diets. Furthermore, genetic inhibition of AMPK is sufficient to block the protective phenotype in SAPS3 knockout mice under HFD. Together, our results reveal that SAPS3 is a negative regulator of AMPK and suppression of SAPS3 functions as a guardian when metabolism is perturbed and represents a potential therapeutic strategy to treat metabolic syndromes.

High maternal weight is associated with detrimental outcomes in offspring, including increased susceptibility to neurological disorders such as anxiety, depression and communicative disorders. Despite widespread acknowledgement of sex biases in the development of these disorders, few studies have investigated potential sex-biased mechanisms underlying disorder susceptibility. Here, we show that a maternal high-fat diet causes endotoxin accumulation in fetal tissue, and subsequent perinatal inflammation contributes to sex-specific behavioural outcomes in offspring. In male offspring exposed to a maternal high-fat diet, increased macrophage Toll-like receptor 4 signalling results in excess microglial phagocytosis of serotonin (5-HT) neurons in the developing dorsal raphe nucleus, decreasing 5-HT bioavailability in the fetal and adult brains. Bulk sequencing from a large cohort of matched first-trimester human samples reveals sex-specific transcriptome-wide changes in placental and brain tissue in response to maternal triglyceride accumulation (a proxy for dietary fat content). Further, fetal brain 5-HT levels decrease as placental triglycerides increase in male mice and male human samples. These findings uncover a microglia-dependent mechanism through which maternal diet can impact offspring susceptibility for neuropsychiatric disorder development in a sex-specific manner.

Biological functions of living things are regulated by the circadian rhythm, a 24-hour cycle. Master clock in the hypothalamus is dependent on light-dark signals, while peripheral clock (present in organs) is cell-independent being synchronized with central clock. Mammals' circadian clocks control various catabolic and anabolic processes in their peripheral tissues. Peripheral organs display tissue-specific differences in the circadian period and phase and exhibit a circadian oscillator. Various diets will affect the peripheral clock in different organ systems. Ketogenic and high-fat diets can alter clock gene expression, while intermittent fasting shows improved circadian rhythm desynchronization. High-sugar diets can cause circadian rhythm-dependent gene amplification involved in hepatic carbohydrate and fat metabolism, leading to dyslipidemia and disturbed metabolism. High-salt diets can increase peripheral clock gene expression. Different diets can affect the peripheral clock rhythm, causing phase shifts, leading to the desynchronization of the central and peripheral clocks subsequently leading to various metabolic diseases. [ABSTRACT FROM AUTHOR]

Orostachys japonicus is a popular traditional medicinal herb used in Asian countries. This study is focused on evaluating its role in lipid and glucose metabolism in cell and animal models to establish the plant as an anti-obesity and antidiabetic herb. A butanol fraction of O. japonicus was used in the study. The lipid production was evaluated by the Oil Red O technique while the expression of adipogenic markers by Western blotting and RT-PCR using 3T3-L1 preadipocyte. The effect on glucose uptake activity was evaluated in C2C12 myoblast cells. The animal study was carried out in C57BL mice to evaluate anti-obesity activity using the high-fat diet model. The evaluation of serum lipid, blood glucose, adipogenic and fibrosis markers in the liver, and fat deposition in the liver and adipose tissue (by histology) of mice was conducted. Butanol fraction of O. japonicus significantly inhibited the lipid production in the 3T3-L1 cells and reduced the expression of PPARγ, C/EBPα, SREBP-1c and aP2. It enhanced glucose uptake in insulin-resistant C2C12 myoblast cells. It reduced body weight, triglycerides, and blood glucose in the obese mice. It significantly inhibited lipid accumulation in the liver and adipose tissue of obese mice along with suppression of expression of adipogenic and fibrosis markers in the liver. In summary, supporting the previous results, this study helped to establish the potent anti-obesity, antidiabetic, and liver-protecting effect of the butanol fraction of O. japonicus. [ABSTRACT FROM AUTHOR]

Purpose: Fucoxanthin extract (FX) is a type of carotenoid with a beneficial effect against obesity. The purpose of this study was to explore its precise action mechanism of losing weight. Methods: A high-fat diet induced obesity mouse model was established to study the effects of different doses of FX on C57BL/6J male mice for 12 weeks. Following intervention, serum indices, tissue sections, liver gene expression, and intestinal microorganisms were analyzed. Results: FX at low, medium, and high dosages (80, 160, and 320 mg/kg/day, respectively) for 12 weeks was associated with the lower body weight of mice when compared to that of high-fat-diet fed mice. It also improved glucose tolerance as well as serum lipid levels, and reduced fat accumulation. Significant regulation of bile acid metabolism and intestinal microbiota may contribute to the above effects. The bile acids in the FXH group were significantly increased. A low-dose and a medium-dose FX increased the level of transmembrane G protein-coupled receptor 5 (TGR5); a low-dose and high-dose FX increased the farnesoid X receptor (FXR) expression, and a medium-dose had no effect. 16S rRNA sequencing indicated that the Lachnospiraceae and Oscillospiraceae contributed to the beneficial effects of FX. Conclusion: Our study sheds light on mechanisms behind the weight-lowering of FX, and manifested that bile acid metabolism and gut microbiota may be potential therapies. These results support that FX is a valuable candidate for promoting health and alleviating obesity. [ABSTRACT FROM AUTHOR]

Objective: To study the remodeling of hemo- and lymphomicrocirculation pathways and structures of the membranes of the small intestine in rats on isolated fatty diet. Methods: The study design is an experimental randomized study. A population of twenty 7-month-old Wistar rats, sexually mature male rats with weight 200-250 gr were divided into main (10 animals) and control (10 animals) groups. The main group was subjected exclusively to a fat diet, and the control group was on standard feed for a month. The age and body weight of the animals were measured and compared in the beginning of the experiment and before autopsy. On the 30th day, the animals were removed from the experiment and a histological analysis with morphometry of inner layer of small intestine and identification of changes in the microcirculatory bed were performed. The t-criterion of independent and paired samples was used for statistical analysis. Results: The animals in both groups were comparable by age and body weight. Over time, the weight of some animals decreased in each group (217.5 (18.5) gr vs. 211.8(18.2) gr, (p=0.0001) for the main group and increased 206.2 (10.6) gr vs. 240.6 (11.7) gr, (p=0.0001) for the control group). Remodeling of the small intestine is observed with noticeable changes in its morphology, manifested in a decrease in the height and thickness of the villi, as well as the thickness of the muscle layer, the depth of crypts and a reduction in the number of goblet cells. The above morphological changes are accompanied with inactivity of the villi capillaries and a sharp decrease in capillary blood flow. The absence of coarse feed in the diet of animals led to hypotrophy of the muscular lining of the small intestine. On the 30th day, in many villi, the bloodstream resembled the appearance of a burnt tree or bush, as individual capillary loops open and their venular ends disappear. Conclusion: Remodeling of the bloodstream vessels was observed in all layers of the small intestine in rats on fatty diet. Insufficiency of the vascularization of the mucous membrane of the small intestine was associated on the one hand with a change in all types of cell populations of the mucous membrane with their reduction, and on the other hand with hypofunction of the blood vessels of the villi of the small intestine and lymphostasis.

ObjectiveThe mitochondrial fission protein Drp1 was proposed to promote NAFLD, as inhibition of hepatocyte Drp1 early in life prevents liver steatosis induced by high-fat diet in mice. However, whether Drp1-knockdown in older mice can reverse established NASH is unknown.MethodsN-acetylgalactosamine-siRNA conjugates, an FDA approved method to deliver siRNA selectively to hepatocytes, were used to knockdown hepatocyte-Drp1 in mice (NAG-Drp1si). NASH was induced in C57BL/6NTac mice by Gubra-Amylin-NASH diet (D09100310, 40% fat, 22% fructose and 2% cholesterol) and treatment with NAG-Drp1si was started at week 24 of diet. Circulating transaminases, liver histology, gene expression of fibrosis and inflammation markers, and hydroxyproline synthesis determined NASH severity. Liver NEFA and triglycerides were quantified by GC/MS. Mitochondrial function was determined by respirometry. Western blots of Oma1, Opa1, p-eIf2α, as well as transcriptional analyses of Atf4-regulated genes determined ISR engagement.ResultsNAG-Drp1si treatment decreased body weight and induced liver inflammation in adult healthy mice. Increased hepatic Gdf15 production was the major contributor to body-weight loss caused by NAG-Drp1si treatment, as Gdf15 receptor deletion (Gfral KO) prevented the decrease in food intake and mitigated weight loss. NAG-Drp1si activated the Atf4-controlled integrated stress response (ISR) to increase hepatic Gdf15 expression. NAG-Drp1si in healthy mice caused ER stress and activated the mitochondrial protease Oma1, which are the ER and mitochondrial triggers that activate the Atf4-controlled ISR. Remarkably, induction of NASH was not sufficient to activate Oma1 in liver. However, NAG-Drp1si treatment was sufficient to activate Oma1 in adult mice with NASH, as well as exacerbating NASH-induced ER stress. Consequently, NAG-Drp1si treatment in mice with NASH led to higher ISR activation, exacerbated inflammation, fibrosis and necrosis.ConclusionDrp1 mitigates NASH by decreasing ER stress, preventing Oma1 activation and ISR exacerbation. The elevation in Gdf15 actions induced by NAG-Drp1si might represent an adaptive response decreasing the nutrient load to liver when mitochondria are misfunctional. Our study argues against blocking Drp1 in hepatocytes to combat NASH.

Abstract Background Autonomic remodeling of the atria plays a pivotal role in the development of atrial fibrillation (AF) and exerts a substantial influence on the progression of this condition. Hyperlipidemia is a predisposing factor for AF, but its effect on atrial nerve remodeling is unclear. The primary goal of this study was to explore the possible mechanisms through which the consumption of a high-fat diet (HFD) induces remodeling of atrial nerves, and to identify novel targets for clinical intervention. Methods Cell models were created in vitro by subjecting cells to palmitic acid (PA), while rat models were established by feeding them a high-fat diet. To investigate the interplay between cardiomyocytes and nerve cells in a co-culture system, we utilized Transwell cell culture plates featuring a pore size of 0.4 μm. The CCK-8 assay was employed to determine cell viability, fluorescent probe DCFH-DA and flow cytometry were utilized for measuring ROS levels, JC-1 was used to assess the mitochondrial membrane potential, the Griess method was employed to measure the nitric oxide (NO) level in the supernatant, a fluorescence-based method was used to measure ATP levels, and MitoTracker was utilized for assessing mitochondrial morphology. The expression of pertinent proteins was evaluated using western blotting (WB) and immunohistochemistry techniques. SNAP was used to treat nerve cells in order to replicate a high-NO atmosphere, and the level of nitroso was assessed using the iodoTMT reagent labeling method. Results The study found that cardiomyocytes’ mitochondrial morphology and function were impaired under high-fat stimulation, affecting nitric oxide (NO) production through the CRIF1/SIRT1/eNOS axis. In a coculture model, overexpression of eNOS in cardiomyocytes increased NO expression. Moreover, the increased Keap1 nitrosylation within neuronal cells facilitated the entry of Nrf2 into the nucleus, resulting in an augmentation of P21 transcription and a suppression of proliferation. Atrial neural remodeling occurred in the HFD rat model and was ameliorated by increasing myocardial tissue eNOS protein expression with trimetazidine (TMZ). Conclusions Neural remodeling is triggered by high-fat stimulation, which decreases the production of NO through the CRIF1/eNOS/P21 axis. Additionally, TMZ prevents neural remodeling and reduces the occurrence of AF by enhancing eNOS expression.

Dietary fructose, especially in the context of a high-fat western diet, has been linked to type 2 diabetes. Although the effect of fructose on liver metabolism has been extensively studied, a significant portion of the fructose is first metabolized in the small intestine. Here, we report that dietary fat enhances intestinal fructose metabolism, which releases glycerate into the blood. Chronic high systemic glycerate levels induce glucose intolerance by slowly damaging pancreatic islet cells and reducing islet sizes. Our findings provide a link between dietary fructose and diabetes that is modulated by dietary fat.

Glucose uptake by peripheral organs is essential for maintaining blood glucose levels within normal range. Impaired glucose uptake is a hallmark of type 2 diabetes (T2D) and metabolic syndrome and is characterized by insulin resistance. Male sex is an independent risk factor for the development of T2D. We tested whether sex and diet are independent variables for differential glucose uptake by various organs. Here, in a longitudinal study, we used 18F-fluorodeoxyglucose (FDG) and positron emission tomography (PET) to determine baseline differences in whole-body glucose uptake in young male and female mice on chow and high-fat diets. We report that sex and diet are important independent variables that account for differential glucose uptake in brown fat, skeletal muscle, liver, heart, kidney, and the stomach, but not the brain, lungs, pancreas, small intestine, or perigonadal adipose. Of the seven organs analyzed, two organs, namely brown fat, and the heart had the highest concentrations of FDG, followed by the brain, kidneys, and skeletal muscle on chow diet. Young female mice had 47% greater FDG uptake in the brown fat compared to male mice, whereas skeletal muscle FDG uptake was 49% greater in male mice. The high-fat diet inhibited FDG uptake in brown fat, skeletal muscle, and the heart, three major organs involved in uptake, whereas brain uptake was enhanced in both sexes. These foundational and groundbreaking findings suggest that mechanisms of glucose homeostasis are context- and organ-dependent and highlight the need to study sex-specific outcomes and mechanisms for diseases such as T2D, obesity, and metabolic syndrome.

Cardiometabolic disease is an increasing cause of morbidity and death in society. While M1-like macrophages contribute to metabolic inflammation and insulin resistance, those polarized to an M2-like phenotype exert protective properties. Building on our observations reporting M2-like macrophage exosomes in atherosclerosis control, we tested whether they could serve to control inflammation in the liver and adipose tissue of obese mice. In thinking of clinical translation, we studied human THP-1 macrophages exposed to interleukin (IL)-4 as a source of exosomes (THP1-IL4-exo). Our findings show that THP1-IL4-exo polarized primary macrophages to an anti-inflammatory phenotype and reprogramed their energy metabolism by increasing levels of microRNA-21/99a/146b/378a (miR-21/99a/146b/378a) while reducing miR-33. This increased lipophagy, mitochondrial activity, and oxidative phosphorylation (OXPHOS). THP1-IL4-exo exerted a similar regulation of these miRs in cultured 3T3-L1 adipocytes. This enhanced insulin-dependent glucose uptake through increased peroxisome proliferator activated receptor gamma (PPARγ)-driven expression of GLUT4. It also increased levels of UCP1 and OXPHOS activity, which promoted lipophagy, mitochondrial activity, and beiging of 3T3-L1 adipocytes. Intraperitoneal infusions of THP1-IL4-exo into obese wild-type and Ldlr-/- mice fed a Western high-fat diet reduced hematopoiesis and myelopoiesis, and favorably reprogramed inflammatory signaling and metabolism in circulating Ly6Chi monocytes. This also reduced leukocyte numbers and inflammatory activity in the circulation, aorta, adipose tissue, and the liver. Such treatments reduced hepatic steatosis and increased the beiging of white adipose tissue as revealed by increased UCP1 expression and OXPHOS activity that normalized blood insulin levels and improved glucose tolerance. Our findings support THP1-IL4-exo as a therapeutic approach to control cardiometabolic disease and diabetes in obesity.

This study investigated the effects of supplementation with a cyanidin- and delphinidin-rich extract (CDRE) on the postprandial dysmetabolism, inflammation, and redox and insulin signaling, triggered by the consumption of a high fat meal (HFM) in healthy individuals. Participants (n = 25) consumed a 1026-kcal HFM simultaneously with either the CDRE providing 320.4 mg of anthocyanins (90% cyanidin and delphinidin) or placebo. Diets were randomly assigned in a double blind, placebo-controlled crossover design. Blood was collected prior to (fasted, time 0), and for 5 h after meal consumption; plasma, serum, and peripheral blood mononuclear cells (PBMC) were isolated. AC metabolites were detected in serum as early as 30 min after CDRE consumption. The CDRE mitigated HFM-induced endotoxemia, reducing increases in plasma LPS and LPS-binding protein. The CDRE also reduced other events associated with HFM-triggered postprandial dysmetabolism including: i) plasma glucose and triglyceride increases; ii) TNFα and NOX4 upregulation in PBMC; and iii) JNK1/2 activation in PBMC. The CDRE did not significantly affect HFM-mediated increases in plasma insulin, GLP-1, GLP-2, GIP, and LDL- and HDL-cholesterol, and IKK phosphorylation in PBMC. In summary, dietary AC, i.e. cyanidin and delphinidin, exerted beneficial actions against unhealthy diets by modulating the associated postprandial dysmetabolism, endotoxemia, alterations of glycemia and lipidemia, and redox and insulin signaling.

Background: Autonomic remodeling of the atria plays a pivotal role in the development of atrial fibrillation (AF) and exerts a substantial influence on the progression of this condition. Hyperlipidemia is a predisposing factor for AF, but its effect on atrial nerve remodeling is unclear. The primary goal of this study was to explore the possible mechanisms through which the consumption of a high-fat diet (HFD) induces remodeling of atrial nerves, and to identify novel targets for clinical intervention. Methods: Cell models were created in vitro by subjecting cells to palmitic acid (PA), while rat models were established by feeding them a high-fat diet. To investigate the interplay between cardiomyocytes and nerve cells in a co-culture system, we utilized Transwell cell culture plates featuring a pore size of 0.4 μm. The CCK-8 assay was employed to determine cell viability, fluorescent probe DCFH-DA and flow cytometry were utilized for measuring ROS levels, JC-1 was used to assess the mitochondrial membrane potential, the Griess method was employed to measure the nitric oxide (NO) level in the supernatant, a fluorescence-based method was used to measure ATP levels, and MitoTracker was utilized for assessing mitochondrial morphology. The expression of pertinent proteins was evaluated using western blotting (WB) and immunohistochemistry techniques. SNAP was used to treat nerve cells in order to replicate a high-NO atmosphere, and the level of nitroso was assessed using the iodoTMT reagent labeling method. Results: The study found that cardiomyocytes' mitochondrial morphology and function were impaired under high-fat stimulation, affecting nitric oxide (NO) production through the CRIF1/SIRT1/eNOS axis. In a coculture model, overexpression of eNOS in cardiomyocytes increased NO expression. Moreover, the increased Keap1 nitrosylation within neuronal cells facilitated the entry of Nrf2 into the nucleus, resulting in an augmentation of P21 transcription and a suppression of proliferation. Atrial neural remodeling occurred in the HFD rat model and was ameliorated by increasing myocardial tissue eNOS protein expression with trimetazidine (TMZ). Conclusions: Neural remodeling is triggered by high-fat stimulation, which decreases the production of NO through the CRIF1/eNOS/P21 axis. Additionally, TMZ prevents neural remodeling and reduces the occurrence of AF by enhancing eNOS expression. [ABSTRACT FROM AUTHOR]

There is a substantial body of clinical evidence supporting the beneficial effects of lower-carbohydrate dietary patterns on multiple established risk factors associated with insulin resistance and cardiovascular diseases in adult populations. Nutrition and health researchers, clinical practitioners, and stakeholders gathered for, “The Scientific Forum on Nutrition, Wellness, and Lower-Carbohydrate Diets: An Evidence- and Equity-Based Approach to Dietary Guidance” to discuss the evidence base around lower-carbohydrate diets, health outcomes, and dietary guidance. Consensus statements were agreed upon to identify current areas of scientific agreement and spotlight gaps in research, education, and practice to help define and prioritize future pathways. Given the evidence base and considering that most American adults are living with at least one nutrition-related chronic disease, there was consensus that including a lower-carbohydrate dietary pattern as one part of the Dietary Guidelines for Americans could help promote health equity among the general population.

Abstract Objective To examine the potential influence of a ketogenic diet on serum concentrations of antiseizure medications (ASMs) in children with drug resistant epilepsy. Methods We investigated the serum concentrations of ASMs in 25 children with drug resistant epilepsy, 2–13 years of age, treated with a classical ketogenic diet for 12 weeks. The patients were recruited from the National Centre for Epilepsy from August 15th, 2017, to January 24th, 2022. Changes in ASM serum concentrations were analyzed using a mixed effect model analysis. Significance level was set at P

Obesity has repeatedly been linked to reorganization of the gut microbiome, yet to this point obesity therapeutics have been targeted exclusively toward the human host. Here, we show that gut microbe-targeted inhibition of the trimethylamine N-oxide (TMAO) pathway protects mice against the metabolic disturbances associated with diet-induced obesity (DIO) or leptin deficiency (Lepob/ob). Small molecule inhibition of the gut microbial enzyme choline TMA-lyase (CutC) does not reduce food intake but is instead associated with alterations in the gut microbiome, improvement in glucose tolerance, and enhanced energy expenditure. We also show that gut microbial CutC inhibition is associated with reorganization of host circadian control of both phosphatidylcholine and energy metabolism. This study underscores the relationship between microbe and host metabolism and provides evidence that gut microbe-derived trimethylamine (TMA) is a key regulator of the host circadian clock. This work also demonstrates that gut microbe-targeted enzyme inhibitors have potential as anti-obesity therapeutics.

STING, Tmem173, is involved in liver injury caused by both infectious and sterile inflammatory models. Its role in toxic liver injury and non-alcoholic fatty liver disease (NAFLD), however, is less clear. While a few groups have investigated its role in NAFLD pathogenesis, results have been conflicting. The objective of this study was to clarify the exact role of STING in toxic liver injury and NAFLD models. Goldenticket mice (Tmem173gt), which lack STING protein, were subjected to either a toxic liver injury with tunicamycin (TM) or one of two dietary models of non-alcoholic fatty liver disease: high fructose feeding or Fructose-Palmitate-Cholesterol (FPC) feeding. Three days after TM injection, Tmem173gt mice demonstrated less liver injury (average ALT of 54 ± 5 IU/L) than control mice (average ALT 108 ± 24 IU/L). In contrast, no significant differences in liver injury were seen between WT and Tmem173gt mice fed either high fructose or FPC. Tmem173gt mice only distinguished themselves from WT mice in their increased insulin resistance. In conclusion, while STING appears to play a role in toxic liver injury mediated by TM, it plays little to no role in two dietary models of NAFLD. The exact role of STING appears to be stimulus-dependent.

Pomelo peel is a natural plant product with numerous pharmacological effects and is used in traditional Chinese medicine. In the present study, we extracted naringin from pomelo peel and aimed to decipher its therapeutic potential against hyperlipidemia. We used ultrasonic-assisted extraction to obtain naringin prior to identifying its structure, to evaluate its ability in binding sodium glycine cholate and sodium bovine cholate in vitro by simulating the gastrointestinal environment, so as to evaluate its blood lipid-lowering activity. The hyperlipidemia mouse model was established. Following the intragastric administration of naringin for 5 weeks, we measured the weight change, organ index, high-density lipoprotein cholesterol (HDL-C), serum total cholesterol (TC), serum triglycerides (TG), liver superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), low-density lipoprotein cholesterol (LDL-C) level, malondialdehyde (MDA), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) level of mice in the normal control and high-fat diet groups in addition to the high-, medium-, and low-dose naringin groups. The pathological changes in the liver were observed under a light microscope. The total RNA of the liver was extracted, and the mRNA expression level of lipid metabolism-related factors in mouse liver was detected via a fluorescence quantitative polymerase chain reaction (PCR). Naringin significantly (p < 0.01) reduced the body weight, organ index, serum TG, LDL-C, and TC levels of hyperlipidemic mice, but increased the serum HDL-C levels (p < 0.01). Furthermore, naringin increased GSH Px and SOD activity (p < 0.01), while decreasing MDA, ALT, and AST levels, as well as the liver index (p < 0.01). There was no statistically significant difference in the brain, heart, spleen, kidney, and other indicators (p > 0.05). A histopathological analysis of mouse liver showed that naringin could alleviate the degenerative damage of fatty liver cells in hyperlipidemic mice. Naringin could significantly (p < 0.01) reduce the expression of FAS and SREBP-1c mRNA, and simultaneously increase PPARα mRNA expression. This study shows that naringin has the strong effect of lowering lipids and protecting the liver in hyperlipidemic mice. Our findings underscore the anti-hyperlipidemia potential of naringin and increase the scientific understanding of its anti-hyperlipidemia effects, that may lead to its potential application as a dietary strategy for hyperlipidemia management in the future.

ObjectiveThe contribution of beta-cell dysfunction to type 2 diabetes (T2D) is not restricted to insulinopenia in the late stages of the disease. Elevated fasting insulinemia in normoglycemic humans is a major factor predicting the onset of insulin resistance and T2D, demonstrating an early alteration of beta-cell function in T2D. Moreover, an early and chronic increase in fasting insulinemia contributes to insulin resistance in high-fat diet (HFD)-fed mice. However, whether there are genetic factors that promote beta-cell-initiated insulin resistance remains undefined. Human variants of the mitochondrial transporter ABCB10, which regulates redox by increasing bilirubin synthesis, have been associated with an elevated risk of T2D. The effects of T2D ABCB10 variants on ABCB10 expression and the actions of ABCB10 in beta-cells are unknown.MethodsThe expression of beta-cell ABCB10 was analyzed in published transcriptome datasets from human beta-cells carrying the T2D-risk ABCB10 variant. Insulin sensitivity, beta-cell proliferation, and secretory function were measured in beta-cell-specific ABCB10 KO mice (Ins1Cre-Abcb10flox/flox). The short-term role of beta-cell ABCB10 activity on glucose-stimulated insulin secretion (GSIS) was determined in isolated islets.ResultsCarrying the T2Drisk allele G of ABCB10 rs348330 variant was associated with increased ABCB10 expression in human beta-cells. Constitutive deletion of Abcb10 in beta-cells protected mice from hyperinsulinemia and insulin resistance by limiting HFD-induced beta-cell expansion. An early limitation in GSIS and H2O2-mediated signaling caused by elevated ABCB10 activity can initiate an over-compensatory expansion of beta-cell mass in response to HFD. Accordingly, increasing ABCB10 expression was sufficient to limit GSIS capacity. In health, ABCB10 protein was decreased during islet maturation, with maturation restricting beta-cell proliferation and elevating GSIS. Finally, ex-vivo and short-term deletion of ABCB10 in islets isolated from HFD-fed mice increased H2O2 and GSIS, which was reversed by bilirubin treatments.ConclusionsBeta-cell ABCB10 is required for HFD to induce insulin resistance in mice by amplifying beta-cell mass expansion to maladaptive levels that cause fasting hyperinsulinemia.

Maternal obesity and consumption of a high-fat diet significantly elevate risk for pediatric nonalcoholic fatty liver disease (NAFLD), affecting 10% of children in the US. Almost half of these children are diagnosed with nonalcoholic steatohepatitis (NASH), a leading etiology for liver transplant. Animal models show that signs of liver injury and perturbed lipid metabolism associated with NAFLD begin in utero; however, safe dietary therapeutics to blunt developmental programming of NAFLD are unavailable. Using a mouse model of maternal Western-style diet (WD), we previously showed that pyrroloquinoline quinone (PQQ), a potent dietary antioxidant, protected offspring of WD-fed dams from development of NAFLD and NASH. Here, we used untargeted mass spectrometry-based lipidomics to delineate lipotoxic effects of WD on offspring liver and identify lipid targets of PQQ. PQQ exposure during pregnancy altered hepatic lipid profiles of WD-exposed offspring, upregulating peroxisome proliferator-activated receptor (PPAR) α signaling and mitochondrial fatty acid oxidation to markedly attenuate triglyceride accumulation beginning in utero. Surprisingly, the abundance of very long-chain ceramides, important in promoting gut barrier and hepatic function, was significantly elevated in PQQ-treated offspring. PQQ exposure reduced the hepatic phosphatidylcholine/phosphatidylethanolamine (PC/PE) ratio in WD-fed offspring and improved glucose tolerance. Notably, levels of protective n - 3 polyunsaturated fatty acids (PUFAs) were elevated in offspring exposed to PQQ, beginning in utero, and the increase in n - 3 PUFAs persisted into adulthood. Our findings suggest that PQQ supplementation during gestation and lactation augments pathways involved in the biosynthesis of long-chain fatty acids and plays a unique role in modifying specific bioactive lipid species critical for protection against NAFLD risk in later life.