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Both maternal obesity and postnatal consumption of obesogenic diets contribute to the development of metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC). However, there is no consensus as to whether diets that are high in fat or carbohydrates/sugars differentially influence the development of HCC. Moreover, the long-term effects of prenatal HF exposure on HCC and whether this is influenced by postnatal diet has not yet been evaluated. C57BL/6 dams were fed either a low-fat, high-carbohydrate control (C) or low-carbohydrate, high-fat (HF) diet. At weaning, male and female offspring were fed the C or HF diet, generating four diet groups: C/C, C/HF, HF/C and HF/HF. Tissues were collected at 16 months of age and livers were assessed for MASLD and HCC. Glucose regulation and pancreatic morphology were also evaluated. Liver tissues were assessed for markers of glycolysis and fatty acid metabolism and validated using a human HCC bioinformatic database. Both C/HF and HF/HF mice developed obesity, hyperinsulinemia and a greater degree of MASLD than C/C and HF/C offspring. However, despite significant liver and pancreas pathology, C/HF mice had the lowest incidence of HCC while tumour burden was highest in HF/C male offspring. The molecular profile of HCC mouse samples suggested an upregulation of the pentose phosphate pathway and a downregulation of fatty acid synthesis and oxidation, which was largely validated in the human dataset. Both pre-weaning HF diet exposure and post-weaning consumption of a high-carbohydrate diet increased the risk of developing spontaneous HCC in aged mice. However, the influence of pre-weaning HF feeding on HCC development appeared to be stronger in the context of post-weaning obesity. As rates of maternal obesity continue to rise, this has implications for the future incidence of HCC and possible dietary manipulation of offspring carbohydrate intake to counteract this risk. [ABSTRACT FROM AUTHOR]

Treatment of fatty acid oxidation disorders is based on dietary, pharmacological and metabolic decompensation measures. It is essential to provide the patient with sufficient glucose to prevent lipolysis and to avoid the use of fatty acids as fuel as far as possible. Dietary management consists of preventing periods of fasting and restricting fat intake by increasing carbohydrate intake, while maintaining an adequate and uninterrupted caloric intake. In long-chain deficits, long-chain triglyceride restriction should be 10% of total energy, with linoleic acid and linolenic acid intake of 3–4% and 0.5–1% (5/1–10/1 ratio), with medium-chain triglyceride supplementation at 10–25% of total energy (total MCT+LCT ratio = 20–35%). Trihepatnoin is a new therapeutic option with a good safety and efficacy profile. Patients at risk of rhabdomyolysis should ingest MCT or carbohydrates or a combination of both 20 min before exercise. In medium- and short-chain deficits, dietary modifications are not advised (except during exacerbations), with MCT contraindicated and slow sugars recommended 20 min before any significant physical exertion. Parents should be alerted to the need to increase the amount and frequency of carbohydrate intake in stressful situations. The main measure in emergency hospital treatment is the administration of IV glucose. The use of carnitine remains controversial and new therapeutic options are under investigation. [ABSTRACT FROM AUTHOR]

The critical role of the human gut microbiota in kidney stone formation remains largely unknown, due to the low taxonomic resolution of previous sequencing technologies. Therefore, this study aimed to explore the gut microbiota using high-throughput sequencing to provide valuable insights and identify potential bacterial species and metabolite roles involved in kidney stone formation. The overall gut bacterial community and its potential functions in healthy participants and patients were examined using PacBio sequencing targeting the full-length 16S rRNA gene, coupled with stone and statistical analyses. Most kidney stones comprised calcium oxalate and calcium phosphate (75%), pure calcium oxalate (20%), and calcium phosphate and magnesium phosphate (5%), with higher content of Ca (130,510.5 ± 108,362.7 ppm) followed by P (18,746.4 ± 23,341.2 ppm). The microbial community structure was found to be weaker in patients' kidney stone samples, followed by patients' stool samples, than in healthy participants' stool samples. The most abundant bacterial species in kidney stone samples was uncultured Morganella, whereas that in patient and healthy participant stool samples was Bacteroides vulgatus. Similarly, Akkermansia muciniphila was significantly enriched in patient stool samples at the species level, whereas Bacteroides plebeius was significantly enriched in kidney stone samples than that in healthy participant stool samples. Three microbial metabolic pathways, TCA cycle, fatty acid oxidation, and urea cycle, were significantly enriched in kidney stone patients compared to healthy participants. Inferring bacteria at the species level revealed key players in kidney stone formation, enhancing the clinical relevance of gut microbiota. [ABSTRACT FROM AUTHOR]

Background: Several studies have demonstrated a strong correlation between impaired Succinate dehydrogenase (SDH) function and the advancement of tumors. As a subunit of SDH, succinate dehydrogenase complex subunit C (SDHC) has been revealed to play tumor suppressive roles in several cancers, while its specific role in colorectal cancer (CRC) still needs further investigation. Methods: Online database were utilized to investigate the expression of SDHC in colorectal cancer and to assess its correlation with patient prognosis. Cell metastasis was assessed using transwell and wound healing assays, while tumor metastasis was studied in a nude mice model in vivo. Drug screening and RNA sequencing were carried out to reveal the tumor suppressor mechanism of SDHC. Triglycerides, neutral lipids and fatty acid oxidation were measured using the Triglyceride Assay Kit, BODIPY 493/503 and Colorimetric Fatty Acid Oxidation Rate Assay Kit, respectively. The expression levels of enzymes involved in fatty acid metabolism and the PI3K/AKT signaling pathway were determined by quantitative real-time PCR and western blot. Results: Downregulation of SDHC was found to be closely associated with a poor prognosis in CRC. SDHC knockdown promoted CRC metastasis both in vitro and in vivo. Through drug screening and Gene set enrichment analysis, it was discovered that SDHC downregulation was positively associated with the fatty acid metabolism pathways significantly. The effects of SDHC silencing on metastasis were reversed when fatty acid synthesis was blocked. Subsequent experiments revealed that SDHC silencing activated the PI3K/AKT signaling axis, leading to lipid accumulation by upregulating the expression of aldehyde dehydrogenase 3 family member A2 (ALDH3A2) and reduction of fatty acid oxidation rate by suppressing the expression of acyl-coenzyme A oxidase 1 (ACOX1) and carnitine palmitoyltransferase 1A (CPT1A). Conclusions: SDHC deficiency could potentially enhance CRC metastasis by modulating the PI3K/AKT pathways and reprogramming lipid metabolism. [ABSTRACT FROM AUTHOR]

Glucagon receptor (GCGR) agonism offers potentially greater effects on the mitigation of hepatic steatosis. However, its underlying mechanism is not fully understood. Here, it screened tetraspanin CD9 might medicate hepatic effects of GCGR agonist. CD9 is decreased in the fatty livers of patients and upregulated upon GCGR activation. Deficiency of CD9 in the liver exacerbated diet‐induced hepatic steatosis via complement factor D (CFD) regulated fatty acid metabolism. Specifically, CD9 modulated hepatic fatty acid synthesis and oxidation genes through regulating CFD expression via the ubiquitination‐proteasomal degradation of FLI1. In addition, CD9 influenced body weight by modulating lipogenesis and thermogenesis of adipose tissue through CFD. Moreover, CD9 reinforcement in the liver alleviated hepatic steatosis, and blockage of CD9 abolished the remission of hepatic steatosis induced by cotadutide treatment. Thus, CD9 medicates the hepatic beneficial effects of GCGR signaling, and may server as a promising therapeutic target for hepatic steatosis. [ABSTRACT FROM AUTHOR]

In spite of recent advances in the field of undernutrition, current dietary therapy relying on the supply of high protein high calorie formulas is still plagued with transient recovery of impaired organs resulting in significant relapse of cases. This is partly attributed to the inadequacy of current research models in recapitulating clinical undernutrition for mechanistic exploration. Using 1636 Macaca fascicularis monkeys, a human‐relevant criterion for determining undernutrition weight‐for‐age z‐score (WAZ), with a cutoff point of ≤ −1.83 is established as the benchmark for identifying undernourished nonhuman primates (U‐NHPs). In U‐NHPs, pathological anomalies in multi‐organs are revealed. In particular, severe dysregulation of hepatic lipid metabolism characterized by impaired fatty acid oxidation due to mitochondria dysfunction, but unlikely peroxisome disorder, is identified as the anchor metabolic aberration in U‐NHPs. Mitochondria dysfunction is typified by reduced mito‐number, accumulated long‐chain fatty acids, and disruption of OXPHOS complexes. Soy peptide‐treated U‐NHPs increase in WAZ scores, in addition to attenuated mitochondria dysfunction and restored OXPHOS complex levels. Herein, innovative criteria for identifying U‐NHPs are developed, and unknown molecular mechanisms of undernutrition are revealed hitherto, and it is further proved that soypeptide supplementation reprogramed mitochondrial function to re‐establish lipid metabolism balance and mitigated undernutrition. [ABSTRACT FROM AUTHOR]

Background Acute kidney injury (AKI) is a serious complication in patients undergoing cardiac surgery, with the underlying mechanism remaining elusive and a lack of specific biomarkers for cardiac surgery-associated AKI (CS-AKI). Methods We performed an untargeted metabolomics analysis of urine samples procured from a cohort of patients with or without AKI at 6 and 24 h following cardiac surgery. Based on the differential urinary metabolites discovered, we further examined the expressions of the key metabolic enzymes that regulate these metabolites in kidney during AKI using a mouse model of ischemia–reperfusion injury (IRI) and in hypoxia-treated tubular epithelial cells (TECs). Results The urine metabolomic profiles in AKI patients were significantly different from those in non-AKI patients, including upregulation of tryptophan metabolism– and aerobic glycolysis–related metabolites, such as l -tryptophan and d -glucose-1-phosphate, and downregulation of fatty acid oxidation (FAO) and tricarboxylic acid (TCA) cycle–related metabolites. Spearman correlation analysis showed that serum creatinine was positively correlated with urinary l -tryptophan and indole, which had high accuracy for predicting AKI. In animal experiments, we demonstrated that the expression of rate-limiting enzymes in glycolysis, such as hexokinase II (HK2), was significantly upregulated during renal IRI. However, the TCA cycle–related key enzyme citrate synthase was significantly downregulated after IRI. In vitro , hypoxia induced downregulation of citrate synthase in TECs. In addition, FAO-related gene peroxisome proliferator-activated receptor alpha (PPARα) was remarkably downregulated in kidney during renal IRI. Conclusion This study presents urinary metabolites related to CS-AKI, indicating the rewiring of the metabolism in kidney during AKI, identifying potential AKI biomarkers. [ABSTRACT FROM AUTHOR]

Drug-induced liver injury (DILI) represents a major issue for pharmaceutical companies, being a potential cause of black-box warnings on marketed pharmaceuticals, or drug withdrawal from the market. Lipid accumulation in the liver also referred to as steatosis, may be secondary to impaired mitochondrial fatty acid oxidation (mtFAO). However, an overall causal relationship between drug-induced mtFAO inhibition and the occurrence of steatosis in patients has not yet been established with a high number of pharmaceuticals. Hence, 32 steatogenic and 13 nonsteatogenic drugs were tested for their ability to inhibit mtFAO in isolated mouse liver mitochondria. To this end, mitochondrial respiration was measured with palmitoyl- l -carnitine, palmitoyl-CoA + l -carnitine, or octanoyl- l -carnitine. This mtFAO tri-parametric assay was able to predict the occurrence of steatosis in patients with a sensitivity and positive predictive value above 88%. To get further information regarding the mechanism of drug-induced mtFAO impairment, mitochondrial respiration was also measured with malate/glutamate or succinate. Drugs such as diclofenac, methotrexate, and troglitazone could inhibit mtFAO secondary to an impairment of the mitochondrial respiratory chain, whereas dexamethasone, olanzapine, and zidovudine appeared to impair mtFAO directly. Mitochondrial swelling, transmembrane potential, and production of reactive oxygen species were also assessed for all compounds. Only the steatogenic drugs amiodarone, ketoconazole, lovastatin, and toremifene altered all these 3 mitochondrial parameters. In conclusion, our tri-parametric mtFAO assay could be useful in predicting the occurrence of steatosis in patients. The combination of this assay with other mitochondrial parameters could also help to better understand the mechanism of drug-induced mtFAO inhibition. [ABSTRACT FROM AUTHOR]

The presence of wheat bran often leads to poor taste and stability of whole wheat flour and its products. By leveraging wheat bran pretreatment technology, the quality characteristics of whole wheat flour and its products can be effectively enhanced. This paper reviewed the common wheat bran pretreatment technologies, analyzed their effects on the processing properties, nutritional characteristics, and storage stability of whole wheat flour, and also discussed the application of these technologies in improving the eating quality of whole wheat products (such as Mantou, deep-fried dough sticks, bread and noodles). It was believed that crushing treatment such as stone mill, roller mill, ultrafine mill, etc. could increase the bioavailability of nutrients and reduce the content of anti-nutrients such as phytic acid, but did not change its chemical composition. While heat treatment (dry heat treatment, wet heat treatment, and superheated steam treatment) and extrusion treatment could inactivate highly active endogenous enzymes in wheat bran and prolong its storage period, they could lead to degradation of phenolic substances, thermal oxidation of fatty acids, and dull color. Biological treatment (enzymatic hydrolysis and fermentation) could increase the contents of soluble dietary fiber and improve the processing and nutritional properties of whole wheat flour, but it could not meet the diverse needs of high fiber flour products. In the future, combining with the advantages of a single pretreatment technology, guided by market demand and industrial production, the process parameters of wheat bran pretreatment technology should be further optimized, to accurately regulate the method and sequence of combined treatment, improve the quality of whole wheat flour and its products. This will provide reference for the study of the regulation mechanism of wheat bran pretreatment technology. [ABSTRACT FROM AUTHOR]

Cellular senescence contributes to inflammatory kidney disease via the secretion of inflammatory and profibrotic factors. Protease‐activating receptor 2 (PAR2) is a key regulator of inflammation in kidney diseases. However, the relationship between PAR2 and cellular senescence in kidney disease has not yet been described. In this study, we found that PAR2‐mediated metabolic changes in renal tubular epithelial cells induced cellular senescence and increased inflammatory responses. Using an aging and renal injury model, PAR2 expression was shown to be associated with cellular senescence. Under in vitro conditions in NRK52E cells, PAR2 activation induces tubular epithelial cell senescence and senescent cells showed defective fatty acid oxidation (FAO). Cpt1α inhibition showed similar senescent phenotype in the cells, implicating the important role of defective FAO in senescence. Finally, we subjected mice lacking PAR2 to aging and renal injury. PAR2‐deficient kidneys are protected from adenine‐ and cisplatin‐induced renal fibrosis and injury, respectively, by reducing senescence and inflammation. Moreover, kidneys lacking PAR2 exhibited reduced numbers of senescent cells and inflammation during aging. These findings offer fresh insights into the mechanisms underlying renal senescence and indicate that targeting PAR2 or FAO may be a promising therapeutic approach for managing kidney injury. [ABSTRACT FROM AUTHOR]

Our previous study has demonstrated that Telomeric repeat-binding factor 2-interacting protein 1(Terf2ip), played an important role in hepatic ischemia reperfusion injury. This study is aimed to explore the function and mechanism of Terf2ip in non-alcoholic steatohepatitis (NASH). The expression of Terf2ip was detected in liver tissue samples obtained from patients diagnosed with NASH. Mice NASH models were constructed by fed with high-fat diet (HFD) or methionine/choline deficient diet (MCD) in Terf2ip knockout and wild type (WT) mice. To further investigate the role of Terf2ip in NASH, adeno-associated viruses (AAV)-Terf2ip was administrated to mice. We observed a significant down-regulation of Terf2ip levels in the livers of NASH patients and mice NASH models. Terf2ip deficiency was associated with an exacerbation of hepatic steatosis in mice under HFD or MCD. Additionally, Terf2ip deficiency impaired lipophagy and fatty acid oxidation (FAO) in NASH models. Mechanically, we discovered that Terf2ip bound to the promoter region of Sirt1 to regulate Sirt1/AMPK pathway activation. As a result, Terf2ip deficiency was shown to inhibit lipophagy through the AMPK pathway, while the activation of Sirt1 alleviated steatohepatitis in the livers of mice. Finally, re-expression of Terf2ip in hepatocyes alleviated liver steatosis, inflammation, and restored lipophagy. These results revealed that Terf2ip played a protective role in the progression of NASH through regulating lipophagy and FAO by binding to Sirt1 promoter. Our findings provided a potential therapeutic target for the treatment of NASH. [Display omitted] • New research uncovers the role of Terf2ip in non-alcoholic steatohepatitis. • Discover how Terf2ip deficiency regulated lipophagy and fatty acid oxidation in diet-induced hepatic steatosis. • This study's findings promise a brighter future for treatment of NASH. Telomeric repeat-binding factor 2-interacting protein 1 deficiency accelerate non-alcoholic steatohepatitis through regulating lipophagy and fatty acid oxidation via silent information regulator 1/adenosine 5'-monophosphate-activated protein kinase pathway, a potential therapeutic target for the treatment of NASH. [ABSTRACT FROM AUTHOR]

Elevated skeletal muscle diacylglycerols (DAGs) and ceramides can impair insulin signaling, and acylcarnitines (acylCNs) reflect impaired mitochondrial fatty acid oxidation, thus, the intramuscular lipid profile is indicative of insulin resistance. Acute (i.e., postprandial) hyperinsulinemia has been shown to elevate lipid concentrations in healthy muscle and is an independent risk factor for type 2 diabetes (T2D). However, it is unclear how the relationship between acute hyperinsulinemia and the muscle lipidome interacts across metabolic phenotypes, thus contributing to or exacerbating insulin resistance. We therefore investigated the impact of acute hyperinsulinemia on the skeletal muscle lipid profile to help characterize the physiological basis in which hyperinsulinemia elevates T2D risk. In a cross-sectional comparison, endurance athletes (n = 12), sedentary lean adults (n = 12), and individuals with obesity (n = 13) and T2D (n = 7) underwent a hyperinsulinemic-euglycemic clamp with muscle biopsies. Although there were no significant differences in total 1,2-DAG fluctuations, there was a 2% decrease in athletes versus a 53% increase in T2D during acute hyperinsulinemia (P = 0.087). Moreover, C18 1,2-DAG species increased during the clamp with T2D only, which negatively correlated with insulin sensitivity (P < 0.050). Basal muscle C18:0 total ceramides were elevated with T2D (P = 0.029), but not altered by clamp. Acylcarnitines were universally lowered during hyperinsulinemia, with more robust reductions of 80% in athletes compared with only 46% with T2D (albeit not statistically significant, main effect of group, P = 0.624). Similar fluctuations with acute hyperinsulinemia increasing 1,2 DAGs in insulin-resistant phenotypes and universally lowering acylcarnitines were observed in male mice. In conclusion, acute hyperinsulinemia elevates muscle 1,2-DAG levels with insulin-resistant phenotypes. This suggests a possible dysregulation of intramuscular lipid metabolism in the fed state in individuals with low insulin sensitivity, which may exacerbate insulin resistance. NEW & NOTEWORTHY: Postprandial hyperinsulinemia is a risk factor for type 2 diabetes and may increase muscle lipids. However, it is unclear how the relationship between acute hyperinsulinemia and the muscle lipidome interacts across metabolic phenotypes, thus contributing to insulin resistance. We observed that acute hyperinsulinemia elevates muscle 1,2-DAGs in insulin-resistant phenotypes, whereas ceramides were unaltered. Insulin-mediated acylcarnitine reductions are also hindered with high-fat feeding. The postprandial period may exacerbate insulin resistance in metabolically unhealthy phenotypes. [ABSTRACT FROM AUTHOR]

Multiple theories have been proposed to explain the pathogenesis of early-onset preeclampsia (EOPE), and angiogenic dysfunction is an important part of this pathogenesis. Carnitine palmitoyltransferase (CPT1A) is a key rate-limiting enzyme in the metabolic process of fatty acid oxidation (FAO). FAO regulates endothelial cell (EC) proliferation during vascular germination and is also essential for ab initio deoxyribonucleotide synthesis, but its role in EOPE needs to be further elucidated. In the present study, we investigated its functional role in EOPE by targeting the circHIPK3/miR-124-3p/CPT1A axis. In our study, reduced expression of circHIPK3 and CPT1A and increased expression of miR-124-3p in placental tissues from patients with EOPE were associated with EC dysfunction. Here, we confirmed that CPT1A regulates fatty acid oxidative activity, cell proliferation, and tube formation in ECs by regulating FAO. Functionally, knockdown of circHIPK3 suppressed EC angiogenesis by inhibiting CPT1A-mediated fatty acid oxidative activity, which was ameliorated by CPT1A overexpression. In addition, circHIPK3 regulates CPT1A expression by sponging miR-124-3p. Hence, circHIPK3 knockdown reduced fatty acid oxidation in ECs by sponging miR-124-3p in a CPT1A-dependent manner and inhibited EC proliferation and tube formation, which may have led to aberrant angiogenesis in EOPE. Thus, strategies targeting CPT1A-driven FAO may be promising approaches for the treatment of EOPE. Key messages: Decreased Carnitine palmitoyltransferase (CPT1A) expression in preeclampsia(PE). CPT1A overexpression promotes FAO activity and tube formation in ECs. CircHIPK3 can affect CPT1A expression and impaire angiogenesis of EOPE. CircHIPK3 regulates CPT1A expression by acting as a ceRNA of miR-124-3p in HUVECs. Confirming the effect of circHIPK3/miR-124-3p/CPT1A axis on EOPE. [ABSTRACT FROM AUTHOR]

The depletion of visceral and subcutaneous adipose tissue (AT) during chemotherapy significantly correlates with diminished overall survival and progression-free survival. Despite its clinical significance, the intricate molecular mechanisms governing this AT loss and its chemotherapy-triggered initiation remain poorly understood. Notably, the evaluation of AT remodeling in most clinical trials has predominantly relied on computerized tomography scans or bioimpedance, with molecular studies often conducted using animal or in vitro models. To address this knowledge gap, a comprehensive narrative review was conducted. The findings underscore that chemotherapy serves as a key factor in inducing AT loss, exacerbating cachexia, a paraneoplastic syndrome that significantly compromises patient quality of life and survival. The mechanism driving AT loss appears intricately linked to alterations in AT metabolic remodeling, marked by heightened lipolysis and fatty acid oxidation, coupled with diminished lipogenesis. However, adipocyte stem cells' lost ability to divide due to chemotherapy also appears to be at the root of the loss of AT. Notably, chemotherapy seems to deactivate the mitochondrial antioxidant system by reducing key regulatory enzymes responsible for neutralizing reactive oxygen species (ROS), thereby impeding lipogenesis. Despite FDG-PET evidence of AT browning, no molecular evidence of thermogenesis was reported. Prospective investigations unraveling the molecular mechanisms modulated in AT by chemotherapy, along with therapeutic strategies aimed at preventing AT loss, promise to refine treatment paradigms and enhance patient outcomes. • Clinical and preclinical studies suggest that chemotherapy promotes body weight loss targeting adipose tissue. • Increased lipolysis and decreased de novo lipogenesis is a mark of cisplatin and doxorubicin treatment in animal models. • Adipose tissue loss is related to thermogenesis and mitochondrial biogenesis post doxorubicin treatment in animal models. • Irinotecan plus 5-fluoracil reduce antioxidant defences in adipose tissue of animal models. [ABSTRACT FROM AUTHOR]

Background: Obesity has become a widespread issue globally. Morin, a flavonoid with traditional use in managing hyperglycemia and hyperlipidemia, has demonstrated antioxidant and anti-inflammatory properties in experimental studies. This research aims to explore the anti-obesity potential of morin in rats subjected to a high-fat diet (HFD) and investigate whether its effects are mediated through PPARα regulation. Methods: Young adult male Wistar albino rats were divided into four groups (n = 8/group): normal, morin (50 mg/kg/BWT, oral), HFD, and HFD + morin (50 mg/kg/BWT, oral). Treatments were administered daily for 17 consecutive weeks. Results: Morin mitigated the elevation in glucose levels and decreased fasting glucose and insulin levels, along with the HOMA-IR index, in HFD-fed rats. Furthermore, morin reduced calorie intake, final body weights, and the masses of subcutaneous, epididymal, peritoneal, and mesenteric fat in these rats. It also attenuated the rise in systolic blood pressure in HFD-fed rats and decreased serum levels of triglycerides, cholesterol, free fatty acids, LDL-c, and leptin, while increasing levels of HDL-c and adiponectin in both normal and HFD-fed rats. Moreover, morin restored normal liver structure and reduced fat vacuole accumulation in HFD-fed rats. Notably, it upregulated mRNA levels of PPARα in the livers and white adipose tissue of both normal and HFD-fed rats. Conclusions: These findings suggest the potential use of morin to enhance fatty acid oxidation in white adipose tissue and mitigate obesity, warranting further clinical investigation into its therapeutic applications. [ABSTRACT FROM AUTHOR]

In most species studied, energy deficits inhibit female reproductive behavior, but the location and nature of energy sensors and how they affect behavior are unknown. Progress has been facilitated by using Drosophila melanogaster, a species in which reproduction and food availability are closely linked. Adult males and females were either fed or food deprived (FD) and then tested in an arena with a fed, opposite-sex conspecific with no food in the testing arena. Only FD females (not FD males) significantly decreased their copulation rate and increased their copulation latency, and the effects of FD were prevented in females fed either yeast alone or glucose alone, but not sucralose alone, cholesterol alone, or amino acids alone. It is well-known that high-fat diets inhibit copulation rate in this species, and the effects of FD on copulation rate were mimicked by treatment with an inhibitor of glucose but not free fatty acid oxidation. The availability of oxidizable glucose was a necessary condition for copulation rate in females fed either yeast alone or fed a nutritive fly medium, which suggests that the critical component of yeast for female copulation rate is oxidizable glucose. Thus, female copulation rate in D. melanogaster is sensitive to the availability of oxidizable metabolic fuels, particularly the availability of oxidizable glucose or substrates/byproducts of glycolysis. NEW & NOTEWORTHY Copulation rate was decreased in food-deprived female but not in male adults when tested without food in the testing arena. Copulation rate was 1) maintained by feeding glucose alone, yeast alone, nutritive medium lacking yeast, but not sucralose, amino acids, or cholesterol alone; 2) decreased by inhibition of glycolysis in females fed either nutritive medium or yeast alone; and 3) not affected by inhibition of fatty acid oxidation. Thus, female copulation rate was linked to glycolytic status. [ABSTRACT FROM AUTHOR]

Ecklonialactones, Eiseniachlorides, and Egregiachlorides are synthesized in living organisms via the lipoxygenase‐mediated oxidation of polyunsaturated fatty acids. Originally isolated and identified from brown seaweed (Ecklonia stolonifera, Eisenia bicyclis, and Egregia menziesii), and later replicated on milligram scale through chemical synthesis, the full biological activities of these compounds remain to be elucidated. To bridge this gap in knowledge, we propose a unified methodology to synthesize the 14‐membered macrocyclic structures of Ecklonialactones, Eiseniachlorides and analogs using a versatile and convergent approach. This study delineates the synthesis of Ecklonialactone A, B, C, D, and Eiseniachlorides A and B, as well as ent‐Ecklonialactone B, 16‐epi‐Ecklonialactone B and 12,13‐diepi‐Ecklonialactone B. [ABSTRACT FROM AUTHOR]

Myosteatosis is highly prevalent in metabolic dysfunction‐associated steatotic liver disease (MASLD) and could reciprocally impact liver function. Decreasing muscle fat could be indirectly hepatoprotective in MASLD. We conducted a review to identify interventions reducing myosteatosis and their impact on liver function. Non‐pharmacological interventions included diet (caloric restriction or lipid enrichment), bariatric surgery and physical activity. Caloric restriction in humans achieving a mean weight loss of 3% only reduces muscle fat. Lipid‐enriched diet increases liver fat in human with no impact on muscle fat, except sphingomyelin‐enriched diet which reduces both lipid contents exclusively in pre‐clinical studies. Bariatric surgery, hybrid training (resistance exercise and electric stimulation) or whole‐body vibration in human decrease both liver and muscle fat. Physical activity impacts both phenotypes by reducing local and systemic inflammation, enhancing insulin sensitivity and modulating the expression of key mediators of the muscle‐liver‐adipose tissue axis. The combination of diet and physical activity acts synergistically in liver, muscle and white adipose tissue, and further decrease muscle and liver fat. Several pharmacological interventions (patchouli alcohol, KBP‐089, 2,4‐dinitrophenol methyl ether, adipoRon and atglistatin) and food supplementation (vitamin D or resveratrol) improve liver and muscle phenotypes in pre‐clinical studies by increasing fatty acid oxidation and anti‐inflammatory properties. These interventions are effective in reducing myosteatosis in MASLD while addressing the liver disease itself. This review supports that disturbances in inter‐organ crosstalk are key pathophysiological mechanisms involved in MASLD and myosteatosis pathogenesis. Focusing on the skeletal muscle might offer new therapeutic strategies to treat MASLD by modulating the interactions between liver and muscles. [ABSTRACT FROM AUTHOR]

A subgroup of endocrine‐disrupting chemicals have the ability to disrupt metabolism. These metabolism‐disrupting chemicals (MDCs) can end up in aquatic environments and lead to adverse outcomes in fish. Although molecular and physiological effects of MDCs have been studied in adult fish, few studies have investigated the consequences of metabolic disruption in fish during the earliest life stages. To investigate the processes affected by metabolic disruption, zebrafish embryos were exposed to peroxisome proliferator–activated receptor gamma (PPARγ) agonist rosiglitazone, the PPARγ antagonist T0070907, and the well‐known environmentally relevant MDC bisphenol A. Decreased apolipoprotein Ea transcript levels indicated disrupted lipid transport, which was likely related to the observed dose‐dependent increases in yolk size across all compounds. Increased yolk size and decreased swimming activity indicate decreased energy usage, which could lead to adverse outcomes because the availability of energy reserves is essential for embryo survival and growth. Exposure to T0070907 resulted in a darkened yolk. This was likely related to reduced transcript levels of genes involved in lipid transport and fatty acid oxidation, a combination of responses that was specific to exposure to this compound, possibly leading to lipid accumulation and cell death in the yolk. Paraoxonase 1 (Pon1) transcript levels were increased by rosiglitazone and T0070907, but this was not reflected in PON1 enzyme activities. The present study shows how exposure to MDCs can influence biochemical and molecular processes involved in early lipid metabolism and may lead to adverse outcomes in the earliest life stages of fish. Environ Toxicol Chem 2024;43:1880–1893. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. [ABSTRACT FROM AUTHOR]

Background: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common acute respiratory failure due to diffuse pulmonary inflammation and oedema. Elaborate regulation of macrophage activation is essential for managing this inflammatory process and maintaining tissue homeostasis. In the past decades, metabolic reprogramming of macrophages has emerged as a predominant role in modulating their biology and function. Here, we observed reduced expression of carnitine palmitoyltransferase 1A (CPT1A), a key rate‐limiting enzyme of fatty acid oxidation (FAO), in macrophages of lipopolysaccharide (LPS)‐induced ALI mouse model. We assume that CPT1A and its regulated FAO is involved in the regulation of macrophage polarization, which could be positive regulated by interleukin‐10 (IL‐10). Methods: After nasal inhalation rIL‐10 and/or LPS, wild type (WT), IL‐10‐/‐, Cre‐CPT1Afl/fl and Cre+CPT1Afl/fl mice were sacrificed to harvest bronchoalveolar lavage fluid, blood serum and lungs to examine cell infiltration, cytokine production, lung injury severity and IHC. Bone marrow‐derived macrophages (BMDMs) were extracted from mice and stimulated by exogenous rIL‐10 and/or LPS. The qRT‐PCR, Seahorse XFe96 and FAO metabolite related kits were used to test the glycolysis and FAO level in BMDMs. Immunoblotting assay, confocal microscopy and fluorescence microplate were used to test macrophage polarization as well as mitochondrial structure and function damage. Results: In in vivo experiments, we found that mice lacking CPT1A or IL‐10 produced an aggravate inflammatory response to LPS stimulation. However, the addition of rIL‐10 could alleviate the pulmonary inflammation in mice effectively. IHC results showed that IL‐10 expression in lung macrophage decreased dramatically in Cre+CPT1Afl/fl mice. The in vitro experiments showed Cre+CPT1Afl/fl and IL‐10‐/‐ BMDMs became more "glycolytic", but less "FAO" when subjected to external attacks. However, the supplementation of rIL‐10 into macrophages showed reverse effect. CPT1A and IL‐10 can drive the polarization of BMDM from M1 phenotype to M2 phenotype, and CPT1A‐IL‐10 axis is also involved in the process of maintaining mitochondrial homeostasis. Conclusions: CPT1A modulated metabolic reprogramming and polarisation of macrophage under LPS stimulation. The protective effects of CPT1A may be partly attributed to the induction of IL‐10/IL‐10 receptor expression. [ABSTRACT FROM AUTHOR]

Cancer and senescent cells share many metabolic features that contribute to their common and unique cellular states. Senescent cells alter both glucose and non-glucose metabolism, including glycolysis, mitochondrial respiration, fatty acid oxidation, and glutaminolysis, to meet their bioenergetic, biosynthetic, and redox homeostatic needs. Senescent cells sustain metabolic signaling pathways in a hardwired manner to direct their metabolic alterations toward pathological anabolic processes. Senescent cells may rely on protein degradation pathways to mitigate errors caused by their hyperactivated anabolism, such as the senescence-associated secretory phenotype (SASP). Targeting senescence metabolism, analogous to targeting cancer metabolism, sensitizes senescent cells or suppresses the SASP, thereby serving as a new therapeutic modality for senotherapy. Cellular metabolism is a flexible and plastic network that often dictates physiological and pathological states of the cell, including differentiation, cancer, and aging. Recent advances in cancer metabolism represent a tremendous opportunity to treat cancer by targeting its altered metabolism. Interestingly, despite their stable growth arrest, senescent cells – a critical component of the aging process – undergo metabolic changes similar to cancer metabolism. A deeper understanding of the similarities and differences between these disparate pathological conditions will help identify which metabolic reprogramming is most relevant to the therapeutic liabilities of senescence. Here, we compare and contrast cancer and senescence metabolism and discuss how metabolic therapies can be established as a new modality of senotherapy for healthy aging. [ABSTRACT FROM AUTHOR]

Inconsistencies between Alzheimer's disease (AD) clinical trials and prevention studies using omega-3 (n-3) polyunsaturated fatty acid (PUFA) supplementation can be largely attributed to differences in age, environmental factors, genetic factors, baseline n-3/n-6 intake, and disease stage. Changes in docosahexaenoic acid (DHA) brain uptake throughout AD progression are influenced by the apolipoprotein E ε4 (APOE4) allele and lifestyle factors, such as DHA intake or exercise, and can be monitored by DHA positron emission tomography (PET) brain imaging. APOE4 carriers are more susceptible to blood–brain barrier dysfunction, oxidative stress, neuroinflammation, and fatty acid oxidation with aging compared to noncarriers. We hypothesize that increasing n-3 PUFA intake provides APOE4 carriers with the highest potential for protection against AD dementia when implemented early in life, many years before the onset of cognitive decline. During the AD dementia phase, alternative strategies targeting neuroinflammation and PUFA metabolism may offer potential benefits. Omega-3 (n-3) polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA), have important roles in human nutrition and brain health by promoting neuronal functions, maintaining inflammatory homeostasis, and providing structural integrity. As Alzheimer's disease (AD) pathology progresses, DHA metabolism in the brain becomes dysregulated, the timing and extent of which may be influenced by the apolipoprotein E ε4 (APOE4) allele. Here, we discuss how maintaining adequate DHA intake early in life may slow the progression to AD dementia in cognitively normal individuals with APOE4 , how recent advances in DHA brain imaging could offer insights leading to more personalized preventive strategies, and how alternative strategies targeting PUFA metabolism pathways may be more effective in mitigating disease progression in patients with existing AD dementia. [ABSTRACT FROM AUTHOR]

Traditional cancer chemotherapy suffers from low efficacy and severe side effects, limiting its use as a first-line treatment. To address this issue, we investigated a novel way to induce lipid peroxidation (LPO), which plays an essential role in ferroptosis and may be useful against cancer cells and tumors. In this study, a pH-responsive synergistic cancer therapy nanoplatform was prepared using CaCO 3 co-loaded with oleanolic acid (OA) and lipoxygenase (LOX), resulting in the formation OLCaP NP. This nanoplatform exhibited good drug release properties in an acidic tumor environment owing to the presence of CaCO 3. As a result of acidic stimulation at tumor sites, the OLCaP NP released OA and LOX. OA, a chemotherapeutic drug with anticancer activity, is already known to promote the apoptosis of cancer cells, and LOX is a natural enzyme that catalyzes the oxidation of polyunsaturated fatty acids, leading to the accumulation of lipid peroxides and promoting the apoptosis of cancer cells. More importantly, OA upregulated the expression of acyl-coenzyme A synthetase long-chain family member 4 (ACSL4), which promoted enzyme-mediated LPO. Based on our combined chemotherapy and nanocatalytic therapy, the OLCaP NP not only had remarkable antitumor ability but also upregulated ACSL4 expression, allowing further amplification of LPO to inhibit tumor growth. These findings demonstrate the potential of this nanoplatform to enhance the therapeutic efficacy against tumors by inducing oxidative stress and disrupting lipid metabolism, highlighting its clinical potential for improved cancer treatment. This study presents a novel nanoplatform that combines oleanolic acid (OA), a chemotherapeutic drug, and lipoxygenase (LOX), which oxidizes polyunsaturated fatty acids to trigger apoptosis, for targeted cancer therapy. Unlike traditional treatments, our nanoplatform exhibits pH-responsive drug release, specifically in acidic tumor environments. This innovation enhances the therapeutic effects of OA and LOX, upregulating acyl-CoA synthetase long-chain family member 4 expression and amplifying lipid peroxidation to promote tumor cell apoptosis. Our findings significantly advance the existing literature by demonstrating a synergistic approach that combines chemotherapy and nanocatalytic therapy. The scientific impact of this work lies in its potential to improve cancer treatment efficacy and specificity, offering a promising strategy for clinical applications and future research in cancer therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Metabolic reprogramming, a hallmark of tumorigenesis, involves alterations in glucose and fatty acid metabolism. Here, we investigate the role of Carnitine palmitoyl transferase 1a (Cpt1a), a key enzyme in long-chain fatty acid (LCFA) oxidation, in ErbB2-driven breast cancers. In ErbB2+ breast cancer models, ablation of Cpt1a delays tumor onset, growth, and metastasis. However, Cpt1a-deficient cells exhibit increased glucose dependency that enables survival and eventual tumor progression. Consequently, these cells exhibit heightened oxidative stress and upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Inhibiting Nrf2 or silencing its expression reduces proliferation and glucose consumption in Cpt1a-deficient cells. Combining the ketogenic diet, composed of LCFAs, or an anti-ErbB2 monoclonal antibody (mAb) with Cpt1a deficiency significantly perturbs tumor growth, enhances apoptosis, and reduces lung metastasis. Using an immunocompetent model, we show that Cpt1a inhibition promotes an antitumor immune microenvironment, thereby enhancing the efficacy of anti-ErbB2 mAbs. Our findings underscore the importance of targeting fatty acid oxidation alongside HER2-targeted therapies to combat resistance in HER2+ breast cancer patients. Metabolic reprogramming is crucial in tumorigenesis, with alterations in glucose and fatty acid metabolism playing key roles. Here, the authors show that inhibiting fatty acid oxidation in HER2-driven breast cancers delays tumor growth and enhances the effectiveness of HER2-targeted therapies. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Chinese Institute of Food Science & Technology / Zhongguo Shipin Xuebao is the property of Journal of Chinese Institute of Food Science & Technology Periodical Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Salinity is a crucial environmental factor influencing the survival, growth, development, and reproduction of aquatic animals. However, the underlying molecular mechanisms of the shrimp's response to salinity stress are not yet fully understood. Therefore, we used the Illumina NovaSeq 6000 platform to perform transcriptome sequencing of the hepatopancreas of Litopenaeus vannamei under high-salinity (30 PSU), medium-salinity (10 PSU), and low-salinity (0.5 PSU) conditions. We obtained 63.23 Gb of high-quality data and identified 3589 differentially expressed genes (DEGs), including 1638 upregulated and 1951 downregulated genes. Notably, a comparison between the control group (30 PSU) and the low-salinity group (0.5 PSU) revealed that the BBOX1 and CHE1 genes were significantly upregulated, while the ACOX1, MPV, CYP2L1, GCH, MVK, TREt1, and XDH genes were significantly downregulated. These genes are primarily involved in key metabolic pathways, such as fatty acid oxidation, cholesterol metabolism, and hormone synthesis and metabolism. The key genes involved in fatty acid β-oxidation, such as ACOX1, ACAD, HADH, HSD17B4, PECR, CROT, PIPOX, and CG5009, all showed a downward trend, suggesting that L. vannamei may respond to salt stress by regulating fatty acid oxidative metabolism, optimizing energy utilization, and maintaining cell homeostasis under low-salinity conditions. Functional annotation of gene ontology (GO) and KEGG pathway enrichment analysis highlighted the roles of these significant DEGs in the adaptation of L. vannamei to environments of varying salinity, underscoring the importance of metabolic pathways in their adaptive physiological responses. This study provides a crucial molecular biological basis for understanding the molecular mechanisms and physiological protection strategies of L. vannamei under salinity stress. [ABSTRACT FROM AUTHOR]

The formation of memory T cells is a fundamental feature of adaptative immunity, allowing the establishment of long-term protection against pathogens. Although emerging evidence suggests that metabolic reprogramming is crucial for memory T cell differentiation and survival, the underlying mechanisms that drive metabolic rewiring in memory T cells remain unclear. Here, we found that up-regulation of the nuclear receptor peroxisome proliferator–activated receptor β/δ (PPARβ/δ) instructs the metabolic reprogramming that occurs during the establishment of central memory CD8+ T cells. PPARβ/δ-regulated changes included suppression of aerobic glycolysis and enhancement of oxidative metabolism and fatty acid oxidation. Mechanistically, exposure to interleukin-15 and expression of T cell factor 1 facilitated activation of the PPARβ/δ pathway, counteracting apoptosis induced by antigen clearance and metabolic stress. Together, our findings indicate that PPARβ/δ is a master metabolic regulator orchestrating a metabolic switch that may be favorable for T cell longevity. Editor's summary: After initial antigen encounter, some T cells persist and differentiate into long-lived memory cells. This process is accompanied by metabolic reprogramming that supports survival and memory functions, but the key factors driving memory T cell metabolic adaptation remain unclear. Using mouse models of viral infection and melanoma, Bevilacqua et al. found that the nuclear receptor peroxisome proliferator–activated receptor β/δ (PPARβ/δ) supports the switch from aerobic glycolysis to oxidative metabolism during central memory CD8+ T cell formation. PPARβ/δ expression was required for memory T cell responses upon rechallenge, as well as the generation of TCF-1+ progenitor exhausted T cells during chronic antigen exposure. Together, these findings identify PPARβ/δ as a key regulator of metabolic reprogramming during memory T cell differentiation. —Claire Olingy [ABSTRACT FROM AUTHOR]

Glioblastoma (IDH-wildtype) represents a formidable challenge in oncology, lacking effective chemotherapeutic or biological interventions. The metabolic reprogramming of cancer cells is a hallmark of tumor progression and drug resistance, yet the role of metabolic reprogramming in glioblastoma during drug treatment remains poorly understood. The dihydroorotate dehydrogenase (DHODH) inhibitor BAY2402234 is a blood–brain barrier penetrant drug showing efficiency in in vivo models of many brain cancers. In this study, we investigated the effect of BAY2402234 in regulating the metabolic phenotype of EGFRWT and EGFRvIII patient-derived glioblastoma cell lines. Our findings reveal the selective cytotoxicity of BAY2402234 toward EGFRWT glioblastoma subtypes with minimal effect on EGFRvIII patient cells. At sublethal doses, BAY2402234 induces triglyceride synthesis at the expense of membrane lipid synthesis and fatty acid oxidation in EGFRWT glioblastoma cells, while these effects are not observed in EGFRvIII glioblastoma cells. Furthermore, BAY2402234 reduced the abundance of signaling lipid species in EGFRWT glioblastoma. This study elucidates genetic mutation-specific metabolic plasticity and efficacy in glioblastoma cells in response to drug treatment, offering insights into therapeutic avenues for precision medicine approaches. [ABSTRACT FROM AUTHOR]

Ascites plays a key role in supporting the metastatic potential of ovarian cancer cells. Shear stress and carry-over of cancer cells by ascites flow support carcinogenesis and metastasis formation. In addition, soluble factors may participate in the procarcinogenic effects of ascites in ovarian cancer. This study aimed to determine the biological effects of cell-free ascites on carcinogenesis in ovarian cancer cells. Cell-free ascites from ovarian cancer patients (ASC) non-selectively induced cell proliferation in multiple models of ovarian cancer and untransformed primary human dermal fibroblasts. Furthermore, ASC induced a Warburg-type rearrangement of cellular metabolism in A2780 ovarian cancer cells characterized by increases in cellular oxygen consumption and glycolytic flux; increases in glycolytic flux were dominant. ASC induced mitochondrial uncoupling and fundamentally reduced fatty acid oxidation. Ascites-elicited effects were uniform among ascites specimens. ASC-elicited transcriptomic changes in A2780 ovarian cancer cells included induction of the TGFβ-ERK/MEK pathway, which plays a key role in inducing cell proliferation and oncometabolism. ASC-induced gene expression changes, as well as the overexpression of members of the TGFβ signaling system, were associated with poor survival in ovarian cancer patients. We provided evidence that the activation of the autocrine/paracrine of TGFβ signaling system may be present in bladder urothelial carcinoma and stomach adenocarcinoma. Database analysis suggests that the TGFβ system may feed forward bladder urothelial carcinoma and stomach adenocarcinoma. Soluble components of ASC support the progression of ovarian cancer. These results suggest that reducing ascites production may play an essential role in the treatment of ovarian cancer by inhibiting the progression and reducing the severity of the disease. [ABSTRACT FROM AUTHOR]

Among the non-communicable neurological diseases, epilepsy is characterized by abnormal brain activity with several peripheral implications. The role of peripheral inflammation in the relationship between seizure development and nonalcoholic fatty liver disease based on sex difference remains still overlooked. Severe early-life infections lead to increased inflammation that can aggravate epilepsy and hepatic damage progression, both related to increased odds of hospitalization for epileptic patients with liver diseases. Here, we induced a post-natal-day 3 (PND3) infection by LPS (1 mg/kg, i.p.) to determine the hepatic damage in a genetic model of young epileptic WAG/Rij rats (PND45). We evaluated intra- and inter-gender differences in systemic and liver inflammation, hepatic lipid dysmetabolism, and oxidative damage related to mitochondrial functional impairment. First, epileptic rats exposed to LPS, regardless of gender, displayed increased serum hepatic enzymes and altered lipid profile. Endotoxin challenge triggered a more severe inflammatory and immune response in male epileptic rats, compared to females in both serum and liver, increasing pro-inflammatory cytokines and hepatic immune cell recruitment. Conversely, LPS-treated female rats showed significant alterations in systemic and hepatic lipid profiles and reduced mitochondrial fatty acid oxidation. The two different sex-dependent mechanisms of LPS-induced liver injury converge in increased ROS production and related mitochondrial oxidative damage in both sexes. Notably, a compensatory increase in antioxidant defense was evidenced only in female rats. Our study with a translational potential demonstrates, for the first time, that early post-natal infections in epileptic rats induced or worsened hepatic disorders in a sex-dependent manner, amplifying inflammation, lipid dysmetabolism, and mitochondrial impairment. [ABSTRACT FROM AUTHOR]

Metabolic alterations in cancers can be exploited for diagnostic, prognostic, and therapeutic purposes. This is exemplified by 18F‐fluorodeoxyglucose (FDG)‐positron emission tomography (FDG‐PET), an imaging tool that relies on enhanced glucose uptake by tumors for diagnosis and staging. By performing transcriptomic analysis of breast cancer (BC) samples from patients stratified by FDG‐PET, a 54‐gene signature (PETsign) is identified that recapitulates FDG uptake. PETsign is independently prognostic of clinical outcome in luminal BCs, the most common and heterogeneous BC molecular subtype, which requires improved stratification criteria to guide therapeutic decision‐making. The prognostic power of PETsign is stable across independent BC cohorts and disease stages including the earliest BC stage, arguing that PETsign is an ab initio metabolic signature. Transcriptomic and metabolomic analysis of BC cells reveals that PETsign predicts enhanced glycolytic dependence and reduced reliance on fatty acid oxidation. Moreover, coamplification of PETsign genes occurs frequently in BC arguing for their causal role in pathogenesis. CXCL8 and EGFR signaling pathways feature strongly in PETsign, and their activation in BC cells causes a shift toward a glycolytic phenotype. Thus, PETsign serves as a molecular surrogate for FDG‐PET that could inform clinical management strategies for BC patients. [ABSTRACT FROM AUTHOR]

Lipid metabolism hinges on a balance between lipogenesis and fatty acid oxidation (FAO). Disruptions in this balance can induce endoplasmic reticulum (ER) stress triggering the unfolded protein response (UPR) and contribute to metabolic diseases. The UPR protein, Luman or CREB3, has recently been implicated in metabolic regulation–CREB3 knockout mice exhibit resistance to diet‐induced obesity and altered insulin sensitivity. Here, we show that CREB3 activated PPARGC1A transcription from a 1 kb promoter region. An increase in CREB3 expression correlated inversely with endogenous PPARGC1A mRNA levels and genes involved in FAO. As PGC‐1α encoded by PPARGC1A is a master regulator of mitochondrial biogenesis and energy homeostasis, these findings demonstrate that CREB3 is a transcriptional regulator of PGC‐1α, underlining the potential role of CREB3 in energy metabolism. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) has emerged as the leading cause of chronic liver disease worldwide. Caspase 8 and FADD-like apoptosis regulator (CFLAR) has been identified as a potent factor in mitigating non-alcoholic steatohepatitis (NASH) by inhibiting the N-terminal dimerization of apoptosis signal-regulating kinase 1 (ASK1). While arginine methyltransferase 1 (PRMT1) was previously reported to be associated with increased hepatic glucose production, its involvement in hepatic lipid metabolism remains largely unexplored. The interaction between PRMT1 and CFLAR and the methylation of CFLAR were verified by Co-IP and immunoblotting assays. Recombinant adenoviruses were generated for overexpression or knockdown of PRMT1 in hepatocytes. The role of PRMT1 in NAFLD was investigated in normal and high-fat diet-induced obese mice. In this study, we found a significant upregulation of PRMT1 and downregulation of CFLAR after 48h of fasting, while the latter significantly rebounded after 12h of refeeding. The expression of PRMT1 increased in the livers of mice fed a methionine choline-deficient (MCD) diet and in hepatocytes challenged with oleic acid (OA)/palmitic acid (PA). Overexpression of PRMT1 not only inhibited the expression of genes involved in fatty acid oxidation (FAO) and promoted the expression of genes involved in fatty acid synthesis (FAS), resulting in increased triglyceride accumulation in primary hepatocytes, but also enhanced the gluconeogenesis of primary hepatocytes. Conversely, knockdown of hepatic PRMT1 significantly alleviated MCD diet-induced hepatic lipid metabolism abnormalities and liver injury in vivo, possibly through the upregulation of CFLAR protein levels. Knockdown of PRMT1 suppressed the expression of genes related to FAS and enhanced the expression of genes involved in FAO, causing decreased triglyceride accumulation in OA/PA-treated primary hepatocytes in vitro. Although short-term overexpression of PRMT1 had no significant effect on hepatic triglyceride levels under physiological conditions, it resulted in increased serum triglyceride and fasting blood glucose levels in normal C57BL/6J mice. More importantly, PRMT1 was observed to interact with and methylate CFLAR, ultimately leading to its ubiquitination-mediated protein degradation. This process subsequently triggered the activation of c-Jun N-terminal kinase 1 (JNK1) and lipid deposition in primary hepatocytes. Together, these results suggested that PRMT1-mediated methylation of CFLAR plays a critical role in hepatic lipid metabolism. Targeting PRMT1 for drug design may represent a promising strategy for the treatment of NAFLD. [ABSTRACT FROM AUTHOR]

Excessive calorie intake leads to mitochondrial overload and triggers metabolic inflexibility and insulin resistance. In this study, we examined how attenuated p38α activity affects glucose and fat metabolism in the skeletal muscles of mice on a high-fat diet (HFD). Mice exhibiting diminished p38α activity (referred to as p38αAF) gained more weight and displayed elevated serum insulin levels, as well as a compromised response in the insulin tolerance test, compared to the control mice. Additionally, their skeletal muscle tissue manifested impaired insulin signaling, leading to resistance in insulin-mediated glucose uptake. Examination of muscle metabolites in p38αAF mice revealed lower levels of glycolytic intermediates and decreased levels of acyl-carnitine metabolites, suggesting reduced glycolysis and β-oxidation compared to the controls. Additionally, muscles of p38αAF mice exhibited severe abnormalities in their mitochondria. Analysis of myotubes derived from p38αAF mice revealed reduced mitochondrial respiratory capacity relative to the myotubes of the control mice. Furthermore, these myotubes showed decreased expression of Acetyl CoA Carboxylase 2 (ACC2), leading to increased fatty acid oxidation and diminished inhibitory phosphorylation of pyruvate dehydrogenase (PDH), which resulted in elevated mitochondrial pyruvate oxidation. The expected consequence of reduced mitochondrial respiratory function and uncontrolled nutrient oxidation observed in p38αAF myotubes mitochondrial overload and metabolic inflexibility. This scenario explains the increased likelihood of insulin resistance development in the muscles of p38αAF mice compared to the control mice on a high-fat diet. In summary, within skeletal muscles, p38α assumes a crucial role in orchestrating the mitochondrial adaptation to caloric surplus by promoting mitochondrial biogenesis and regulating the selective oxidation of nutrients, thereby preventing mitochondrial overload, metabolic inflexibility, and insulin resistance. [ABSTRACT FROM AUTHOR]

Ovarian clear cell carcinoma (OCCC) is a histological subtype that constitutes approximately 20% of epithelial ovarian cancer cases in Asian countries, but has a relatively low incidence in Western countries. Meanwhile, clear cell renal cell carcinoma (ccRCC) is a major subtype of kidney cancer. OCCC and ccRCC resemble one another histologically and have clear cytoplasmic appearances. Studies have revealed some genetic similarities between OCCC and ccRCC. However, information regarding common biological background factors between these cancers remains scarce. For example, accumulation of cellular lipid droplets was shown to play a crucial role in ccRCC progression, while similar information is lacking for OCCC. In this perspective article, we propose that lipid droplets may be candidates for future exploration to better understand the common biological backgrounds between OCCC and ccRCC, potentially leading to subtype-specific treatment strategies. We further discuss the relationship between poly ADP-ribose polymerase inhibition treatment and lipid metabolism because this therapeutic strategy has attracted considerable attention as a treatment for epithelial ovarian cancer. [ABSTRACT FROM AUTHOR]

Copyright of Science & Technology of Food Industry is the property of Science & Technology of Food Industry Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The Arctic fox (Vulpes lagopus) is a species indigenous to the Arctic and has developed unique lipid metabolism, but the mechanisms remain unclear. Here, the significantly increased body weight of Arctic foxes was consistent with the significantly increased serum very-low-density lipoprotein (VLDL), and the 40% crude fat diet further increased the Arctic fox body weight. The enhanced body weight gain stems primarily from increased subcutaneous adipose tissue accumulation. The adipose triacylglycerol and phosphatidylethanolamine were significantly greater in Arctic foxes. The adipose fatty-acid synthase content was significantly lower in Arctic foxes, highlighting the main role of exogenous fatty-acids in fat accumulation. Considering the same diet, liver-derived fat dominates adipose expansion in Arctic foxes. Liver transcriptome analysis revealed greater fat and VLDL synthesis in Arctic foxes, consistent with the greater VLDL. Glucose homeostasis wasn’t impacted in Arctic foxes. And the free fatty-acids in adipose, which promote insulin resistance, also did not differ between groups. However, the hepatic glycogen was greater in Arctic foxes and transcriptome analysis revealed upregulated glycogen synthesis, improving glucose homeostasis. These results suggest that the superior fat accumulation capacity and distinct characteristics of hepatic and adipose lipid and glucose metabolism facilitate glucose homeostasis and massive fat accumulation in Arctic foxes. [ABSTRACT FROM AUTHOR]

Cellular metabolism is a crucial determinant of immune cell fate and function. Extensive studies have demonstrated that metabolic decisions influence immune cell activation, differentiation, and cellular capacity, in the process impacting an organism’s ability to stave off infection or recover from injury. Conversely, metabolic dysregulation can contribute to the severity of multiple disease conditions including autoimmunity, alloimmunity, and cancer. Emerging data also demonstrate that metabolic cues and profiles can influence the success or failure of adoptive cellular therapies. Importantly, immunometabolism is not one size fits all; and different immune cell types, and even subdivisions within distinct cell populations utilize different metabolic pathways to optimize function. Metabolic preference can also change depending on the microenvironment in which cells are activated. For this reason, understanding the metabolic requirements of different subsets of immune cells is critical to therapeutically modulating different disease states or maximizing cellular function for downstream applications. Fatty acid oxidation (FAO), in particular, plays multiple roles in immune cells, providing both pro- and anti-inflammatory effects. Herein, we review the major metabolic pathways available to immune cells, then focus more closely on the role of FAO in different immune cell subsets. Understanding how and why FAO is utilized by different immune cells will allow for the design of optimal therapeutic interventions targeting this pathway. [ABSTRACT FROM AUTHOR]

Purpose: To analyze the causal relationship between 486 human serum metabolites and the active tuberculosis (ATB) in European population. Methods: In this study, the causal relationship between human serum metabolites and the ATB was analyzed by integrating the genome-wide association study (GWAS). The 486 human serum metabolites were used as the exposure variable, three different ATB GWAS databases in the European population were set as outcome variables, and single nucleotide polymorphisms were used as instrumental variables for Mendelian Randomization. The inverse variance weighting was estimated causality, the MR-Egger intercept to estimate horizontal pleiotropy, and the combined effects of metabolites were also considered in the meta-analysis. Furthermore, the web-based MetaboAnalyst 6.0 was engaged for enrichment pathway analysis, while R (version 4.3.2) software and Review Manager 5.3 were employed for statistical analysis. Results: A total of 21, 17, and 19 metabolites strongly associated with ATB were found in the three databases after preliminary screening (P < 0.05). The intersecting metabolites across these databases included tryptophan, betaine, 1-linoleoylglycerol (1-monolinolein) (1-LG), 1-eicosatrienoylglycerophosphocholine, and oleoylcarnitine. Among them, betaine (I2 = 24%, P = 0.27) and 1-LG (I2 = 0%, P = 0.62) showed the lowest heterogeneity among the different ATB databases. In addition, the metabolic pathways of phosphatidylethanolamine biosynthesis (P = 0.0068), methionine metabolism (P = 0.0089), betaine metabolism (P = 0.0205) and oxidation of branched-chain fatty acids (P = 0.0309) were also associated with ATB. Conclusion: Betaine and 1-LG may be biomarkers or auxiliary diagnostic tools for ATB. They may provide new guidance for medical practice in the early diagnosis and surveillance of ATB. In addition, by interfering with phosphatidylethanolamine biosynthesis, methionine metabolism, betaine metabolism, oxidation of branched-chain fatty acids, and other pathways, it is helpful to develop new anti-tuberculosis drugs and explore the virulence or pathogenesis of ATB at a deeper level, providing an effective reference for future studies. [ABSTRACT FROM AUTHOR]

Background: Despite rapid advances in genomic-resolved metagenomics and remarkable explosion of metagenome-assembled genomes (MAGs), the function of uncultivated anaerobic lineages and their interactions in carbon mineralization remain largely uncertain, which has profound implications in biotechnology and biogeochemistry. Results: In this study, we combined long-read sequencing and metatranscriptomics-guided metabolic reconstruction to provide a genome-wide perspective of carbon mineralization flow from polymers to methane in an anaerobic bioreactor. Our results showed that incorporating long reads resulted in a substantial improvement in the quality of metagenomic assemblies, enabling the effective recovery of 132 high-quality genomes meeting stringent criteria of minimum information about a metagenome-assembled genome (MIMAG). In addition, hybrid assembly obtained 51% more prokaryotic genes in comparison to the short-read-only assembly. Metatranscriptomics-guided metabolic reconstruction unveiled the remarkable metabolic flexibility of several novel Bacteroidales-affiliated bacteria and populations from Mesotoga sp. in scavenging amino acids and sugars. In addition to recovering two circular genomes of previously known but fragmented syntrophic bacteria, two newly identified bacteria within Syntrophales were found to be highly engaged in fatty acid oxidation through syntrophic relationships with dominant methanogens Methanoregulaceae bin.74 and Methanothrix sp. bin.206. The activity of bin.206 preferring acetate as substrate exceeded that of bin.74 with increasing loading, reinforcing the substrate determinantal role. Conclusion: Overall, our study uncovered some key active anaerobic lineages and their metabolic functions in this complex anaerobic ecosystem, offering a framework for understanding carbon transformations in anaerobic digestion. These findings advance the understanding of metabolic activities and trophic interactions between anaerobic guilds, providing foundational insights into carbon flux within both engineered and natural ecosystems. 38JKnB3DNsQtzzVWuKzfx4 Video Abstract [ABSTRACT FROM AUTHOR]

Background: Primary carnitine deficiency (PCD) is a rare autosomal recessive fatty acid oxidation disorder caused by variants in SLC22A5, with its prevalence and SLC22A5 gene mutation spectrum varying across races and regions. This study aimed to systematically analyze the incidence of PCD in China and delineate regional differences in the prevalence of PCD and SLC22A5 gene variants. Methods: PubMed, Embase, Web of Science, and Chinese databases were searched up to November 2023. Following quality assessment and data extraction, a meta-analysis was performed on screening results for PCD among Chinese newborns. Results: After reviewing 1,889 articles, 22 studies involving 9,958,380 newborns and 476 PCD cases were included. Of the 476 patients with PCD, 469 underwent genetic diagnosis, revealing 890 variants of 934 alleles of SLC22A5, among which 107 different variants were detected. The meta-analysis showed that the prevalence of PCD in China was 0.05‰ [95%CI, (0.04‰, 0.06‰)] or 1/20 000 [95%CI, (1/16 667, 1/25 000)]. Subgroup analyses revealed a higher incidence in southern China [0.07‰, 95%CI, (0.05‰, 0.08‰)] than in northern China [0.02‰, 95%CI, (0.02‰, 0.03‰)] (P < 0.001). Furthermore, the result of the meta-analysis showed that the frequency of the variant with c.1400C > G, c.51C > G, c.760C > T, c.338G > A, and c.428C > T were 45% [95%CI, (34%, 59%)], 26% [95%CI, (22%, 31%)], 14% [95%CI, (10%, 20%)], 6% [95%CI, (4%, 8%)], and 5% [95%CI, (4%, 8%)], respectively. Among the subgroup analyses, the variant frequency of c.1400C > G in southern China [39%, 95%CI, (29%, 53%)] was significantly lower than that in northern China [79‰, 95%CI, (47‰, 135‰)] (P < 0.05). Conclusions: This study systematically analyzed PCD prevalence and identified common SLC22A5 gene variants in the Chinese population. The findings provide valuable epidemiological insights and guidance for future PCD screening effects in newborns. [ABSTRACT FROM AUTHOR]

OBJECTIVE Anthracycline chemotherapy agents have significant dose-dependent cardiotoxic effects. Carnitine, a non-essential amino acid, is involved in long chain fatty acid oxidation, and carnitine deficiency can result in cardiomyopathy and cardiac arrhythmias. If administered concurrently with chemotherapy, carnitine supplementation could be a potential strategy to prevent cardiotoxicity. However, the association between serum carnitine concentrations and anthracycline cardiotoxicity during cancer treatment in the childhood, adolescent, and young adult (CAYA) age range has not been established. METHODS This prospective pilot cohort study characterized changes in serum carnitine concentrations and cardiac function before, during, and approximately 1 year after large-dose anthracycline therapy in newly diagnosed CAYA cancer patients. RESULTS Among 21 patients with a mean cumulative anthracycline dose exposure of 409 mg/m2 of doxorubicin equivalents, left ventricular ejection fraction and relative wall thickness decreased, indicating an overall decline in cardiac function. A reversible decrease in serum carnitine concentrations was also observed. A non-statistically significant positive correlation was observed; for every 1 mmol/L decrease in serum carnitine concentration, there was a 0.09% decrease in LVEF (p = 0.2). CONCLUSIONS These findings from this small pilot study suggest that there may be a relationship between serum carnitine concentrations and cardiac function after anthracycline therapy that should be evaluated in larger studies. [ABSTRACT FROM AUTHOR]

Background: A cluster of metabolic indicators responsible to elevate the risk of high blood sugar, heart diseases along with stroke is called metabolic syndrome (MetS). Adipokines play critical roles in the formation and progression of these clusters of diseases. Adiponectin enhances fatty acid oxidation, prevents foam cell formation and improves lipid metabolism. In contrast, plasminogen activator inhibitor-1 (PAI-1) possesses pro-atherogenic properties. Carotid intima-media thickness (CIMT) is directly associated with an increased risk of myocardial infarction and stroke. Complete information about the association related to adipokines and CIMT in MetS of Indian population is lacking. Objective: To evaluate the association of adipokine levels and PAI-1 with CIMT in MetS patients, including its components. Materials and methods: We performed a cross-sectional study and IDF criteria were used for the screening of MetS. A total of 164 subjects with MetS (88 males and 76 females) and 100 controls (54 males and 46 females) were enrolled. Serum levels of adiponectin and PAI-1 were measured using ELISA. A CIMT measurement of carotid arteries was also done. The relationship between various parameters was assessed by the Pearson correlation coefficient test. Results: The levels of adiponectin were lower (p < 0.001), while those of PAI-1 and CIMT were higher (p < 0.001) when we compared patients with controls. When the number of metabolic abnormalities increased, the levels of adiponectin decreased and those of PAI-1 increased. There was a strong negative association between PAI-1 levels and those of adiponectin (p <0.001). Conclusion: Our findings indicate that elevated PAI-1 levels are associated with a higher probability of having MetS and negatively impact MetS-related components. [ABSTRACT FROM AUTHOR]

Aims Cardiac energy metabolism is perturbed in ischaemic heart failure and is characterized by a shift from mitochondrial oxidative metabolism to glycolysis. Notably, the failing heart relies more on ketones for energy than a healthy heart, an adaptive mechanism that improves the energy-starved status of the failing heart. However, whether this can be implemented therapeutically remains unknown. Therefore, our aim was to determine if increasing ketone delivery to the heart via a ketogenic diet can improve the outcomes of heart failure. Methods and results C57BL/6J male mice underwent either a sham surgery or permanent left anterior descending coronary artery ligation surgery to induce heart failure. After 2 weeks, mice were then treated with either a control diet or a ketogenic diet for 3 weeks. Transthoracic echocardiography was then carried out to assess in vivo cardiac function and structure. Finally, isolated working hearts from these mice were perfused with appropriately 3H or 14C labelled glucose (5 mM), palmitate (0.8 mM), and β-hydroxybutyrate (β-OHB) (0.6 mM) to assess mitochondrial oxidative metabolism and glycolysis. Mice with heart failure exhibited a 56% drop in ejection fraction, which was not improved with a ketogenic diet feeding. Interestingly, mice fed a ketogenic diet had marked decreases in cardiac glucose oxidation rates. Despite increasing blood ketone levels, cardiac ketone oxidation rates did not increase, probably due to a decreased expression of key ketone oxidation enzymes. Furthermore, in mice on the ketogenic diet, no increase in overall cardiac energy production was observed, and instead, there was a shift to an increased reliance on fatty acid oxidation as a source of cardiac energy production. This resulted in a decrease in cardiac efficiency in heart failure mice fed a ketogenic diet. Conclusion We conclude that the ketogenic diet does not improve heart function in failing hearts, due to ketogenic diet-induced excessive fatty acid oxidation in the ischaemic heart and a decrease in insulin-stimulated glucose oxidation. [ABSTRACT FROM AUTHOR]

Simple Summary: High carbonate alkalinity and high pH are the main characteristics of saline–alkaline water environments. This study aimed to elucidate the physiological mechanism of the hepatopancreas of Fenneropenaeus chinensis in response to saline–alkaline stress. Proteomics and metabolomics of hepatopancreas were employed to analyze the effects of high carbonate alkalinity (CA) stress and combined high carbonate alkalinity and high pH (CP) stress on shrimps after 24 h. The results indicated that several key proteins and metabolites involved in carbohydrate metabolism and fatty acid oxidation were significantly upregulated. Additionally, the antioxidant and immune systems were found to have been affected. These findings suggest that CA and CP stressors induced oxidative stress in the hepatopancreas of F. chinensis, resulting in impaired immunity and diminished inflammatory responses. F. chinensis may resist osmotic pressure imbalances caused by CA or CP stress by upregulating the energy metabolism level in the hepatopancreas. Our findings may offer valuable insights for further investigations into the saline–alkaline water culture of F. chinensis. The rapid development of the mariculture industry has been hindered by limited coastal aquaculture space. To utilize the abundant inland saline–alkaline water, we studied the physiological effects of high carbonate alkalinity stress and high pH stress on Fenneropenaeus chinensis. The study employed quantitative proteomics by tandem mass tag (TMT) and non-targeted metabolomics analysis using a liquid chromatograph mass spectrometer (LC-MS) to understand the physiological and biochemical adaptive mechanisms of the hepatopancreas of F. chinensis in response to saline–alkaline stress at the molecular level. We designed two stress groups as follows: a high carbonate alkalinity (CA) group and a combined high carbonate alkalinity and high pH (CP) group. The study found that the protein and metabolic profiles of the two stress groups were changed, and the CP group, which was exposed to dual stresses, incurred more severe damage to the hepatopancreas compared to that of the CA group. After exposure to CA and CP, the hepatopancreas of F. chinensis showed significant alterations in 455 proteins and 50 metabolites, and 1988 proteins and 272 metabolites, respectively. In addition, F. chinensis upregulated the level of energy metabolism in the hepatopancreas to defend against osmotic imbalance caused by CA or CP stress, which was demonstrated by the significant upregulation of important proteins and metabolites in glycolysis, pyruvate metabolism, TCA cycle, and fatty acid oxidation. Additionally, pattern recognition receptors, the phenol oxidase system, and various immune-related metabolic enzymes and metabolites were also affected. The immune homeostasis of F. chinensis was affected by the alteration of the antioxidant system following exposure to CA or CP. These findings provide valuable information for F. chinensis saline–alkaline water cultivation practices. [ABSTRACT FROM AUTHOR]

The mitochondrial translocator protein 18 kDa (TSPO) has been linked to functions from steroidogenesis to regulation of cellular metabolism and is an attractive therapeutic target for chronic CNS inflammation. Studies in Leydig cells and microglia indicate that TSPO function may vary between cells depending on their specialized roles. Astrocytes are critical for providing trophic and metabolic support in the brain. Recent work has highlighted that TSPO expression increases in astrocytes under inflamed conditions and may drive astrocyte reactivity. Relatively little is known about the role TSPO plays in regulating astrocyte metabolism and whether this protein is involved in immunometabolic processes in these cells. Using TSPO‐deficient (TSPO−/−) mouse primary astrocytes in vitro (MPAs) and a human astrocytoma cell line (U373 cells), we performed extracellular metabolic flux analyses. We found that TSPO deficiency reduced basal cellular respiration and attenuated the bioenergetic response to glucopenia. Fatty acid oxidation was increased, and lactate production was reduced in TSPO−/− MPAs and U373 cells. Co‐immunoprecipitation studies revealed that TSPO forms a complex with carnitine palmitoyltransferase 1a in U373 and MPAs, presenting a mechanism wherein TSPO may regulate FAO in these cells. Compared to TSPO+/+ cells, in TSPO−/− MPAs we observed attenuated tumor necrosis factor release following 3 h lipopolysaccharide (LPS) stimulation, which was enhanced at 24 h post‐LPS stimulation. Together these data suggest that while TSPO acts as a regulator of metabolic flexibility, TSPO deficiency does not appear to modulate the metabolic response of MPAs to inflammation, at least in response to the model used in this study. [ABSTRACT FROM AUTHOR]

Glucagon's ability to promote hepatic glucose production has been known for over a century, with initial observations touting this hormone as a diabetogenic agent. However, glucagon receptor agonism [when balanced with an incretin, including glucagon-like peptide 1 (GLP-1) to dampen glucose excursions] is now being developed as a promising therapeutic target in the treatment of metabolic diseases, like metabolic dysfunction-associated steatotic disease/metabolic dysfunction-associated steatohepatitis (MASLD/MASH), and may also have benefit for obesity and chronic kidney disease. Conventionally regarded as the opposing tag-team partner of the anabolic mediator insulin, glucagon is gradually emerging as more than just a "catabolic hormone." Glucagon action on glucose homeostasis within the liver has been well characterized. However, growing evidence, in part thanks to new and sensitive "omics" technologies, has implicated glucagon as more than just a "glucose liberator." Elucidation of glucagon's capacity to increase fatty acid oxidation while attenuating endogenous lipid synthesis speaks to the dichotomous nature of the hormone. Furthermore, glucagon action is not limited to just glucose homeostasis and lipid metabolism, as traditionally reported. Glucagon plays key regulatory roles in hepatic amino acid and ketone body metabolism, as well as mitochondrial turnover and function, indicating broader glucagon signaling consequences for metabolic homeostasis mediated by the liver. Here we examine the broadening role of glucagon signaling within the hepatocyte and question the current dogma, to appreciate glucagon as more than just that "catabolic hormone." [ABSTRACT FROM AUTHOR]

Objective: Mitochondrial fatty acid oxidation is a metabolic pathway whose dysregulation is recognized as a critical factor in various cancers, because it sustains cancer cell survival, proliferation, and metastasis. The acyl-CoA synthetase long-chain (ACSL) family is known to activate long-chain fatty acids, yet the specific role of ACSL3 in breast cancer has not been determined. Methods: We assessed the prognostic value of ACSL3 in breast cancer by using data from tumor samples. Gain-of-function and lossof- function assays were also conducted to determine the roles and downstream regulatory mechanisms of ACSL3 in vitro and in vivo. Results: ACSL3 expression was notably downregulated in breast cancer tissues compared with normal tissues, and this phenotype correlated with improved survival outcomes. Functional experiments revealed that ACSL3 knockdown in breast cancer cells promoted cell proliferation, migration, and epithelial-mesenchymal transition. Mechanistically, ACSL3 was found to inhibit β-oxidation and the formation of associated byproducts, thereby suppressing malignant behavior in breast cancer. Importantly, ACSL3 was found to interact with YES proto-oncogene 1, a member of the Src family of tyrosine kinases, and to suppress its activation through phosphorylation at Tyr419. The decrease in activated YES1 consequently inhibited YAP1 nuclear colocalization and transcriptional complex formation, and the expression of its downstream genes in breast cancer cell nuclei. Conclusions: ACSL3 suppresses breast cancer progression by impeding lipid metabolism reprogramming, and inhibiting malignant behaviors through phospho-YES1 mediated inhibition of YAP1 and its downstream pathways. These findings suggest that ACSL3 may serve as a potential biomarker and target for comprehensive therapeutic strategies for breast cancer. [ABSTRACT FROM AUTHOR]

Cancer cells undergo metabolic adaptation to promote their survival and growth under energy stress conditions, yet the underlying mechanisms remain largely unclear. Here, we report that tripartite motif‐containing protein 2 (TRIM2) is upregulated in response to glutamine deprivation by the transcription factor cyclic AMP‐dependent transcription factor (ATF4). TRIM2 is shown to specifically interact with carnitine O‐palmitoyltransferase 1 (CPT1A), a rate‐limiting enzyme of fatty acid oxidation. Via this interaction, TRIM2 enhances the enzymatic activity of CPT1A, thereby regulating intracellular lipid levels and protecting cells from glutamine deprivation‐induced apoptosis. Furthermore, TRIM2 is able to promote both in vitro cell proliferation and in vivo xenograft tumor growth via CPT1A. Together, these findings establish TRIM2 as an important regulator of the metabolic adaptation of cancer cells to glutamine deprivation and implicate TRIM2 as a potential therapeutic target for cancer. [ABSTRACT FROM AUTHOR]

Forkhead box O1 (FOXO1) regulates muscle growth, but the metabolic role of FOXO1 in skeletal muscle and its mechanisms remain unclear. To explore the metabolic role of FOXO1 in skeletal muscle, we generated skeletal muscle–specific Foxo1 inducible knockout (mFOXO1 iKO) mice and fed them a high-fat diet to induce obesity. We measured insulin sensitivity, fatty acid oxidation, mitochondrial function, and exercise capacity in obese mFOXO1 iKO mice and assessed the correlation between FOXO1 and mitochondria-related protein in the skeletal muscle of patients with diabetes. Obese mFOXO1 iKO mice exhibited improved mitochondrial respiratory capacity, which was followed by attenuated insulin resistance, enhanced fatty acid oxidation, and improved skeletal muscle exercise capacity. Transcriptional inhibition of FOXO1 in peroxisome proliferator–activated receptor δ (PPARδ) expression was confirmed in skeletal muscle, and deletion of PPARδ abolished the beneficial effects of FOXO1 deficiency. FOXO1 protein levels were higher in the skeletal muscle of patients with diabetes and negatively correlated with PPARδ and electron transport chain protein levels. These findings highlight FOXO1 as a new repressor in PPARδ gene expression in skeletal muscle and suggest that FOXO1 links insulin resistance and mitochondrial dysfunction in skeletal muscle via PPARδ. Article Highlights: Skeletal muscle FOXO1 is upregulated in metabolically unhealthy conditions, such as obesity and aging. We generated skeletal muscle–specific inducible Foxo1 -deficient mice to clarify the metabolic role of FOXO1 in skeletal muscle. FOXO1 deficiency improved mitochondrial dysfunction by increasing peroxisome proliferator–activated receptor δ (PPARδ) transcription, leading to improved insulin resistance and lipid metabolism in the skeletal muscle of obese mice. This study shows that FOXO1 is a new repressor in PPARδ gene expression in skeletal muscle and links insulin resistance and mitochondrial dysfunction in skeletal muscle via PPARδ. [ABSTRACT FROM AUTHOR]