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Diabetic nephropathy (DN) is a crucial metabolic health problem. The renin–angiotensin system (RAS) is well known to play an important role in DN. Abnormal RAS activity can cause the over-accumulation of angiotensin II (Ang II). Angiotensin-converting enzyme inhibitor (ACEI) administration has been proposed as a therapy, but previous studies have also indicated that chymase, the enzyme that hydrolyzes angiotensin I to Ang II in an ACE-independent pathway, may play an important role in the progression of DN. Therefore, this study established a model of severe DN progression in a db/db and ACE2 KO mouse model (db and ACE2 double-gene-knockout mice) to explore the roles of RAS factors in DNA and changes in their activity after short-term (only 4 weeks) feeding of a high-fat diet (HFD) to 8-week-old mice. The results indicate that FD-fed db/db and ACE2 KO mice fed an HFD represent a good model for investigating the role of RAS in DN. An HFD promotes the activation of MAPK, including p-JNK and p-p38, as well as the RAS signaling pathway, leading to renal damage in mice. Blocking Ang II/AT1R could alleviate the progression of DN after administration of ACEI or chymase inhibitor (CI). Both ACE and chymase are highly involved in Ang II generation in HFD-induced DN; therefore, ACEI and CI are potential treatments for DN. [ABSTRACT FROM AUTHOR]

The effects of coffee (Coffea arabica L.) berry pulp extracts (CBP extracts) on the improvement of diabetes, obesity, and non-alcoholic fatty liver disease (NAFLD) were evaluated using various in vitro antioxidant activity assays and through a high-fat diet-induced mild diabetic obese mouse model. After an 84-day oral administration of CBP extracts (400–100 mg/kg), bioactivities were evaluated. The in vitro analysis showed the highest DPPH● scavenging activity of 73.10 ± 4.27%, ABTS● scavenging activity of 41.18 ± 1.14%, and SOD activity of 56.24 ± 2.81%, at a CBP extract concentration of 1000 µg/mL. The in vivo analysis of the CBP extracts showed favorable and dose-dependent anti-obesity, anti-diabetic, NAFLD, nephropathy, and hyperlipidemia refinement effects through hepatic glucose enzyme activity, 5′-AMP-activated protein kinase (AMPK) up-regulation, antioxidant activity, lipid metabolism-related gene expression, and pancreatic lipid digestion enzyme modulatory activities. This study shows that an appropriate oral dosage of CBP extracts could function as a potent herbal formulation for a refinement agent or medicinal food ingredient to control type 2 diabetes and related complications. [ABSTRACT FROM AUTHOR]

Objective: Diet structure has changed greatly over the last few decades, and high-calorie diets have become an integral part of people's daily diet, as well as the important cause of obesity in society. Several organ systems, including the skeletal system, are seriously affected by high-fat-diets (HFD) in the world. There is, however, still a lack of knowledge about the effects of HFD on bone regeneration and the possible mechanisms involved. In this study, the difference in bone regeneration between rats under HFD and low-fat-diets (LFD) was evaluated by monitoring the process of bone regeneration in distraction osteogenesis (DO) model animals, as well as the possible mechanisms. Methods: A total of 40 Sprague Dawley (SD) rats (5 weeks old) were randomly divided into HFD group (n=20) and LFD group (n=20). Except for feeding methods, there were no differences between the two groups in terms of treatment conditions. All animals received the DO surgery eight weeks after starting to feed. After a delay of 5 days (latency phase), the active lengthening phase was performed for 10 days (0.25 mm/12 h), and the consolidation phase followed for 42 days. An observational study of bone included radioscopy (once a week), micro-computed tomography (CT), general morphology, biomechanics, histomorphometry, and immunohistochemistry. Result: The results showed that HFD group had a higher body weight than LFD group after 8, 14, and 16 weeks of feeding. Furthermore, at the final observation, there were statistically significant differences between LFD group and HFD group in terms of total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) levels. Additionally, observations on bone regeneration showed a slower regeneration and a lower biomechanical strength in HFD group than LFD group, based on radiography, micro-CT, general morphology, biomechanics, histomorphometry, and immunohistochemistry. Conclusion: In this study, HFD resulted in elevated blood lipids, increased adipose differentiation at the bone marrow level, and delayed bone regeneration. The pieces of evidence are beneficial to better understand the association between diet and bone regeneration and to adjust the diet optimally for fracture patients. [ABSTRACT FROM AUTHOR]

This paper aims to study the preventive effect of barley consumption on lipid disorders associated to obesity during a high-fat-diet. In this study, Eighteen (18) male Wistar rats (142.63 ± 5 g) were divided into 3 equal groups. Indeed, the first received a standard diet (C), the second received a high-fat-diet containing an Ordinary Bread (OB) and the third received the same high-fat-diet only the OB was replaced by Barley Bread (BB). The weight of rats was measured weekly, after 12 weeks of diet, the rats were sacrificed, the lipid and hepatic assays were performed. As results, the consumption of barley limited food intake, weight gain, and improved lipid imbalance. The comparison between the BB and OB groups shows that: In the BB group, a highly significant decrease in total lipids is observed (36.64%). Additionally, the consumption of BB decreases very significantly total cholesterol (36.39%) and significantly other serum lipid parameters: Low Density Lipoprotein (LDL-C, 59.44%), Very Low Density Lipoprotein (VLDL-C, 28.67%) and triglycerides (55.23%), and it improves liver function by reducing the levels of Aspartate aminotransferase (ASAT, 37.38%) and Alanine aminotransferase (ALAT, 37.77%). Therefore, replacing OB, which is used by the majority of people around the world, with healthy bread like BB rich in bioactive substances, such as Beta-Glucan, may participate in the improvement and balance of the lipid and hepatic profile, and also contributes to limiting weight gain by reducing food intake, thus preventing metabolic diseases. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is a crucial metabolic health problem. The renin–angiotensin system (RAS) is well known to play an important role in DN. Abnormal RAS activity can cause the over-accumulation of angiotensin II (Ang II). Angiotensin-converting enzyme inhibitor (ACEI) administration has been proposed as a therapy, but previous studies have also indicated that chymase, the enzyme that hydrolyzes angiotensin I to Ang II in an ACE-independent pathway, may play an important role in the progression of DN. Therefore, this study established a model of severe DN progression in a db/db and ACE2 KO mouse model (db and ACE2 double-gene-knockout mice) to explore the roles of RAS factors in DNA and changes in their activity after short-term (only 4 weeks) feeding of a high-fat diet (HFD) to 8-week-old mice. The results indicate that FD-fed db/db and ACE2 KO mice fed an HFD represent a good model for investigating the role of RAS in DN. An HFD promotes the activation of MAPK, including p-JNK and p-p38, as well as the RAS signaling pathway, leading to renal damage in mice. Blocking Ang II/AT1R could alleviate the progression of DN after administration of ACEI or chymase inhibitor (CI). Both ACE and chymase are highly involved in Ang II generation in HFD-induced DN; therefore, ACEI and CI are potential treatments for DN.

The effects of coffee (Coffea arabica L.) berry pulp extracts (CBP extracts) on the improvement of diabetes, obesity, and non-alcoholic fatty liver disease (NAFLD) were evaluated using various in vitro antioxidant activity assays and through a high-fat diet-induced mild diabetic obese mouse model. After an 84-day oral administration of CBP extracts (400–100 mg/kg), bioactivities were evaluated. The in vitro analysis showed the highest DPPH● scavenging activity of 73.10 ± 4.27%, ABTS● scavenging activity of 41.18 ± 1.14%, and SOD activity of 56.24 ± 2.81%, at a CBP extract concentration of 1000 µg/mL. The in vivo analysis of the CBP extracts showed favorable and dose-dependent anti-obesity, anti-diabetic, NAFLD, nephropathy, and hyperlipidemia refinement effects through hepatic glucose enzyme activity, 5′-AMP-activated protein kinase (AMPK) up-regulation, antioxidant activity, lipid metabolism-related gene expression, and pancreatic lipid digestion enzyme modulatory activities. This study shows that an appropriate oral dosage of CBP extracts could function as a potent herbal formulation for a refinement agent or medicinal food ingredient to control type 2 diabetes and related complications.

Clinical studies provide strong evidence that obesity and associated adipose tissue (AT) inflammation are risk factors for breast cancer (BrCA); however, mechanistic knowledge of the interaction of obesity, BrCA, and menopausal status has proven to be not only lacking, but contradictory. Obesity-induced inflammation and elevated biosynthesis of estrogens, through aromatase-mediated metabolism of precursors, have been linked with hormone receptor positive (HP) postmenopausal BrCA but not previously associated with premenopausal BrCA risk. Thus, further delineation of the interaction of obesity, inflammation, and aromatase is required for the development of therapeutic treatment options. The purpose of this study was to examine the effect of high fat diet (HFD)-induced inflammation on tumorigenesis in a model of pre and postmenopausal HP BrCA. Female PyMT/MMTV ovary intact and ovariectomized mice were fed low and HFD diets to examine the role of obesity-induced inflammation and hormone production in the development of HP BrCA. Tumor statistics for number, volume, weight, histopathology scoring and gene expression of macrophage and inflammatory mediators were measured in the AT and mammary gland at sacrifice. HFD feedings of ovary intact mice resulted in increased adiposity and tumorigenesis, indicated by increased primary tumor volume, multiplicity, tumor burden, and increased tumor progression represented by histopathological scoring. HFD-induced obesity significantly upregulated aromatase and macrophage marker expression in the AT (F4/80 and CD11c) and mammary gland (Mertk) in a premenopausal model of BrCA. Conversely, HFD feedings had no significant effect on tumorigenesis in a postmenopausal model of BrCA despite large increases in adiposity in ovariectomized mice; however, limitations within the model may have precluded any significant findings. This data suggests that obesity-induced increases in inflammation and hormone production, via aromatase expression, is associated with increases in tumorigenesis in a model of premenopausal HP BrCA in the PyMT/MMTV strain.

Cornelian cherry (Cornus mas L.) has been used for centuries as a traditional herbal medicine in Europe and Asia. In this study, we aimed to describe the effect of Cornus mas L. (C. mas) on the activity of the antioxidant enzymes and a detoxification agent in rats fed a high-fat diet. Forty-eight adult Sprague Dawley rats were randomly assigned to six groups of eight animals each: Standard diet (Control), High Fat Diet (HFD), HFD + C. mas (200 mg/kg/day; 8 weeks), HFD + Atorvastatin (20 mg/kg/day; 8 weeks), HFD post-treated with C. mas (200 mg/kg/day; 4 weeks), HFD posttreated with Atorvastatin (20 mg/kg/day; 4 weeks). The activity of the antioxidant enzymes, Superoxide dismutase (SOD), Catalase (CAT), Glutathione peroxidase (GPx), detoxification agent glutathione (GSH), and oxidative stress parameter thiobarbituric acid reactive substances (TBARS) were measured in the liver tissues. GPx, SOD, and CAT enzyme levels were decreased in HFD groups compared to the control (p < 0.05). However, Cornus mas L. promoted antioxidant activity by increasing GPx, SOD, and CAT enzymes and It also reduced oxidative stress (as an increase in GSH) both in the HFD + C. mas group and the HFD post-treated C. mas group compared to the HFD group (p < 0.05). Our study showed that feeding a high-fat diet increases oxidative stress. Cornus mas L treatment improves antioxidant enzyme activity and oxidative stress parameters in the liver tissues of rats. [ABSTRACT FROM AUTHOR]

Delayed wound healing in patients having type-II diabetes mellitus (T2DM) often results in a high rate of amputation. We report an innovative Guar Gum-based macroporous hydrogel (HG) infused with an antibacterial agent (Ag NPs), and antioxidant, epigallocatechin gallate (EGCG) to address rapid wound healing and interestingly could inhibit the associated pathophysical bone infection in a high-fat-diet-induced T2DM C57BL/6 mice model. The HG-Ag-EGCG elicits scar-free wound healing in subcutaneous wounds and histopathological evidence confirmed HG-Ag-EGCG hydrogel patch elicits better wound healing through enhanced cell proliferation, mature connecting tissue fiber formation, minimum void spaces formation, and better re-epithelialization when compared with a market available hydrogel patch material (Luofucon®). Supportive of the in vivo outcomes, in vitro experiments delineated better-wound closure due to improved management of ROS by the HG-Ag-EGCG. Additionally, a favorable non-toxicity outcome assessed through both in vitro and in vivo conditions confirmed its potential applicability in clinical wound care management. [ABSTRACT FROM AUTHOR]

Growing evidence suggests that gut microbiota are associated with atherosclerosis (AS). However, the functional heterogeneity of each gut segment gives rise to regional differences in gut microbiota. We established a rat model of AS by feeding the rats a high-fat diet for a long period. The pathological and microbiota changes in the ileum and colon of the rats were examined, and correlations between AS and microbiota were analyzed. The aortic mesothelium of the experimental rats was damaged. The intima showed evident calcium salt deposition, indicating that the AS rat model was successfully developed. We noted varying degrees of pathological damage in the ileum and colon of the experimental rats. The 16S rDNA high-throughput sequencing showed significant differences in α-diversity, β-diversity, and microbiota comparisons in the ileum and colon. Furthermore, the ileum and colon of AS rats showed varying degrees of intestinal microbiota disturbance. This article contributes to the study of the relationship between the microbiota in different regions of the gut and AS, and provides new approaches in gut microbiota intervention for the treatment of AS. [ABSTRACT FROM AUTHOR]

Aim: A high‐fat diet (HFD) is generally considered to negatively influence the body, the brain, and cognition. Nonetheless, fat and fatty acids are essential for nourishing and constructing brain tissue. Astrocytes are central for lipolysis and fatty acids metabolism. We tested how HFD affects astrocyte metabolism, morphology, and physiology. Methods: We used Raman microspectroscopy to assess the redox state of mitochondria and lipid content in astrocytes and neurons in hippocampal slices of mice subjected to HFD. Astrocytes were loaded with fluorescent dye through patch pipette for morphological analysis. Whole‐cell voltage‐clamp recordings were performed to measure transporter and potassium currents. Western blot analysis quantified the expression of astrocyte‐specific proteins. Field potential recordings measured the magnitude of long‐term potentiation (LTP). Open filed test was performed to evaluate the effect of HFD on animal behavior. Results: We found that exposure of young mice to 1 month of HFD increases lipid content and relative amount of reduced cytochromes in astrocytes but not in neurons. Metabolic changes were paralleled with an enlargement of astrocytic territorial domains due to an increased outgrowth of branches and leaflets. Astrocyte remodeling was associated with an increase in expression of ezrin and with no changes in glial fibrillary acidic protein (GFAP), glutamate transporter‐1 (GLT‐1), and glutamine synthetase (GS). Such physiological (non‐reactive) enlargement of astrocytes in the brain active milieu promoted glutamate clearance and LTP and translated into behavioral changes. Conclusion: Dietary fat intake is not invariably harmful and might exert beneficial effects depending on the biological context. [ABSTRACT FROM AUTHOR]

Sirtuin 3 (SIRT3) is the primary mitochondrial deacetylase that controls the antioxidant pathway and energy metabolism. We previously found that renal Sirt3 expression and activity were reduced in mice with type 2 diabetic nephropathy associated with oxidative stress and mitochondrial abnormalities and that a specific SIRT3 activator improved renal damage. SIRT3 is modulated by diet, and to assess whether Sirt3 deficiency aggravates mitochondrial damage and accelerates kidney disease in response to nutrient overloads, wild-type (WT) and Sirt3−/− mice were fed a high-fat-diet (HFD) or standard diet for 8 months. Sirt3−/− mice on HFD exhibited earlier and more severe albuminuria compared to WT mice, accompanied by podocyte dysfunction and glomerular capillary rarefaction. Mesangial matrix expansion, tubular vacuolization and inflammation, associated with enhanced lipid accumulation, were more evident in Sirt3−/− mice. After HFD, kidneys from Sirt3−/− mice showed more oxidative stress than WT mice, mitochondria ultrastructural damage in tubular cells, and a reduction in mitochondrial mass and energy production. Our data demonstrate that Sirt3 deficiency renders mice more prone to developing oxidative stress and mitochondrial abnormalities in response to HFD, resulting in more severe kidney diseases, and this suggests that mitochondria protection may be a method to prevent HFD-induced renal injury. [ABSTRACT FROM AUTHOR]

Abstract Background Obesity is a top public health problem associated with an increase in colorectal cancer incidence. Stem cells are the chief cells in tissue homeostasis that self-renew and differentiate into other cells to regenerate the organ. It is speculated that an increase in stem cell pool makes cells susceptible to carcinogenesis. In this review, we looked at the recent investigations linking obesity/high-fat diet-induced obesity to intestinal carcinogenesis with regard to intestinal stem cells and their niche. Findings High-fat diet-induced obesity may rise intestinal carcinogenesis by increased Intestinal stem cells (ISC)/progenitor’s population, stemness, and niche independence through activation of PPAR-δ with fatty acids, hormonal alterations related to obesity, and low-grade inflammation. However, these effects may possibly relate to the interaction between fats and carbohydrates, and not a fatty acid per se. Nonetheless, literature studies are inconsistency in their results, probably due to the differences in the diet components and limitations of genetic models used. Conclusion High-fat diet-induced obesity affects carcinogenesis by changing ISC proliferation and function. However, a well-matched diet and the reliable colorectal cancer models that mimic human carcinogenesis is necessary to clearly elucidate the influence of high-fat diet-induced obesity on ISC behavior.

Abstract Background Low dose of NP exposure can alter adipose tissue formation, and the intake of high-fat diet (HFD) can also lead to the fatty liver disease. We investigated the combined effect of NP and HFD on the first offspring of rats, and whether this effect can be passed to the next generation and the possible mechanisms involved. Methods Pregnant rats had access to be treated with 5 μg/kg/day NP and normal diet. The first generation rats were given normal diet and HFD on postnatal day 21, respectively. Then the second generation rats started to only receive normal diet without NP or HFD. Body weight, organ coefficient of liver tissues, lipid profile, biochemical indexes and the expression of genes involved in lipid metabolism, as well as liver histopathology were investigated in male offspring of rats. Results NP and HFD interaction had significant effect on the birth weight, body weight and liver tissue organ coefficient of first generation male rats. And HFD aggravated abnormal lipid metabolism, even abnormal liver function and liver histopathological damage of first generation male rats produced by the NP. And this effect can be passed on to the second generation rats. HFD also accelerated the mRNA level of fatty acid synthesis genes such as Lpl, Fas, Srebp-1 and Ppar-γ of first generation rats induced by perinatal exposure to NP, even passed on to the second generation of male rats. NP and HFD resulted in synergistical decrease of the protein expression level of ERα in liver tissue in F2 male rats. Conclusion HFD and NP synergistically accelerated synthesis of fatty acids in liver of male offspring rats through reducing the expression of ERα, which induced abnormal lipid metabolism, abnormal liver function and hepatic steatosis. Moreover, all of these damage passed on to the next generation rats.

The obesity epidemic has serious implications for women of reproductive age; its rising incidence is associated not just with health implications for the mother but also has transgenerational ramifications for the offspring. Increased incidence of diabetes, cardiovascular disease, obesity, and kidney disease are seen in both the mothers and the offspring. Animal models, such as rodent studies, are fundamental to studying maternal obesity and its impact on maternal and offspring health, as human studies lack rigorous controlled experimental design. Furthermore, the short and prolific reproductive potential of rodents enables examination across multiple generations and facilitates the exploration of interventional strategies to mitigate the impact of maternal obesity, both before and during pregnancy. Given that obesity is a major public health concern, it is important to obtain a greater understanding of its pathophysiology and interaction with reproductive health, placental physiology, and foetal development. This narrative review focuses on the known effects of maternal obesity on the mother and the offspring, and the benefits of interventional strategies, including dietary intervention, before or during pregnancy on maternal and foetal outcomes. It further examines the contribution of rodent models of maternal obesity to elucidating pathophysiological pathways of disease development, as well as methods to reduce the impact of obesity on the mothers and the developing foetus. The translation of these findings into the human experience will also be discussed. [ABSTRACT FROM AUTHOR]

Growing evidence suggests that gut microbiota are associated with atherosclerosis (AS). However, the functional heterogeneity of each gut segment gives rise to regional differences in gut microbiota. We established a rat model of AS by feeding the rats a high-fat diet for a long period. The pathological and microbiota changes in the ileum and colon of the rats were examined, and correlations between AS and microbiota were analyzed. The aortic mesothelium of the experimental rats was damaged. The intima showed evident calcium salt deposition, indicating that the AS rat model was successfully developed. We noted varying degrees of pathological damage in the ileum and colon of the experimental rats. The 16S rDNA high-throughput sequencing showed significant differences in α-diversity, β-diversity, and microbiota comparisons in the ileum and colon. Furthermore, the ileum and colon of AS rats showed varying degrees of intestinal microbiota disturbance. This article contributes to the study of the relationship between the microbiota in different regions of the gut and AS, and provides new approaches in gut microbiota intervention for the treatment of AS.

Microalgae are emerging as a good source of natural nutraceuticals and medicines. This study aims at evaluating the anti-obesity effects of two microalgae polysaccharides (CPS from Chlorella pyrenoidosa and SPS from Spirulina platensis) in high-fat diet (HFD)-induced obese C57BL/6 mice, with β-glucan as a positive control polysaccharide. CPS, SPS and β-glucan were daily administered intragastrically during 10-week HFD feeding, and conferred equally effective protection against overweight, energy imbalance, glucose tolerance impairment, systemic inflammation, dyslipidemia, and fat deposition in the liver and epididymal white adipose tissues. By western blotting analysis of CPT-1, PPARγ and SREBP-1c, those polysaccharides increased lipolysis and decreased lipogenesis in the liver. According to high-throughput sequencing of fecal 16S rRNA, CPS, SPS and β-glucan corrected the HFD-induced gut dysbiosis similarly by increasing beneficial bacteria especially Clostridia, Bacterioidia and Mollicutes and decreasing unfavorable bacteria especially Actinobacteria and Verrucomicrobia and, as revealed by PICRUSt functional analysis, they restored the HFD-induced perturbations in many gut bacterial enzymes and pathways involved in the metabolism of SCFAs, secondary bile acids and trimethylamine, implicating a possible anti-obesity mechanism through gut microbiome-mediated modulation of host lipid metabolism. Microalgae polysaccharides can thus serve as potent alternative food ingredients to improve disease conditions in obese patients. [Display omitted] • High molecular weight heteropolysaccharides are obtained from Chlorella and Spirulina. • Chlorella and Spirulina polysaccharides attenuate high-fat-diet-induced mouse obesity. • Chlorella and Spirulina polysaccharides modulate hepatic lipolysis and lipogenesis. • Chlorella and Spirulina polysaccharides improve high-fat-diet-induced gut dysbiosis. [ABSTRACT FROM AUTHOR]

Abstract Background Obesity is a risk factor for chronic kidney disease (CKD). While the exact mechanisms remain unclear, inflammation may be a consequence of obesity that directly impacts the kidneys. The aim of this study was to examine the inflammatory status of the kidneys and potential ongoing renal damage, i.e., tubular damage and fibrosis after long-term obesity maintained through persistent consumption of a high-fat diet (HFD). Results Twenty-four-week-old male Long-Evans (LEV) rats were continuously fed a control diet (CD) or HFD for 51 weeks. The mean body weight was higher in HFD-fed rats than in control diet-fed rats and markedly elevated during the last 24 weeks. Blood analyses revealed no substantial alterations in renal functional parameters by HFD consumption but a substantial increase in creatine kinase, a muscle loss marker. Magnetic resonance imaging (MRI) was utilized to quantify rat quadriceps muscle mass. The data showed that HFD-induced obesity in LEV rats was accompanied by minor decreases in muscle mass and strength at 75 weeks of age. Rat kidney inflammatory status was evaluated using histological and immunohistological techniques. The number of foci with immune cell infiltrates and infiltrating monocytes/macrophages was significantly increased in HFD-fed rat kidneys at week 75. Renal fibrosis parameters, including glomerulosclerosis and tubular damage, were also markedly increased in renal tissues from HFD-fed rats compared to the controls. The significant increase in tubular protein casts in HFD-fed rat tissues indicated that renal function was already disturbed. Rat kidney inflammatory status was further evaluated using the simultaneous profiling of twenty-two inflammatory markers in kidney tissue extracts. Consistently, MCP-1 and eotaxin (CCL11) levels were elevated in obese LEV rat kidneys. Conclusions Compared to CD-fed rats, HFD-fed obese LEV rats show significant damage of renal structures with aging. These subtle changes may sensitize the kidneys to the development of progressive CKD.

Type 2 diabetes—associated with impaired insulin/insulin-like growth factor-1 (IGF1) signaling (IIS)—is a risk factor for cognitive impairment and dementia including Alzheimer’s disease (AD). The insulin receptor substrate (IRS) proteins are major components of IIS, which transmit upstream signals via the insulin receptor and/or IGF1 receptor to multiple intracellular signaling pathways, including AKT/protein kinase B and extracellular-signal-regulated kinase cascades. Of the four IRS proteins in mammals, IRS1 and IRS2 play key roles in regulating growth and survival, metabolism, and aging. Meanwhile, the roles of IRS1 and IRS2 in the central nervous system with respect to cognitive abilities remain to be clarified. In contrast to IRS2 in peripheral tissues, inactivation of neural IRS2 exerts beneficial effects, resulting in the reduction of amyloid β accumulation and premature mortality in AD mouse models. On the other hand, the increased phosphorylation of IRS1 at several serine sites is observed in the brains from patients with AD and animal models of AD or cognitive impairment induced by type 2 diabetes. However, these serine sites are also activated in a mouse model of type 2 diabetes, in which the diabetes drug metformin improves memory impairment. Because IRS1 and IRS2 signaling pathways are regulated through complex mechanisms including positive and negative feedback loops, whether the elevated phosphorylation of IRS1 at specific serine sites found in AD brains is a primary response to cognitive dysfunction remains unknown. Here, we examine the associations between IRS1/IRS2-mediated signaling in the central nervous system and cognitive decline.

Sirtuin 3 (SIRT3) is the primary mitochondrial deacetylase that controls the antioxidant pathway and energy metabolism. We previously found that renal Sirt3 expression and activity were reduced in mice with type 2 diabetic nephropathy associated with oxidative stress and mitochondrial abnormalities and that a specific SIRT3 activator improved renal damage. SIRT3 is modulated by diet, and to assess whether Sirt3 deficiency aggravates mitochondrial damage and accelerates kidney disease in response to nutrient overloads, wild-type (WT) and Sirt3−/− mice were fed a high-fat-diet (HFD) or standard diet for 8 months. Sirt3−/− mice on HFD exhibited earlier and more severe albuminuria compared to WT mice, accompanied by podocyte dysfunction and glomerular capillary rarefaction. Mesangial matrix expansion, tubular vacuolization and inflammation, associated with enhanced lipid accumulation, were more evident in Sirt3−/− mice. After HFD, kidneys from Sirt3−/− mice showed more oxidative stress than WT mice, mitochondria ultrastructural damage in tubular cells, and a reduction in mitochondrial mass and energy production. Our data demonstrate that Sirt3 deficiency renders mice more prone to developing oxidative stress and mitochondrial abnormalities in response to HFD, resulting in more severe kidney diseases, and this suggests that mitochondria protection may be a method to prevent HFD-induced renal injury.

Min Zhang,1 Xiaohong Jiang,2 Meidi Qu,1 Hongliu Gu,1 Qi Sha,1 Fei Hua2 1Department of Clinical Nutrition, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China; 2Department of Endocrinology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China Background: The prevalence of obesity is growing rapidly and has become a global problem that increases the risk for many diseases. It is influenced by many factors, including consumption of the Western-style diet, characterized as a high-fat diet. Within the central nervous system, the hypothalamus is a critical site in maintaining energy homeostasis and sensing nutrient status, including palmitate, the major component of high-fat-diet.Methods: In the present study, we conducted a variety of studies to investigate the specific role of salubrinal on palmitate-induced hypothalamic cell death, leptin signaling, and ER stress in an embryonic hypothalamic cell line. Experiments were also performed to identify the underlying mechanisms of the protective effect of salubrinal.Results: Our results indicate that salubrinal protects hypothalamic cells against PA-induced ER stress and improves hypothalamic leptin sensitivity. Conclusion: Taken together, our findings conclusively reveal that salubrinal abrogates palmitate-induced hypothalamic leptin resistance and ER stress via NF-κB pathway. Keywords: obesity, high-fat diet, palmitate, leptin resistance, ER stress, salubrinal

Background: Low dose of NP exposure can alter adipose tissue formation, and the intake of high-fat diet (HFD) can also lead to the fatty liver disease. We investigated the combined effect of NP and HFD on the first offspring of rats, and whether this effect can be passed to the next generation and the possible mechanisms involved. Methods: Pregnant rats had access to be treated with 5 μg/kg/day NP and normal diet. The first generation rats were given normal diet and HFD on postnatal day 21, respectively. Then the second generation rats started to only receive normal diet without NP or HFD. Body weight, organ coefficient of liver tissues, lipid profile, biochemical indexes and the expression of genes involved in lipid metabolism, as well as liver histopathology were investigated in male offspring of rats. Results: NP and HFD interaction had significant effect on the birth weight, body weight and liver tissue organ coefficient of first generation male rats. And HFD aggravated abnormal lipid metabolism, even abnormal liver function and liver histopathological damage of first generation male rats produced by the NP. And this effect can be passed on to the second generation rats. HFD also accelerated the mRNA level of fatty acid synthesis genes such as Lpl, Fas, Srebp-1 and Ppar-γ of first generation rats induced by perinatal exposure to NP, even passed on to the second generation of male rats. NP and HFD resulted in synergistical decrease of the protein expression level of ERα in liver tissue in F2 male rats. Conclusion: HFD and NP synergistically accelerated synthesis of fatty acids in liver of male offspring rats through reducing the expression of ERα, which induced abnormal lipid metabolism, abnormal liver function and hepatic steatosis. Moreover, all of these damage passed on to the next generation rats. [ABSTRACT FROM AUTHOR]

Background: Obesity is a top public health problem associated with an increase in colorectal cancer incidence. Stem cells are the chief cells in tissue homeostasis that self-renew and differentiate into other cells to regenerate the organ. It is speculated that an increase in stem cell pool makes cells susceptible to carcinogenesis. In this review, we looked at the recent investigations linking obesity/high-fat diet-induced obesity to intestinal carcinogenesis with regard to intestinal stem cells and their niche. Findings: High-fat diet-induced obesity may rise intestinal carcinogenesis by increased Intestinal stem cells (ISC)/progenitor's population, stemness, and niche independence through activation of PPAR-δ with fatty acids, hormonal alterations related to obesity, and low-grade inflammation. However, these effects may possibly relate to the interaction between fats and carbohydrates, and not a fatty acid per se. Nonetheless, literature studies are inconsistency in their results, probably due to the differences in the diet components and limitations of genetic models used. Conclusion: High-fat diet-induced obesity affects carcinogenesis by changing ISC proliferation and function. However, a well-matched diet and the reliable colorectal cancer models that mimic human carcinogenesis is necessary to clearly elucidate the influence of high-fat diet-induced obesity on ISC behavior. [ABSTRACT FROM AUTHOR]

In this paper, extracts from male zooid of Antheraea pernyi (EMZAP) were investigated for their antiobesity activity in C57BL/6 male mice. Mice were randomly divided into 4 groups and fed on basal control group diet (Control Group), high-fat diet (Model Group), high-fat diet containing high dose of EMZAP (High Group), and high-fat diet containing low dose of EMZAP (Low Group), respectively. The levels of serum lipid, antioxidant capacity, body weight, and adipose weight were measured. The levels of expression of genes involved in cholesterol metabolism were also determined by Real-Time PCR. The results showed that EMZAP could reduce body weight and epididymal adipose weight of mice on fed high-fat diet, and also decrease serum lipid levels in mice with induced obesity. Treatment with EMZAP also produced significant amelioration of lipid accumulation and improved the antioxidant capacity in the liver. EMZAP reduced the expression of HMG-CoA reductase (HMG-CoA-R) and increased the expression of cholesterol 7-alpha hydroxylase (CYP7A1) and LDL receptor (LDLR). But it has no obvious effect on the expression of LXR-. According to the above results, EMZAP had good anti-obesity attributes and improvement in conditions arising out of cholesterol accumulation. [ABSTRACT FROM AUTHOR]

The obesity epidemic has serious implications for women of reproductive age; its rising incidence is associated not just with health implications for the mother but also has transgenerational ramifications for the offspring. Increased incidence of diabetes, cardiovascular disease, obesity, and kidney disease are seen in both the mothers and the offspring. Animal models, such as rodent studies, are fundamental to studying maternal obesity and its impact on maternal and offspring health, as human studies lack rigorous controlled experimental design. Furthermore, the short and prolific reproductive potential of rodents enables examination across multiple generations and facilitates the exploration of interventional strategies to mitigate the impact of maternal obesity, both before and during pregnancy. Given that obesity is a major public health concern, it is important to obtain a greater understanding of its pathophysiology and interaction with reproductive health, placental physiology, and foetal development. This narrative review focuses on the known effects of maternal obesity on the mother and the offspring, and the benefits of interventional strategies, including dietary intervention, before or during pregnancy on maternal and foetal outcomes. It further examines the contribution of rodent models of maternal obesity to elucidating pathophysiological pathways of disease development, as well as methods to reduce the impact of obesity on the mothers and the developing foetus. The translation of these findings into the human experience will also be discussed.

Green tea could reportedly modify gut microbiota and benefit on High-Fat-Diet (HFD) induced obesity. However, most of the studies usually gave green tea (GT) to animals while feeding them HFD. When thin or obese mice, drink GT continuously or only for a period of time, what kind of benefit will them get, is still need to evaluate. In this study, we found that preventive GT consumption by lean mice could prevent HFD-induced-obesity event after stop drinking GT, while the mice with pre-existing obesity couldn’t get such benefit. Gut microbiota structure analysis indicated that the anti-obesity effect by GT consumption always accompanied with microbiota structure modification. We hypothesized that this difference depended upon the status of gut microbiota. Therefore, to gain the persistently protective effect from GT, the precondition is drinking GT before getting fat; otherwise, GT could only slowdown the weight gain of the pre-obese mice by continuously consumption.

Background/Aims: Nonalcoholic steatohepatitis (NASH) is defined as lipid accumulation with hepatic injury, inflammation and early to moderate fibrosis. Kupffer cells play a crucial role in promoting hepatic inflammation, which further facilitates the development of NASH. Here we investigated the effects of Cangju Qinggan Jiangzhi decoction (CQJD) on high fat diet (HFD) and methionine-choline deficient (MCD) induced mouse NASH pathogenesis. Methods: Mouse NASH models were developed by HFD and MCD diet. The treated mice were divided into three groups: the control group (n = 10), the low-dose CQJD treatment group (n = 10) and the high-dose CQJD treatment group (n = 10). The hepatic injury, inflammation, and apoptotic molecules were evaluated by H&E staining, immunohistochemistry and real-time PCR. Kupffer cells were isolated from control mice and CQJD-treated mice after stimulation by lipopolysaccharide (LPS) and/or palmitic acid. The level of the inflammatory cytokines TNFα, IL1β, and CCL2 was measured by ELISA. Results: The HFD-fed mice displayed significant metabolic, inflammatory, and oxidative stress-related alterations due to hepatic lipid accumulation. CQJD treatment largely normalized the hepatic injury, lowered the ALT/AST level, and reduced the severity of liver inflammation, as revealed by the decreased inflammatory cytokines levels. In vitro, CQJD blocked the activation of LPS- or palmitic acid-primed Kupffer cells in a dose-dependent manner. In the MCD diet-induced NASH mice, similar therapeutic effects of CQJD were also observed. Conclusion: CQJD ameliorates mouse nonalcoholic steatohepatitis. The reduction in liver injury and inflammation induced by CQJD is associated with reduced activation of Kupffer cells. Our results suggest that CQJD is a promising therapeutic strategy in clinical steatohepatitis.

Abstract Background Obesity is currently one of the major epidemics of this millennium and affects poeples throughout the world. It causes multiple systemic complications as it significantly interferes with respiratory function. Objective We aimed in the present work to study the effect of high fat diet (HFD) on lung oxidative stress and energy metabolism alterations, as well as the putative protection afforded by grape seed and skin extract (GSSE). Methods We started by characterizing the GSSE and its composition using gas chromatography coupled to mass spectrometry (GC-MS). We used a rat model of high-fat-diet and we evaluated the effect of GSSE on oxidative stress and energetic disturbances induced by HFD. We analyzed the effect of HFD on lung oxidative status by assessing lipid oxidation level, non-protein thiols (NPSH) and superoxide anion level… We also evaluated the effect of HFD on creatine kinase (CK), malate dehydrogenase (MDH) and mitochondrial complex IV. Results HFD induced body weight gain, increased lung weight and lipid content without affecting insulinemia and dropped adiponectemia. HFD also provoked on lung oxidative stress characterized by increased carbonylation (+ 95%; p = 0.0045), decreased of NPSH (− 32%; p = 0.0291) and inhibition of antioxidant enzyme activities such as glutathione peroxidase (− 25%; p = 0.0074). HFD also altered lung intracellular mediators as superoxide anion O2¯ (+ 59%; p = 0.0027) and increased lung xanthine oxidase activity (+ 27%; p = 0.0122). HFD induced copper depletion (− 24%; p = 0.0498) and lead (− 51%: p = 0.0490) from the lung. Correlatively HFD decreased the copper associated enzyme tyrosinase (− 29%; p = 0.0500) and decreased glutamine synthetase activity (− 31%; p = 0.0027). HFD altered also lung energy metabolism by increasing CK activity (+ 22%; p = 0.0108) and decreasing MDH and mitochondrial complex IV activities (− 28%; p = 0.0120, − 31%; p = 0.0086 respectively). Importantly all these alterations were efficiently corrected with GSSE treatment. Conclusion In conclusion, GSSE has the potential to alleviate the deleterious lipotoxic effect of HFD on lung and it could find potential application in the protection against HFD-induced lung complications.

The study was designed to evaluate the detrimental effects of dietary consumption of Banaspati ghee on renal function of mice. Two locally manufactured brand of Banaspati ghee daily to mice at a rate of 10% of their daily food intake for a period of 4 weeks. After 4 weeks, both male and female mice were sacrificed and kidneys were taken out. Biochemical parameters e.g., lipid peroxidation (LPO), catalase (CAT), glutathione-S-transferase (GST), reduced glutathione (GSH) were determined to evaluate oxidative stress while urea and creatinine, was used to evaluate kidney function. It was found that there was an increase in weight (p<0.05) of both males and female mice fed with diet containing ghee. Kidney LPO and CAT were significantly increased in both male and female mice. GSH level showed decreasing trend in female while increase was observed for male kidney. Creatinine level increased in both male and female experimental groups compared with control. In the light of present results, it was concluded that high daily intake of ghee available in market can cause damage to vital organs like kidney. In general female physiological system seems to be more prone to damage caused by these diets as compared to male physiological system. [ABSTRACT FROM AUTHOR]

Both aging and diet play an important role in influencing the gut ecosystem. Using premature senescent rats induced by d-galactose and fed with high-fat diet, this study aims to investigate the effects of different potential probiotic strains on the dynamic changes of fecal microbiome and metabolites. In this study, male Sprague–Dawley rats were fed with high-fat diet and injected with d-galactose for 12 weeks to induce aging. The effect of Lactobacillus plantarum DR7, L. fermentum DR9, and L. reuteri 8513d administration on the fecal microbiota profile, short-chain fatty acids, and water-soluble compounds were analyzed. It was found that the administration of the selected strains altered the gut microbiota diversity and composition, even at the phylum level. The fecal short-chain fatty acid content was also higher in groups that were administered with the potential probiotic strains. Analysis of the fecal water-soluble metabolites revealed that administration of L. plantarum DR7 and L. reuteri 8513d led to higher fecal content of compounds related to amino acid metabolism such as tryptophan, leucine, tyrosine, cysteine, methionine, valine, and lysine; while administration of L. fermentum DR9 led to higher prevalence of compounds related to carbohydrate metabolism such as erythritol, xylitol, and arabitol. In conclusion, it was observed that different strains of lactobacilli can cause difference alteration in the gut microbiota and the metabolites, suggesting the urgency to explore the specific metabolic impact of specific strains on the host. [ABSTRACT FROM AUTHOR]

Objecfive: Constructing the specific overexpression of Nmnat gene in the heart of fruit flies using UAS/ hand-gal4 system to study the effect of the overexpression of Nmnat gene in the heart combined with endurance exercise on lipid toxicity induced by high-fat diet, and to analyze the molecular mechanism. Methods: Male w1118 and Nmnat-UAS fruit flies were respectively hybridized with female hand-gal4. Collecting the normal expression of heart Nmnat (hand>w1118) and the overexpression (hand>Nmnat) of F1 generation female flies. After feeding for 15 days, they began to perform endurance exercise (E) and high-fat diet (HFD). They were divided into hand>w1118, hand>w1118+E, hand>w1118+HFD. hand>w1118+HFD+E, hand>Nmnat, hand>Nmnat +E, hand>Nmnat+HFD, hand>Nmnat+HFD+E, 410 flies in each group. The levels of cardiac TAG, NAD+, SIR2 protein deacetylation, SOD activity and MDA were detected by ELISA. The expression of cardiac related genes by RT-PCR; M-mode detects cardiac function. Results: the expression of Nmnat, dFoxo, bmm, NAD+ level, SIR2 deacetylation, SOD activity and shortened fraction of hand>w1118+HFD+E group were significantly higher than that of hand>w1118+HFD group (P<0.05 or P<0.01), but the expression of dFAS, Col4al, TAG and MDA level, heart rate and fibrillation were significantly lower than that of hand>w"18+HFD group (P<0.05 or P<0.01). There was no significant difference between the heart hand>Nmnat group and hand>Nmnat+HFD group (P>0.05). The expression of Nmnat, dFoxo, bmm, NAD+, SIR2 deacetylation, SOD activity and shortened heart fraction in the hand>Nmnat+HFD+E group were significantly higher than those in the hand>Nmnat+HFD group (P<0.05 or P<0.01), but the expression of dFAS, Col4al, TAG and MDA levels, heart rate and fibrillation were significantly lower than those in the hand>Nmnat+HFD group (P<0.05 or P<0.01). Conclusion: both overexpression of cardiac Nmnat and endurance exercise can prevent excessive accumulation of cardiac lipids, oxidative damage, decreased cardiac contractility and increased fibrillation induced by high-fat diet. The molecular mechanism is related to the fact that both of them can up-regulate the activity of cardiac Nm-nat/NAD+/SIR2/dFoxo pathway. The overexpression of cardiac Nmnat gene combined with endurance exercise can better reduce the occurrence of lipid toxic cardiomyopathy, which is related to the superposition effect of the combination on the up-regulation of cardiac Nmnat/NAD+/SIR2/dFoxo pathway activity. [ABSTRACT FROM AUTHOR]

The aim of this study is to investigate whether exercise can reverse some of the adverse effects of high-fat-diet-induced obesity on lipid metabolism and bone biomechanical properties. A total of 26 adult male C57bl/6J mice were randomly assigned into three groups: (A) Control group (n=6), (B) High-fat diet group (n=10), (C) High-fat diet and exercise group (n=10). Body mass and relevant biochemical parameters were measured for the duration of the experimental protocol (37 weeks). Mechanical strength of both femurs of each animal was assessed in-vitro based on three point bending tests. It was re¬vealed that exposure to high-fat diet led to significant increase of body mass and cholesterol levels and also to substantial changes in bone mor-phology and strength. Ultimate stress for the animals exposed to high-fat diet and those exposed to high-fat-diet and exercise was 25% and 24% lower compared to control, respectively. Exercise increased bone thickness by 15% compared to animals that were not exposed to exer¬cise. It was concluded that high-fat-diet ap¬pears to have a detrimental effect on bone biomechanics and strength. Exer¬cise reversed the reduction in bone thickness that appears to be induced by high-fat diet. However no statistically significant increase in bone strength was observed.

BackgroundHigh-fat-diet (HFD) is associated with chronic low-grade inflammation. P2X7 purinergic receptors (P2X7R) are key regulators of inflammasome activation. The benefits of exercise are partly attributed to its anti-inflammatory effect, but whether it regulates P2X7R expression to improve remodeling in cardiac myocytes treated by HFD is not completely clarified.MethodsThree groups of Sprague-Dawley (SD) rats were studied: (1) control group (fed a normal chow diet), (2) HFD group, and (3) HFD+ exercise group. H9c2 myocytes were pretreated with or without A438079 (a P2X7R inhibitor) and then exposed to 200 μM palmitic acid (PA) for 24 h. The levels of mRNA and protein were measured by real-time PCR and Western blot, respectively. Masson staining and hematoxylin-eosin (HE) staining were used to identify remodeling of the heart. The concentration of IL-1β in serum or supernatants were measured by ELISA.ResultsIn vivo, collagen deposition and the number of disordered cells significantly increased in the hearts of the HFD group compared to the control group. However, exercise markedly reversed these changes in the myocardium, and the same trends were observed in the expression of MMP9, collagen I and TGF-β. Notably, the expression of P2X7R, NLRP3, caspase-1 in the hearts, and serum IL-1β level were also greatly upregulated in the heart of the HFD diet rats, and all these changes were ameliorated in the HFD + EX group. As expected, exercise also reduced the number of TUNEL-positive cells, which was consistent with the caspase-3, Bax, and Bcl-2 results. Moreover, exercise reduced body weight and blood lipid concentrations in the HFD diet rats. In vitro, we observed that the hallmark of fibrosis, inflammation and apoptosis in H9c2 myocytes enhanced by PA, and the P2X7R inhibitor treatment significantly reduced the expression of the NLRP3, caspase-1, suppressed the secretion of IL-1β of H9c2 cells, inhibited collagen I, TGF-β, MMP9, Bax, caspase-3 levels and increased the expression of Bcl-2, compared with the PA group. In addition, a decrease of the number of TUNEL-positive cells used by A438079 further support that cardiomyocytes apoptosis could be inhibited.ConclusionAerobic exercise reversed the cardiac remodeling via the reduction of inflammation, fibrosis and apoptosis in HFD rats, at least in part through inhibiting P2X7R expression in cardiomyocytes.

Diabetic nephropathy (DN) is a crucial metabolic health problem. The renin-angiotensin system (RAS) is well known to play an important role in DN. Abnormal RAS activity can cause the over-accumulation of angiotensin II (Ang II). Angiotensin-converting enzyme inhibitor (ACEI) administration has been proposed as a therapy, but previous studies have also indicated that chymase, the enzyme that hydrolyzes angiotensin I to Ang II in an ACE-independent pathway, may play an important role in the progression of DN. Therefore, this study established a model of severe DN progression in a db/db and ACE2 KO mouse model (db and ACE2 double-gene-knockout mice) to explore the roles of RAS factors in DNA and changes in their activity after short-term (only 4 weeks) feeding of a high-fat diet (HFD) to 8-week-old mice. The results indicate that FD-fed db/db and ACE2 KO mice fed an HFD represent a good model for investigating the role of RAS in DN. An HFD promotes the activation of MAPK, including p-JNK and p-p38, as well as the RAS signaling pathway, leading to renal damage in mice. Blocking Ang II/AT1R could alleviate the progression of DN after administration of ACEI or chymase inhibitor (CI). Both ACE and chymase are highly involved in Ang II generation in HFD-induced DN; therefore, ACEI and CI are potential treatments for DN.

The effects of coffee ( Coffea arabica L.) berry pulp extracts (CBP extracts) on the improvement of diabetes, obesity, and non-alcoholic fatty liver disease (NAFLD) were evaluated using various in vitro antioxidant activity assays and through a high-fat diet-induced mild diabetic obese mouse model. After an 84-day oral administration of CBP extracts (400-100 mg/kg), bioactivities were evaluated. The in vitro analysis showed the highest DPPH ● scavenging activity of 73.10 ± 4.27%, ABTS ● scavenging activity of 41.18 ± 1.14%, and SOD activity of 56.24 ± 2.81%, at a CBP extract concentration of 1000 µg/mL. The in vivo analysis of the CBP extracts showed favorable and dose-dependent anti-obesity, anti-diabetic, NAFLD, nephropathy, and hyperlipidemia refinement effects through hepatic glucose enzyme activity, 5'-AMP-activated protein kinase (AMPK) up-regulation, antioxidant activity, lipid metabolism-related gene expression, and pancreatic lipid digestion enzyme modulatory activities. This study shows that an appropriate oral dosage of CBP extracts could function as a potent herbal formulation for a refinement agent or medicinal food ingredient to control type 2 diabetes and related complications.

Background: High-fat-diet (HFD) is associated with chronic low-grade inflammation. P2X7 purinergic receptors (P2X7R) are key regulators of inflammasome activation. The benefits of exercise are partly attributed to its anti-inflammatory effect, but whether it regulates P2X7R expression to improve remodeling in cardiac myocytes treated by HFD is not completely clarified. Methods: Three groups of Sprague-Dawley (SD) rats were studied: (1) control group (fed a normal chow diet), (2) HFD group, and (3) HFD+ exercise group. H9c2 myocytes were pretreated with or without A438079 (a P2X7R inhibitor) and then exposed to 200 μM palmitic acid (PA) for 24 h. The levels of mRNA and protein were measured by real-time PCR and Western blot, respectively. Masson staining and hematoxylin-eosin (HE) staining were used to identify remodeling of the heart. The concentration of IL-1β in serum or supernatants were measured by ELISA. Results: In vivo , collagen deposition and the number of disordered cells significantly increased in the hearts of the HFD group compared to the control group. However, exercise markedly reversed these changes in the myocardium, and the same trends were observed in the expression of MMP9, collagen I and TGF-β. Notably, the expression of P2X7R, NLRP3, caspase-1 in the hearts, and serum IL-1β level were also greatly upregulated in the heart of the HFD diet rats, and all these changes were ameliorated in the HFD + EX group. As expected, exercise also reduced the number of TUNEL-positive cells, which was consistent with the caspase-3, Bax, and Bcl-2 results. Moreover, exercise reduced body weight and blood lipid concentrations in the HFD diet rats. In vitro , we observed that the hallmark of fibrosis, inflammation and apoptosis in H9c2 myocytes enhanced by PA, and the P2X7R inhibitor treatment significantly reduced the expression of the NLRP3, caspase-1, suppressed the secretion of IL-1β of H9c2 cells, inhibited collagen I, TGF-β, MMP9, Bax, caspase-3 levels and increased the expression of Bcl-2, compared with the PA group. In addition, a decrease of the number of TUNEL-positive cells used by A438079 further support that cardiomyocytes apoptosis could be inhibited. Conclusion: Aerobic exercise reversed the cardiac remodeling via the reduction of inflammation, fibrosis and apoptosis in HFD rats, at least in part through inhibiting P2X7R expression in cardiomyocytes. [ABSTRACT FROM AUTHOR]

Objective: The aims of this study were to investigate the adverse effects of the high-fat-diet (HFD) on the testosterone level and testicular structure of male rats as well as to examine whether Eurycoma Longifolia (EL) is able to ameliorate these effects. Methods: Twenty-four male Sprague-Dawley (SD) rats were divided into four groups each containing 6 rats. Group ND was given only normal diet, group NDEL was given normal diet and EL extracts (15 mg/kg) dissolved in distilled water, group HFD was given only high-fat-diet and group HFDEL was given high-fat-diet and EL extracts (15 mg/kg). EL was administered orally for 12 weeks. The animal's testosterone level was measured at week 0, 6 and 12. The rats were sacrificed at the end of 12th weeks and the testes samples were processed for histological examination Results: The testosterone level was significantly increased (p < 0.05) in the in the treated rats with EL (NDEL and HFDEL) compared with ND and HFD groups. Treatment with HFD revealed a marked degeneration of the seminiferous tubule epithelium and disruption of interstitial cells of the testis thereby interfering with spermatogenesis. Treatment of HFD rats with El reduced the adverse effects of HFD and improved the morphological structure of the seminiferous tubules. Conclusion: These findings revealed that EL has ameliorative effects against the testicular damage caused by high-fat-diet. [ABSTRACT FROM AUTHOR]

Biological exploration of early biomarkers for chronic kidney disease (CKD) in (pre)diabetic individuals is crucial for personalized management of diabetes. Here, we evaluated two candidate biomarkers of incident CKD (sphingomyelin (SM) C18:1 and phosphatidylcholine diacyl (PC aa) C38:0) concerning kidney function in hyperglycemic participants of the Cooperative Health Research in the Region of Augsburg (KORA) cohort, and in two biofluids and six organs of leptin receptor-deficient (db/db) mice and wild type controls. Higher serum concentrations of SM C18:1 and PC aa C38:0 in hyperglycemic individuals were found to be associated with lower estimated glomerular filtration rate (eGFR) and higher odds of CKD. In db/db mice, both metabolites had a significantly lower concentration in urine and adipose tissue, but higher in the lungs. Additionally, db/db mice had significantly higher SM C18:1 levels in plasma and liver, and PC aa C38:0 in adrenal glands. This cross-sectional human study confirms that SM C18:1 and PC aa C38:0 associate with kidney dysfunction in pre(diabetic) individuals, and the animal study suggests a potential implication of liver, lungs, adrenal glands, and visceral fat in their systemic regulation. Our results support further validation of the two phospholipids as early biomarkers of renal disease in patients with (pre)diabetes.

Due to the demonstrated intestinal microbial transformation of strawberry ellagitannins (ET) into bioactive metabolites, in the current study on rats, we hypothesised that the dietary addition of a strawberry ET-rich extract (S-ET) to a high-fat diet (HFD) would attenuate disturbances in the redox and lipid status as well as in the inflammatory response. We randomly distributed 48 Wistar rats into six groups and used two-way analysis of variance (ANOVA) to assess the effects of two main factors—diet type (standard and high-fat) and ET dosage (without, low, and 3× higher)—applied to rats for 4 weeks. In relation to the hypothesis, irrespective of the dosage, the dietary application of ET resulted in the desired attenuating effects in rats fed a HFD as manifested by decreased body weight gain, relative mass of the epididymal pad, hepatic fat, oxidized glutathione (GSSG), triglycerides (TG), total cholesterol (TC), and thiobarbituric acid-reactive substances (TBARS) concentrations as well as desired modifications in the blood plasma parameters. These beneficial changes were enhanced by the high dietary addition of ET, which was associated with considerably higher concentrations of ET metabolites in the urine and plasma of rats. The results indicated that S-ET could be effectively used for the prevention and treatment of metabolic disturbances associated with obesity, dyslipidaemia, redox status imbalance, and inflammation.

Background/Aims: Nonalcoholic steatohepatitis (NASH) is defined as lipid accumulation with hepatic injury, inflammation and early to moderate fibrosis. Kupffer cells play a crucial role in promoting hepatic inflammation, which further facilitates the development of NASH. Here we investigated the effects of Cangju Qinggan Jiangzhi decoction (CQJD) on high fat diet (HFD) and methionine-choline deficient (MCD) induced mouse NASH pathogenesis. Methods: Mouse NASH models were developed by HFD and MCD diet. The treated mice were divided into three groups: the control group (n = 10), the low-dose CQJD treatment group (n = 10) and the high-dose CQJD treatment group (n = 10). The hepatic injury, inflammation, and apoptotic molecules were evaluated by H&E staining, immunohistochemistry and real-time PCR. Kupffer cells were isolated from control mice and CQJD-treated mice after stimulation by lipopolysaccharide (LPS) and/or palmitic acid. The level of the inflammatory cytokines TNFα, IL1β, and CCL2 was measured by ELISA. Results: The HFD-fed mice displayed significant metabolic, inflammatory, and oxidative stress-related alterations due to hepatic lipid accumulation. CQJD treatment largely normalized the hepatic injury, lowered the ALT/AST level, and reduced the severity of liver inflammation, as revealed by the decreased inflammatory cytokines levels. In vitro, CQJD blocked the activation of LPS- or palmitic acid-primed Kupffer cells in a dose-dependent manner. In the MCD diet-induced NASH mice, similar therapeutic effects of CQJD were also observed. Conclusion: CQJD ameliorates mouse nonalcoholic steatohepatitis. The reduction in liver injury and inflammation induced by CQJD is associated with reduced activation of Kupffer cells. Our results suggest that CQJD is a promising therapeutic strategy in clinical steatohepatitis. [ABSTRACT FROM AUTHOR]

Human obesity and overweight, caused by accumulated of fat, is the most commonly phenomenon from all over the world, especially in Western countries and Chinese mainland during the past three decades. Sodium Alginate, a polysaccharide extracted from brown seaweeds, has been proved its strong ability on body weight loss and anti-inflammatory response. However, no studies have been explored the effects of Sodium Alginate on colonic transcriptome, especially in obese individuals. Therefore, the current study was designed to detect whether Sodium Alginate could remit obesity and ease chronic metabolism disease through strengthening the bio-functionality of the lower intestine, particularly in colon. The data showed after Sodium Alginate gavaged for four weeks, the body weight, fat accumulation, triglyceride and total cholesterol were ameliorated in high fat diet induced obese mice. Sodium Alginate also improved the blood glucose level and lipopolysaccharides in serum. Furthermore, data from RNA sequence indicated that there were significantly changes in several genes, which involved in lipid metabolism and carbohydrate metabolism. In conclusion, these results suggested that Sodium Alginate could effectively suppress obesity and obesity related metabolic syndromes, due to the colonic transcriptome changes. [ABSTRACT FROM AUTHOR]

• Casein/cyanidin-3-O-glucoside nanoparticles (Cs-C3G) are prepared. • Cs-C3G can inhibit the fat accumulation in vivo. • Cs-C3G can inhibit oxidative stress in HFD mice. • Cs-C3G can restore the abundance and diversity of gut microbiota. This study aims to investigate the dietary intervention effect of casein/cyanidin-3-O-glucoside nanoparticles (Cs-C3G) on high-fat-diet (HFD)induced gut microbiota disorders. In HFD-fed C57BL/6mice, Cs-C3G has ameliorated HFD-caused fat accumulation and liver oxidative stress. Cs-C3G as a dietary supplementation can restore the abundance and diversity of gut microbiota with descending the ratio of Firmicutes to Bacteroidetes , increasing some beneficial microorganisms, and reducing some opportunistic pathogenic bacteria. In general, Cs-C3G has a effect on regulating the disturbance of gut microbiota, and then prevents HFD-induced obesity and liver damage. [ABSTRACT FROM AUTHOR]

Objective: Aging causes chronic, low-grade inflammation in a manner similar to a high-fat diet (HFD). Understanding how inflammation due to diet and drug treatments contributes to the neuronal changes in the aging brain and determining whether drugs can reverse the adverse effects are the main aims of this study. This study will provide evidence as to how the aged versus young brain responds to neuroinflammation as well as possible therapeutic targets. Methods: Three different 6-weeks HFD feeding regimens, intermittent fasting (IF), ad libitum (AL), and overfeeding (OF), as well as 1-hour copper sulfate (proinflammatory drug) and 3-hour rapamycin (anti-inflammatory drug) treatments were applied to wild-type zebrafish. Fifty-seven young (9 months) and sixty old (24-27 months) fish were maintained in standard conditions for all treatments. Body weight and length were measured, and the comparison was performed with oneway between-subject ANOVA. Brain protein levels of markers of mammalian-target-of-rapamycin (mTOR), phosphorylatedmTOR (p-mTOR), Tumor-Necrosis-Factor-α (TNF-a), proliferating-cell-nuclear-antigen (PCNA), doublecortin-likekinase-1 (DCAMKL1) and glial-fibrillary-acidic-protein (GFAP) were measured using Western-Blot analysis. Data were analyzed with two-way ANOVA followed by post hoc analysis using a Bonferroni Correction. Results: Our results demonstrated significant increases in the body mass index (BMI) between young animals fed with OF and IF (p=<.01), as well as OF and AL (p=<.001). However, in the old group, the significant differences were between OF and IF (p =<.01), as well as AL and IF (p=<.001) fish. Protein levels of p-mTOR indicated a significant increase in old-OF compared to young-OF (p=.04). TNF-a levels showed a main effect of aging (p=.002), especially in non-treated OF groups (p=.04) and AL groups (p=.007), as well as the copper sulfate-treated IF groups (p=.04). Analysis of protein levels of relevant markers indicates statistically significant differences in response to diet and drug treatment in and between both age groups. Conclusion: HFD feeding with various regimens caused significant BMI changes in both young and old zebrafish; preliminary data suggest that both dietary and drug treatments affect the expression levels of proteins of interest in an expected manner. Taken together, these results indicate that diets and drug treatments modulate inflammation. [ABSTRACT FROM AUTHOR]

The aim of the present work was to improve our knowledge on the mechanisms underlying the beneficial or deleterious effects on testicular function of the so-called Mediterranean and Western diet by analyzing glutamyl aminopeptidase (GluAP), gamma glutamyl transpeptidase (GGT) and dipeptidyl peptidase IV (DPP IV) activities in testis, as enzymes involved in testicular function. MaleWistar rats (6 months old) were fed for 24 weeks with three different diets: standard (S), an S diet supplemented with virgin-olive-oil (20%) (VOO), or a S diet enriched with butter (20%) plus cholesterol (0.1%) (Bch). At the end of the experimental period, plasma lipid profiled (total triglycerides, total cholesterol and cholesterol fractions (HDL, LDL and VDL)) were measured. Enzymatic activities were determined by fluorimetric methods in soluble (sol) and membrane-bound (mb) fractions of testicular tissue using arylamide derivatives as substrates. Results indicated an increase in plasmatic triglycerides, total cholesterol, LDL and VLDL in Bch. A significant increase of mb GluAP and GGT activities was also found in this diet in comparison with the other two diets. Furthermore, significant and positive correlations were established between these activities and plasma triglycerides and/or total cholesterol. These results support a role for testicular GluAP and GGT activities in the effects of saturated fat (Western diet) on testicular functions. In contrast, VOO increased sol DPP IV activity in comparison with the other two diets, which support a role for this activity in the effects of monounsaturated fat (Mediterranean diet) on testicular function. The present results strongly support the influence of fatty acids and cholesterol on testicular GluAP and GGT activities and also provide support that the reported beneficial influence of the Mediterranean diet in male fertility may be mediated in part by an increase of testicular sol DPP IV activity. [ABSTRACT FROM AUTHOR]

The aim of this study is to investigate whether exercise can reverse some of the adverse effects of high-fat-diet-induced obesity on lipid metabolism and bone biomechanical properties. A total of 26 adult male C57bl/6J mice were randomly assigned into three groups: (A) Control group (n=6), (B) High-fat diet group (n=10), (C) High-fat diet and exercise group (n=10). Body mass and relevant biochemical parameters were measured for the duration of the experimental protocol (37 weeks). Mechanical strength of both femurs of each animal was assessed in-vitro based on three point bending tests. It was revealed that exposure to high-fat diet led to significant increase of body mass and cholesterol levels and also to substantial changes in bone morphology and strength. Ultimate stress for the animals exposed to high-fat diet and those exposed to high-fat-diet and exercise was 25% and 24% lower compared to control, respectively. Exercise increased bone thickness by 15% compared to animals that were not exposed to exercise. It was concluded that high-fat-diet appears to have a detrimental effect on bone biomechanics and strength. Exercise reversed the reduction in bone thickness that appears to be induced by high-fat diet. However no statistically significant increase in bone strength was observed. [ABSTRACT FROM AUTHOR]

Obesity and metabolic disorders are threats to human health. Extracellular matrix (ECM) is an important member of adipose microenvironment. ECM remodeling contributes to obesity and insulin resistance, but the roles of every single ECM component is still not fully understood. We observed glucose and lipids metabolic disorders in high-fat diet (HFD)-fed mice and humans with obesity. Higher levels of inflammatory factors and hormones existed in serum of HFD-fed mice. Multiple collagens, laminins, fibronectin, nidogen, and Hspg2 were upregulated in obese white adipose tissue (WAT) from mice and humans. These effects were stronger in subcutaneous WAT than visceral WAT in mice, but the fat depot difference was reversed in humans. The ECM structure and the morphology of adipocytes seeded on ECM were changed in the HFD group. In human visceral WAT, ECM genes showed positive correlations with blood lipids and glucose. In vitro, collagen I/IV and LAMA4 proteins showed similar changes with C/EBPα during the differentiation of adipocytes. Macromolecular crowders (MMC) promoted partial collagen and non-collagen gene expression. Oleic acid (OA) and MMC upregulated collagen I/IV and LAMA4 proteins, and the effects of MMC were stronger than that of OA. Moreover, MMC promoted the differentiation of adipocytes, but OA increased the size of lipid droplets. Positive correlations were observed between ECM genes and adipogenesis-related genes in adipocytes. In conclusion, some obesogens (such as HFD) induce ECM remodeling, and the upregulation of ECM components is closely related to adipogenesis, suggesting that adipose ECM deposition is an indicator of obesity and metabolic disorders. [ABSTRACT FROM AUTHOR]

[Display omitted] • Inulin supplementation could alleviate high-fat diet-induced hepatic steatosis, mediated through increasing ATGL on liver lipid droplets. • The beneficial effects of inulin, such as increasing energy expenditure, alleviating adiposity, and improving glucose intolerance, could only be achieved in mice fed with high-fat diet for 1 month, not for 4 months. • Gut microbiota in the short- and long-term fat-loaded mice was shown to be modulated in a different way, which may mediate the differential effects of inulin. Increased consumption of high-fat low-fiber foods has been shown to contribute to the development of metabolic syndromes, such as fatty liver, obesity, diabetes, et al. Fermentable dietary fiber, such as inulin, is broadly used to mitigate host metabolic abnormalities. In this work, we studied systematically the effect of inulin on mice with metabolic disorders, induced by either short- or long-term high-fat feeding. As expected, inulin reduced the body weight of mice in both groups. However, it was found that inulin feeding could only increase energy expenditure, alleviate adiposity, and improve glucose intolerance in mice fed with high-fat diet (HFD) for 1 month but not for 4 months. Surprisingly, inulin supplementation could alleviate HFD-induced hepatic steatosis, mediated through increasing adipose triglyceride lipase (ATGL) on liver lipid droplets, in both groups. Gut microbiota in the short- and long-term fat-loaded mice were shown to be modulated differently, which may mediate the differential effects of inulin. These results may help in understanding the role and mechanism of fermentable fiber regulating host metabolism. [ABSTRACT FROM AUTHOR]