High-fat Diet-induced Obesity Research Articles

Glycogen synthesis is required for adaptive thermogenesis in beige adipose tissue and affects diet-induced obesity.

Glycogen is a form of energy storage for glucose in different tissues such as liver and skeletal muscle. It remains incompletely understood how glycogen impacts on adipose tissue functionality. Cold exposure elevated the expression of Gys1 that encodes glycogen synthase 1 in brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT). The in vivo function of Gys1 was analyzed using a mouse model in which Gys1 was deleted specifically in adipose tissues. Under normal chow conditions, Gys1 deletion caused little changes to body weight and glucose metabolism. Deletion of Gys1 abrogated upregulation of UCP1 and other thermogenesis-related genes in iWAT upon prolonged cold exposure or treatment with β3-adrenergic receptor agonist CL-316,243. Stimulation of UCP1 by CL-316,243 in adipose-derived stromal cells (stromal vascular fractions, SVFs) was also reduced by Gys1 deletion. Both the basal glycogen content and CL-316,243-stimulated glycogen accumulation in adipose tissues were reduced by Gys1 deletion. High-fat diet-induced obesity and insulin resistance were aggravated in Gys1-deleted mice. The loss of body weight upon CL-316,243 treatment was also abrogated by the loss of Gys1. In conclusion, our results underscore the pivotal role of glycogen synthesis in adaptive thermogenesis in beige adipose tissue and its impact on diet-induced obesity in mice.NEW & NOTEWORTHY Glycogen is one of major types of fuel reserve in the body and its classical function is to maintain blood glucose level. This study uncovers that glycogen synthesis is required for beige fat tissue to generate heat upon cold exposure. Such a function of glycogen is linked to development of high-fat diet-induced obesity, thus extending our understanding about the physiological functions of glycogen.

High temperature ameliorates high-fat diet-induced obesity by promoting ceramide breakdown in skeletal muscle tissue

Abstract Obesity is considered an epidemic often accompanied by insulin resistance (IR). Heat treatment (HT) has been shown to prevent high-fat diet-induced IR in skeletal muscle, but the underlying mechanisms are poorly understood. In this study, we discovered that high temperature alleviated the hallmarks of obesity by promoting glycogen synthesis and lowering blood glucose levels in skeletal muscle tissue (SMT). Additionally, HT maintained the decay phase of heat shock factor 1 (HSF1), leading to the activation of gene expression of heat shock proteins (HSPs), which contributed to the alleviation of IR in SMT of diet-induced obese (DIO) mice. Metabolomics and lipidomics analyses showed that HT promoted ceramide (Cer) breakdown, resulting in an elevation of both sphingomyelin (SM) and sphingosine, which further contributed to the amelioration of IR in SMT of DIO mice. Importantly, the increase in sphingosine was attributed to the heightened expression of the acid ceramidase N-acylsphingosine amidohydrolase 1 (ASAH1), and the inhibition of ASAH1 attenuated HT-relieved IR in SMT of DIO mice. Surprisingly, high temperature increased the composition of Cer and cholesteryl ester in lipid droplets of skeletal muscle cells. This not only helped alleviate IR but also prevented lipotoxicity in SMT of DIO mice. These findings revealed a previously unknown connection between a high-temperature environment and sphingolipid metabolism in obesity, suggesting that high temperature can improve IR by promoting Cer catabolism in SMT of obese mice.

Oral supplementation of Njansan (Ricinodendron heudelotii Bail) and sardine fillets (Sardina pilchardus) oils alleviate high-fat diet-induced obesity in rats by regulating lipid metabolism and stress oxidative parameters

Background: Obesity has become one of the most common metabolic disorders in the world, characterized by the accumulation of excess fat in the body. Research into natural compounds to improve obesity has become increasingly important. Aims and Objectives: The aim of the study was to explore the effects of Sardina pilchardus and Ricinodendron heudelotii oils on the management of obesity. Materials and Methods: Njansan (R. heudelotii) oil was extracted by cold pressing using an automatic oil press machine and Sardine fish oil by a cooking method. To evaluate the anti-obesity effect of these oils, six groups of six male Wistar rats were fed different diets: C0 group received a normal diet; HFD was fed a high-fat diet; N1, N2, F1 and F2 followed by a high-fat diet supplemented with njansan and sardine oils at 1 g/kg body weight/day and 2 g/kg body weight/day, respectively. Results: There was an increase in body weight, relative abdominal fat, and liver weight in the HFD group compared to the control group. There was also a decrease in anthropometric parameters such as the Lee index of the HFD group treated with njansan and fish oils, regardless of the concentration. The hyperlipidemic state in the HFD-fed rats was then normalized after treatment with both oils as well as hyperglycemia compared to the control group. Besides, fish and njansan oils attenuated HFD-induced oxidative stress, as indicated by a significant increase CA and superoxide dismutase. Conclusion: This study demonstrated that njansan oils at a low daily dose (1 g/kg body weight) can be helpful in managing obesity and also reduce the risk of developing coronary heart diseases.

Abstract 2190: Transcriptomic signatures of obesity-driven colon cancer: A multi-species transdisciplinary approach

Abstract Obesity is a highly prevalent metabolic disease and an established risk factor for colon cancer. However, critical biological pathways underpinning this relationship remain undetermined. Herein, we integrate human and murine colon tumor transcriptomic data to identify obesity-responsive pathways conserved between species. Human colon cancer samples (n=155) were collected as part of the clinical ColoCare Study, a prospective cohort study of patients newly diagnosed with colorectal cancer. Enrolled patients were diagnosed with stage I-III colon cancer and treatment naïve at time of tissue collection. Patients were classified as having a BMI <30 kg/m2 (i.e., non-obese) or BMI ≥30 kg/m2 (i.e., obese) at baseline. Age, sex, tumor stage, and collection site were adjusted for in all analyses. Patients were 63.3 ± 13.7 years, 51% male, and 34% had a BMI ≥30. C57BL/6J adult female mice were fed a low-fat control diet (Research Diets D12450J, n= 8) or a high-fat diet-induced obesity regimen (D12492, n=7) for ~23 weeks, at which time 700 Apc-null;KrasG12D/+;Trp53-null;Smad4-null;tdTomato (i.e., AKPS) organoids were orthotopically transplanted into the colonic submucosa via colonoscopy-guided injection. Obese mice weighed more than controls (controls 26.4 ± 3.7 g vs. DIO 45.9 ± 9.7 g) and had more mesenteric fat surrounding the colon (controls 201 ± 143 mg vs. 1176 ± 589 mg). Tumors were excised after 4 weeks of growth. RNA was extracted from bulk human tumor samples and from the epithelial-enriched EpCAM+ cell population in murine tumor samples for RNA sequencing. Genes differentially expressed between the reference and obese groups were identified using DESeq2. For gene set enrichment analysis, genes were preranked by log2 fold change for both human and mouse datasets. There were 76 and 132 differentially expressed genes (DEGs; FDRq<0.10) identified in the human and mouse datasets, respectively. None of these 208 DEGs were common to both datasets. Thirty-five Hallmark gene sets in the human dataset and 25 Hallmark gene sets in the mouse dataset were significantly enriched in the obese group; 18 of these gene sets were common to both mouse and human datasets. These overlapping pathways were largely related to inflammation (e.g., inflammatory response, IL6 JAK STAT3 signaling, TNFɑ signaling) and metabolism (e.g., cholesterol homeostasis, glycolysis, and fatty acid metabolism). Additional analysis revealed 204 genes common between the leading edges of both transcriptomic datasets. These transdisciplinary data suggest that obesity induces a set of metabolic and inflammatory processes and/or pathways in colon tumors which is conserved between mice and humans. Future studies will mechanistically evaluate the role of candidate genes and pathways in obesity-associated colorectal carcinogenesis in our AKPS orthotopic organoid transplant mouse model. Citation Format: Elaine M. Glenny, Tengda Lin, Victoria M. Bandera, Biljana Gigic, Aik Choon Tan, Babak Mirminachi, Saratchandra S. Khumukcham, Alessandro Carpanese, Christy A. Warby, Olena Aksonova, Caroline Himbert, Jennifer Ose, Chris Stubben, David Nix, Kenneth Boucher, Peter Schirmacher, Ildiko Strehli, Jolanta Jedrzkiewicz, Alexander Brobeil, Martin A. Schneider, Christoph Kahlert, Erin M. Siegel, Adetunji T. Toriola, David Shibata, Christopher I. Li, Jane C. Figueiredo, Jatin Roper, Cornelia M. Ulrich, Stephen D. Hursting. Transcriptomic signatures of obesity-driven colon cancer: A multi-species transdisciplinary approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2190.

Inhibition of the RPS6KA1/FoxO1 signaling axis by hydroxycitric acid attenuates HFD-induced obesity through MCE suppression

BackgroundBecause obesity is associated with a hyperplasia-mediated increase in adipose tissue, inhibiting cell proliferation during mitotic clonal expansion (MCE) is a leading strategy for preventing obesity. Although (–)-hydroxycitric acid (HCA) is used to control obesity, the molecular mechanisms underlying its effects on MCE are poorly understood. PurposeThis study aimed to investigate the potential effects of HCA on MCE and underlying molecular mechanisms affecting adipogenesis and obesity improvements. MethodsPreadipocyte cell line, 3T3-L1, were treated with HCA; oil red O, cell proliferation, cell cycle, and related alterations in signaling pathways were examined. High-fat diet (HFD)-fed mice were administered HCA for 12 weeks; body and adipose tissues weights were evaluated, and the regulation of signaling pathways in epidydimal white adipose tissue were examined in vivo. ResultsHere, we report that during MCE, HCA attenuates the proliferation of the preadipocyte cell line, 3T3-L1, by arresting the cell cycle at the G0/G1 phase. In addition, HCA markedly inhibits Forkhead Box O1 (FoxO1) phosphorylation, thereby inducing the expression of cyclin-dependent kinase inhibitor 1B and suppressing the levels of cyclin-dependent kinase 2, cyclin E1, proliferating cell nuclear antigen, and phosphorylated retinoblastoma. Importantly, we found that ribosomal protein S6 kinase A1 (RPS6KA1) influences HCA-mediated inactivation of FoxO1 and its nuclear exclusion. An animal model of obesity revealed that HCA reduced high-fat diet-induced obesity by suppressing adipocyte numbers as well as epididymal and mesenteric white adipose tissue mass, which is attributed to the regulation of RPS6KA1, FoxO1, CDKN1B and PCNA that had been consistently identified in vitro. ConclusionsThese findings provide novel insights into the mechanism by which HCA regulates adipogenesis and highlight the RPS6KA1/FoxO1 signaling axis as a therapeutic target for obesity.

Roles of fibroblast growth factors in the treatment of diabetes.

Diabetes affects about 422 million people worldwide, causing 1.5 million deaths each year. However, the incidence of diabetes is increasing, including several types of diabetes. Type 1 diabetes (5%-10% of diabetic cases) and type 2 diabetes (90%-95% of diabetic cases) are the main types of diabetes in the clinic. Accumulating evidence shows that the fibroblast growth factor (FGF) family plays important roles in many metabolic disorders, including type 1 and type 2 diabetes. FGF consists of 23 family members (FGF-1-23) in humans. Here, we review current findings of FGFs in the treatment of diabetes and management of diabetic complications. Some FGFs (e.g., FGF-15, FGF-19, and FGF-21) have been broadly investigated in preclinical studies for the diagnosis and treatment of diabetes, and their therapeutic roles in diabetes are currently under investigation in clinical trials. Overall, the roles of FGFs in diabetes and diabetic complications are involved in numerous processes. First, FGF intervention can prevent high-fat diet-induced obesity and insulin resistance and reduce the levels of fasting blood glucose and triglycerides by regulating lipolysis in adipose tissues and hepatic glucose production. Second, modulation of FGF expression can inhibit renal and cardiac fibrosis by regulating the expression of extracellular matrix components, promote diabetic wound healing process and bone repair, and inhibit cancer cell proliferation and migration. Finally, FGFs can regulate the activation of glucose-excited neurons and the expression of thermogenic genes.

Cymbopogon schoenanthus (L) extract ameliorates high fat diet-induced obesity and dyslipidemia via reducing expression of lipogenic and thermogenic proteins

Globally, obesity has become one of the major health problems. This study was conducted to evaluate the anti-obesity potential of Cymbopogon schoenanthus methanolic extract (CS) in rats. Fifty male Wistar rats of six to eight weeks old, 100–120 g body weight (BW) were randomly assigned into 5 groups (n = 10): The control group was fed a basal diet. CS-group was supplied with basal diet and orally given CS (200 mg/kg BW) for 12 weeks. HFD-group was fed a high-fat diet (HFD) for 18 weeks. HFD + CS-group was fed on HFD and CS HFD then CS-group was fed HFD for 12 weeks then shifted to basal diet and CS for another 6 weeks. Phytochemical analysis of CS indicated the presence of various terpenes and flavonoid compounds. Among the compounds characterized are quercetin, apigenin, luteolin, orientin, eudesmene, cymbopogonol, caffeic acid, coumaric acid, and linolenic acid. Supplementation of HFD significantly increased the body weight, levels of serum triacylglycerol, total cholesterol, very low-density lipoprotein, low-density lipo-protein (HDL), glucose, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. In addition, HFD up-regulated the protein expression of uncoupling protein (UCP)-1 in both brown and white adipose tissue; and the expression of hepatic mRNA of sterol regulatory element-binding protein (SREBP)-1c and SREBP-2. However, it decreased the serum level of HDL, and protein expression level of UCP-1 in both brown and white adipose tissue. Treatment of HFD-fed animals with CS extract either concurrently (HFD + CS-group), or after obesity induction (HFD then CS-group) significantly reversed all HFD-induced alterations in body weight; food intake; serum biochemical profile (including hyperglycemia, dyslipidemia); and tissue gene expressions. These results indicate that CS methanolic extract ameliorated HFD-induced obesity, serum biochemical, hepatic, and adipose tissue gene expression alterations. CS extract accomplished these effects mostly through its various identified bioactive compounds which have been proven to have anti-obesity and anti-diabetic activities.

Potential Benefits of Ethanol extract of Anredera cordifolia for Antiobesity of High Fat diet-Induced Obesity in White Male Rat Wistar

تستمر الوفيات المرتبطة بالسمنة في الارتفاع ، لذلك من الضروري إنقاص الوزن لتجنب المضاعفات ، نريديرا كورديفوليا هو نوع من النباتات النضرة من الجنس، باسيللسيا يستخدم على نطاق واسع في طب الأعشاب لتقليل وزن الجسم. تهدف الدراسة الحالية إلى تقييم الفوائد المحتملة لمستخلص الإيثانول من نريديرا كورديفوليا لنماذج الفئران السمنة لتقليل الوزن الناجم عن نظام غذائي عالي الدهون. من خلال تجريب مع اختبارات ما بعد فقد تم تصميم مجموعة ضابطة مع نموذج سمنة 36 جرذًا ، مقسمة إلى مجموعتين: ثلاث مجموعات تحكم (K1 ، K2 ، K3) وثلاث مجموعات معالجة (K1 ، K3 ، K4) (P1 ، P2 ، P3) ، أعطيت جميع مجموعات تحتوي على نسبة عالية من الدهون باستثناء K1 نظام غذائي قياسي ، K2 بدون علاج ، و K3 مع أورليستات. تلقت مجموعة العلاج من مستخلص الإيثانول نريديرا كورديفوليا بجرعات مختلفة ، P1 50 مجم / كجم من وزن الجسم ، P2 100 مجم / كجم من وزن الجسم، و P3 150 مجم / كجم من وزن الجسم. بعد 4 أسابيع من العلاج، قُتلت جميع مجموعات الفئران ، وتم قياس مستويات ERK و PPARγ في الأنسجة الدهنية الحشوية في البطن باستخدام ELISA والكيمياء المناعية. يتم قياس وزن الجسم ومحيط البطن أثناء فحص القياسات، وقد لوحظ فقدان الوزن عند تناول مستخلص الإيثانول نريديرا كورديفوليا بجرعات 100 و 150 مجم / كجم من وزن الجسم، مع انخفاض مستويات ERK و PPAR . يستخدم مستخلص الإيثانول من نريديرا كورديفوليا كمضاد للسمنة. تقلل آلية فقدان الوزن هذه من عامل نسخ PPARγ وتقلل من مستويات ERK بحيث تقل عملية تكوين الدهون.

Metabolic Interaction Between Host and the Gut Microbiota During High-Fat Diet-Induced Colorectal Cancer.

Colorectal cancer (CRC) is the second-highest cause of cancer-associated mortality among both men and women worldwide. One of the risk factors for CRC is obesity, which is correlated with a high-fat diet prevalent in Western dietary habits. The association between an obesogenic high-fat diet and CRC has been established for several decades; however, the mechanisms by which a high-fat diet increases the risk of CRC remain unclear. Recent studies indicate that gut microbiota strongly influence the pathogenesis of both high-fat diet-induced obesity and CRC. The gut microbiota is composed of hundreds of bacterial species, some of which are implicated in CRC. In particular, the expansion of facultative anaerobic Enterobacteriaceae, which is considered a microbial signature of intestinal microbiota functional imbalance (dysbiosis), is associated with both high-fat diet-induced obesity and CRC. Here, we review the interaction between the gut microbiome and its metabolic byproducts in the context of colorectal cancer (CRC) during high-fat diet-induced obesity. In addition, we will cover how a high-fat diet can drive the expansion of genotoxin-producing Escherichia coli by altering intestinal epithelial cell metabolism during gut inflammation conditions.

The hedonic overdrive model best explains high-fat diet-induced obesity in C57BL/6 mice.

High-fat diets cause obesity in male mice; however, the underlying mechanisms remain controversial. Here, three contrasting ideas were assessed: hedonic overdrive, reverse causality, and passive overconsumption models. A total of 12 groups of 20 individually housed 12-week-old C57BL/6 male mice were exposed to 12 high-fat diets with varying fat content from 40% to 80% (by calories), protein content from 5% to 30%, and carbohydrate content from 8.4% to 40%. Body weight and food intake were monitored for 30 days after 7 days at baseline on a standard low-fat diet. After exposure to the diets, energy intake increased first, and body weight followed later. Intake then declined. The peak energy intake was dependent on both dietary protein and carbohydrate, but not the dietary fat and energy density, whereas the rate of decrease in intake was only related to dietary protein. On high-fat diets, the weight of food intake declined, but despite this average reduction of 14.4 g in food intake, they consumed, on average, 357 kJ more energy than at baseline. The hedonic overdrive model fit the data best. The other two models were not supported.

Elevated extracellular matrix protein 1 in circulating extracellular vesicles supports breast cancer progression under obesity conditions

The cargo content in small extracellular vesicles (sEVs) changes under pathological conditions. Our data shows that in obesity, extracellular matrix protein 1 (ECM1) protein levels are significantly increased in circulating sEVs, which is dependent on integrin-β2. Knockdown of integrin-β2 does not affect cellular ECM1 protein levels but significantly reduces ECM1 protein levels in the sEVs released by these cells. In breast cancer (BC), overexpressing ECM1 increases matrix metalloproteinase 3 (MMP3) and S100A/B protein levels. Interestingly, sEVs purified from high-fat diet-induced obesity mice (D-sEVs) deliver more ECM1 protein to BC cells compared to sEVs from control diet-fed mice. Consequently, BC cells secrete more ECM1 protein, which promotes cancer cell invasion and migration. D-sEVs treatment also significantly enhances ECM1-mediated BC metastasis and growth in mouse models, as evidenced by the elevated tumor levels of MMP3 and S100A/B. Our study reveals a mechanism and suggests sEV-based strategies for treating obesity-associated BC.

Ginkgolide B alleviates glucolipid metabolism disorders and adipose tissue inflammation by inhibiting thromboxane A2 synthesis

Thromboxane A2 (TXA2) is traditionally known for its role in inducing platelet aggregation, but our previous study has discovered its crucial involvement in hepatic glucolipid metabolism and adipose tissue inflammation. Ginkgolide B (GB), a naturally occurring terpene lactone, possesses various pharmacological functions through its antagonism of the platelet activating factor (PAF) receptor. However, the metabolic regulation mechanism link between the anti-obesity efficiency of GB and TXA2 has remained elusive. Therefore, this research aimed to explore the potential of GB in protecting against obesity by inhibiting TXA2 synthesis. The results showed that GB inhibited TXA2 biosynthesis which shares a similar action with eicosapentaenoic acid (EPA) and aspirin. GB treatment ameliorated hyperglycemia by decreasing gluconeogenesis. Additionally, GB supplementation relieved hepatic lipid deposition and dyslipidemia. Furthermore, GB intervention promoted macrophage M2 polarization, thus mitigating adipose tissue inflammation. In summary, our study provided evidence that GB alleviated glucolipid metabolism disorders and adipose tissue inflammation through the inhibition of the TXA2 pathway. These findings shed light on the mechanism underlying the anti-obesity efficacy of GB and lay foundations for the future use of GB as a functional dietary supplement to alleviate high-fat diet-induced obesity.

Anti-Obesity Potentials of Methanol Extracts of Phragmanthera Incana Leaves Hemi-Parasitic on Guava, Cashew, Kolanut and Mango Trees in High-Fat Diet-Induced Obese Rats

The anti-obesity potential of methanol extracts of Phragmanthera incana leaves hemi-parasitic on guava Psidium guajava (PIPG), cashew Anacardium occidentale (PIAO), mango Mangifera indica (PIMI) and kolanut Cola acuminata (PICA) trees were evaluated. Thirty high-fat diet-induced rats were grouped into six; four experimental, negative control and positive controls were orally administered lipid emulsion (5 mL/kg). Experimental received 400 mg/kg body weight from each of the four methanol extracts in addition to the lipid emulsion, positive control received 120 mg/kg bw Orlistat in addition to lipid emulsion while negative control received lipid emulsion alone. Blood samples were collected from ophthalmic venous plexus at 0, 90, and 180 minutes to determine plasma pancreatic lipase (PL) activity, alpha amylase activity and lipid profiles. PL inhibitory activity of the four methanol extracts showed that methanol extracts of PICA and PIAO had greater than 50% inhibition at 400 µg/mL. The α-amylase inhibitory activity of PICA was significantly higher (p < 0.05) when compared with PIAO, PIPG and PIMI. A significant decrease (p < 0.05) in total cholesterol, low density Lipoprotein-cholesterol levels and atherogenic index of plasma of PICA when compared with other treatment groups after 180 minutes of extracts administration was observed. Methanol extract of PICA was found to exhibit higher inhibitory pancreatic lipase and α-amylase activities and higher hypocholesterolemic activity when compared with those of guava (PIPG), cashew (PIAO) and mango (PIMI). This indicates that methanol extract of P. incana leaves could serve as a source of phyto-compounds that could be developed as antiobesity drugs.

Neuronal ablation of GHSR mitigates diet-induced depression and memory impairment via AMPK-autophagy signaling-mediated inflammation.

Obesity is associated with chronic inflammation in the central nervous system (CNS), and neuroinflammation has been shown to have detrimental effects on mood and cognition. The growth hormone secretagogue receptor (GHSR), the biologically relevant receptor of the orexigenic hormone ghrelin, is primarily expressed in the brain. Our previous study showed that neuronal GHSR deletion prevents high-fat diet-induced obesity (DIO). Here, we investigated the effect of neuronal GHSR deletion on emotional and cognitive functions in DIO. The neuron-specific GHSR-deficient mice exhibited reduced depression and improved spatial memory compared to littermate controls under DIO. We further examined the cortex and hippocampus, the major regions regulating cognitive and emotional behaviors, and found that the neuronal deletion of GHSR reduced DIO-induced neuroinflammation by suppressing proinflammatory chemokines/cytokines and decreasing microglial activation. Furthermore, our data showed that neuronal GHSR deletion suppresses neuroinflammation by downregulating AMPK-autophagy signaling in neurons. In conclusion, our data reveal that neuronal GHSR inhibition protects against DIO-induced depressive-like behavior and spatial cognitive dysfunction, at least in part, through AMPK-autophagy signaling-mediated neuroinflammation.

Aerobic exercise attenuates high-fat diet–induced renal injury through kidney metabolite modulation in mice

Purpose To investigate the preventive effect of aerobic exercise on renal damage caused by obesity. Methods The mice in the Control (Con) and Control + Exercise (Con + Ex) groups received a standard chow diet for the 21-week duration of the study, while the High-fat diet (HFD) group and High-fat diet + Exercise (HFD + Ex) group were fed an HFD. Mice were acclimated to the laboratory for 1 week, given 12 weeks of being on their respective diets, and then the Con + Ex and HFD + Ex groups were subjected to moderate intensity aerobic treadmill running 45 min/day, 5 days/week for 8 weeks. Results We found that HFD-induced obesity mainly impacts kidney glycerin phospholipids, glycerides, and fatty acyls, and aerobic exercise mainly impacts kidney glycerides, amino acids and organic acids as well as their derivatives. We identified 18 metabolites with significantly altered levels that appear to be involved in aerobic exercise mediated prevention of HFD-induced obesity and renal damage, half of which were amino acids and organic acids and their derivatives. Conclusion Aerobic exercise rewires kidney metabolites to reduce high-fat diet-induced obesity and renal injury.

Solid Dispersions of Genistein via Solvent Rotary Evaporation for Improving Solubility, Bioavailability, and Amelioration Effect in HFD-Induced Obesity Mice.

Genistein (GEN) is an active pharmaceutical ingredient that presents the challenges of poor water solubility and low oral bioavailability. To tackle these challenges, a GEN solid dispersion was prepared by solvent rotary evaporation using polyvinylpyrrolidone K30 (PVP K30) as a carrier. The optimal formulation was determined by drug loading efficiency and in vitro release. The physical state of the solid dispersion was characterized by DSC, XRD, SEM and FT-IR. And the results of the in vitro release study indicate that the drug release of SD (1:7) increased 482-fold that of pure GEN at 60 min. Following oral administration to rats, the Cmax and AUC0-24 of SD (1:7) was increased 6.86- and 2.06-fold to that of pure GEN. The adipose fat index and body weight of the SD (1:7) group were significantly lower than those of the GEN group (p < 0.05). Meanwhile, the levels of TC and TG in the serum were significantly decreased in the SD (1:7) group compared with the GEN group (p < 0.05). All experiments revealed that solid dispersion could be a promising formulation approach to improve the dissolution rate, oral bioavailability, and effect on the reduction of lipid accumulation in high-fat diet-induced obesity mice.

Investigation of the therapeutic effect of Hedan tablets on high-fat diet-induced obesity in rats by GC-MS technology and 16S ribosomal RNA gene sequencing.

Obesity is a persistent metabolic condition resulting from the excessive accumulation or abnormal distribution of body fat. This study aimed to establish an experimental rat model of obesity. The efficacy of treating obesity with Hedan tablets (HDT) was assessed by monitoring changes in weight, blood lipid levels, analyzing inflammatory factors, evaluating organ indices, and observing liver tissue pathology. Furthermore, we utilized 16S ribosomal RNA gene sequencing technology to explore changes in intestinal flora. In addition, GC-MS was used to measure fecal short-chain fatty acid (SCFA) content. The onset of obesity led to a significant decrease in the relative abundance of beneficial bacteria. Conversely, the administration of HDT demonstrated a substantial ability to increase the relative abundance of beneficial bacteria. Obesity resulted in a noteworthy reduction in total SCFAs, a trend significantly reversed in the HDT group. Through correlation analysis, it was determined that HDT mitigated the inflammatory response and improved blood lipid levels by augmenting the abundance of Lactobacillus, Limosilactobacillus, Ruminococcus, and Enterococcus. These particular intestinal flora were identified as regulators of SCFA metabolism, thereby ameliorating metabolic abnormalities associated with obesity. Moreover, HDT intervention elevated the overall fecal concentration of SCFAs, thereby improving metabolic disorders induced by obesity. The anti-obesity effects of HDT are likely attributable to their capacity to influence the composition of intestinal flora and boost SCFA levels in the intestine.

Low-dose polystyrene microplastics exposure impairs fertility in male mice with high-fat diet-induced obesity by affecting prostate function

The harmful effects of microplastics (MPs) on male fertility are receiving more and more attention. However, the impact of low-dose MPs exposure on the reproductive function of male mice is still unclear. In this study, we exposed male mice to low-dose MPs (25–30 μg/kg body weight/day) or low-dose MPs combined with high-fat diet (HFD) feeding. Our results showed that low-dose MPs exposure or HFD feeding significantly reduced sperm quality and the number of offspring born, while low-dose MPs exposure combined with HFD feeding further enhanced the above effects. The combination of low-dose MPs exposure and HFD feeding resulted in a notable elevation of inflammatory level within the prostate of mice and induced apoptosis of prostate epithelium and a decrease in nutrients (zinc, citrate) in seminal plasma fluid. Our findings in this study could provide valuable clues for better understanding the influence of low-dose MPs exposure on the reproductive system under metabolic disorders and facilitate the development of the prevention of reproductive toxicity caused by MPs exposure.

Effect of high-fat diet on the fatty acid profiles of brain in offspring mice exposed to maternal gestational diabetes mellitus.

Fatty acids play a critical role in the proper functioning of the brain. This study investigated the effects of a high-fat (HF) diet on brain fatty acid profiles of offspring exposed to maternal gestational diabetes mellitus (GDM). Insulin receptor antagonist (S961) and HF diet were used to establish the GDM animal model. Brain fatty acid profiles of the offspring mice were measured by gas chromatography at weaning and adulthood. Protein expressions of the fatty acid transport pathway Wnt3/β-catenin and the target protein major facilitator superfamily domain-containing 2a (MFSD2a) were measured in the offspring brain by Western blot. Maternal GDM increased the body weight of male offspring (P < 0.05). In weaning offspring, factorial analysis showed that maternal GDM increased the monounsaturated fatty acid (MUFA) percentage of the weaning offspring's brain (P < 0.05). Maternal GDM decreased offspring brain arachidonic acid (AA), but HF diet increased brain linoleic acid (LA) (P < 0.05). Maternal GDM and HF diet reduced offspring brain docosahexaenoic acid (DHA), and the male offspring had higher DHA than the female offspring (P < 0.05). In adult offspring, factorial analysis showed that HF diet increased brain MUFA in offspring, and male offspring had higher brain MUFA than female offspring (P < 0.05). The HF diet increased brain LA in the offspring. Male offspring had higher level of AA than female offspring (P < 0.05). HF diet reduced DHA in the brains of female offspring. The brain protein expression of β-catenin and MFSD2a in both weaning and adult female offspring was lower in the HF + GDM group than in the CON group (P < 0.05). Maternal GDM increased the susceptibility of male offspring to HF diet-induced obesity. HF diet-induced adverse brain fatty acid profiles in both male and female offspring exposed to GDM.

Reversal of High Fat Diet-Induced Obesity, Systemic Inflammation, and Astrogliosis by the NLRP3 Inflammasome Inhibitors NT-0249 and NT-0796.

Systemic and cerebral inflammatory responses are implicated in the pathogenesis of obesity and associated metabolic impairment. While the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome has been linked to obesity-associated inflammation, whether it contributes to the development or maintenance of obesity is unknown. We provide support for a direct role of saturated fatty acids, such as palmitic acid, as NLRP3 activating stimuli in obese states. To investigate whether NLRP3 activation contributes to the pathogenesis of diet-induced obesity (DIO) in mice, we tested two different clinical-stage NLRP3 inflammasome inhibitors. We demonstrate a contributory role of this key inflammasome to established obesity and associated systemic and cerebral inflammation. By comparing their effects to calorie restriction, we aimed to identify specific NLRP3-sensitive mechanisms contributing to obesity-induced inflammation (as opposed to be those regulated by weight loss per se). In addition, a direct comparison of an NLRP3 inhibitor to a glucagon like peptide-1 receptor agonist, semaglutide (Wegovy), in the DIO model allowed an appreciation of the relative efficacy of these two therapeutic strategies on obesity, its associated systemic inflammatory response, and cerebral gliosis. We show that two structurally distinct, NLRP3 inhibitors, NT-0249 and NT-0796, reverse obesity in the DIO mouse model and that brain exposure appears necessary for efficacy. In support of this, we show that DIO-driven hypothalamic glial fibrillary acidic protein expression is blocked by dosing with NT-0249/NT-0796. While matching weight loss driven by semaglutide or calorie restriction, remarkably, NLRP3 inhibition provided enhanced improvements in disease-relevant biomarkers of acute phase response, cardiovascular inflammation, and lipid metabolism. SIGNIFICANCE STATEMENT: Obesity is a global health concern that predisposes individuals to chronic disease such as diabetes and cardiovascular disease at least in part by promoting systemic inflammation. We report that in mice fed a high-fat, obesogenic diet, obesity is reversed by either of two inhibitors of the intracellular inflammatory mediator NLRP3. Furthermore, NLRP3 inhibition reduces both hypothalamic gliosis and circulating biomarkers of cardiovascular disease risk beyond what can be achieved by either the glucagon like peptide-1 agonist semaglutide or calorie restriction alone.