Mouse Model Of Diet-induced Obesity Research Articles

The combination of berberine and isoliquiritigenin synergistically improved adipose inflammation and obesity-induced insulin resistance.

White adipose tissue accumulation and inflammation contribute to obesity by inducing insulin resistance. Herein, we aimed to screen the synergistic components of the herbal pair Coptidis Rhizoma-Glycyrrhizae Radix et Rhizoma for the treatment of insulin resistance and explore the potential synergistic mechanisms. Enzyme-linked immunosorbent assay and quantitative PCR were used to detect expression levels of inflammatory genes in vitro and in vivo. Western blotting and immunohistochemistry were performed to detect protein levels of the insulin signaling pathway and macrophage markers. The effects on obesity-induced insulin resistance were verified using a diet-induced obesity (DIO) mouse model. Interactions between macrophage and adipocyte were assessed using a cellular supernatant transfer assay. Berberine (BBR) and isoliquiritigenin (ISL) alleviated mRNA levels and secretion of inflammatory genes in vitro and in vivo. Furthermore, BBR acted synergistically with ISL to ameliorate obesity and dyslipidemia in DIO mice. Meanwhile, the combination treatment significantly improved glucose intolerance and insulin resistance and decreased M1-macrophage accumulation and infiltration in the adipose tissue. Mechanistically, co-treatment with BBR and ISL upregulated the protein expression of the IRS1-PI3K-Akt insulin signaling pathway, enhanced glucose uptake in adipocyte, and suppressed the interaction between macrophage and adipocyte. BBR and ISL were identified as the synergistic components of the herbal pair Coptidis Rhizoma-Glycyrrhizae Radix et Rhizoma for treating insulin resistance. The synergistic combination of BBR with ISL can be a promising and effective strategy for improving obesity-induced adipose inflammation and insulin resistance.

The prostaglandin E2 EP3 receptor has disparate effects on islet insulin secretion and content in β-cells in a high-fat diet-induced mouse model of obesity.

Signaling through prostaglandin E2 EP3 receptor (EP3) actively contributes to the β-cell dysfunction of type 2 diabetes (T2D). In T2D models, full-body EP3 knockout mice have a significantly worse metabolic phenotype than wild-type controls due to hyperphagia and severe insulin resistance resulting from loss of EP3 in extra-pancreatic tissues, masking any potential beneficial effects of EP3 loss in the β cell. We hypothesized β-cell-specific EP3 knockout (EP3 βKO) mice would be protected from high-fat diet (HFD)-induced glucose intolerance, phenocopying mice lacking the EP3 effector, Gαz, which is much more limited in its tissue distribution. When fed a HFD for 16 wk, though, EP3 βKO mice were partially, but not fully, protected from glucose intolerance. In addition, exendin-4, an analog of the incretin hormone, glucagon-like peptide 1, more strongly potentiated glucose-stimulated insulin secretion in islets from both control diet- and HFD-fed EP3 βKO mice as compared with wild-type controls, with no effect of β-cell-specific EP3 loss on islet insulin content or markers of replication and survival. However, after 26 wk of diet feeding, islets from both control diet- and HFD-fed EP3 βKO mice secreted significantly less insulin as a percent of content in response to stimulatory glucose, with or without exendin-4, with elevated total insulin content unrelated to markers of β-cell replication and survival, revealing severe β-cell dysfunction. Our results suggest that EP3 serves a critical role in temporally regulating β-cell function along the progression to T2D and that there exist Gαz-independent mechanisms behind its effects.NEW & NOTEWORTHY The EP3 receptor is a strong inhibitor of β-cell function and replication, suggesting it as a potential therapeutic target for the disease. Yet, EP3 has protective roles in extrapancreatic tissues. To address this, we designed β-cell-specific EP3 knockout mice and subjected them to high-fat diet feeding to induce glucose intolerance. The negative metabolic phenotype of full-body knockout mice was ablated, and EP3 loss improved glucose tolerance, with converse effects on islet insulin secretion and content.

Anti-obesity potentiality of Lactiplantibacillus plantarum E2_MCCKT isolated from a fermented beverage, haria: a high fat diet-induced obese mice model study.

Obesity is a growing epidemic worldwide. Several pharmacologic drugs are being used to treat obesity but these medicines exhibit side effects. To find out the alternatives of these drugs, we aimed to assess the probiotic properties and anti-obesity potentiality of a lactic acid bacterium E2_MCCKT, isolated from a traditional fermented rice beverage, haria. Based on the 16S rRNA sequencing, the bacterium was identified as Lactiplantibacillus plantarum E2_MCCKT. The bacterium exhibited in vitro probiotic activity in terms of high survivability in an acidic environment and 2% bile salt, moderate auto-aggregation, and hydrophobicity. Later, E2_MCCKT was applied to obese mice to prove its anti-obesity potentiality. Adult male mice (15.39 ± 0.19g) were randomly divided into three groups (n = 5) according to the type of diet: normal diet (ND), high-fat diet (HFD), and HFD supplemented with E2_MCCKT (HFT). After four weeks of bacterial treatment on the obese mice, a significant reduction of body weight, triglyceride, and cholesterol levels, whereas, improvements in serum glucose levels were observed. The bacterial therapy led to mRNA up-regulation of lipolytic transcription factors such as peroxisome proliferator-activated receptor-α which may increase the expression of fatty acid oxidation-related genes such as acyl-CoA oxidase and carnitine palmitoyl-transferase-1. Concomitantly, both adipocytogenesis and fatty acid synthesis were arrested as reflected by the down-regulation of sterol-regulatory element-binding protein-1c, acetyl-CoA carboxylase, and fatty acid synthase genes. In protein expression study, E2_MCCKT significantly increased IL-10 expression while decreasing pro-inflammatory cytokine (IL-1Ra and TNF-α) expression. In conclusion, the probiotic Lp. plantarum E2_MCCKT might have significant anti-obesity effects on mice.

Comparative analysis of anti-obesity effects of green, fermented, and γ-aminobutyric acid teas in a high-fat diet-induced mouse model

Obesity, a prevalent disease associated with numerous chronic conditions, including hyperlipidemia, hyperglycemia, diabetes, and metabolic syndrome, remains a major global health challenge. This study investigated the potential of green tea (GT), fermented tea (FT), and γ-aminobutyric acid (GABA) tea (GBT), which are rich in phytonutrients and polyphenols, for the management of obesity. Using a high-fat diet-induced obese mouse model (C57BL/6N), we explored the effect of these teas on various obesity-related parameters. The mice were categorized into five groups: normal diet with water, high-fat diet with water, and high-fat diet supplemented with GT, FT, or GBT. Over 13 weeks, we monitored body weight, perirenal and liver fat, adipocyte lipid accumulation, and key metabolic indicators, such as serum cholesterol, leptin, insulin, and fasting blood glucose. These teas contain beneficial phytochemicals such as GABA, theanine, and caffeine, and have demonstrated an enhanced antioxidant capacity, which increases the scavenging of free radicals and may reduce oxidative stress. The animal study indicated a decrease in feeding efficiency and significant reductions in body weight liver fat, epididymal fat, and perirenal fat, as well as in adipocyte lipid accumulation. Additionally, notable improvements were observed in metabolic health indicators, including reductions in serum cholesterol, leptin, insulin, and fasting blood glucose levels. Our findings revealed that GT, FT, or GBT significantly counteracted the negative effects of a high-fat diet, suggesting their potential in combating obesity and related metabolic disorders.

Abstract 3980: Investigating the role of host obesity in promoting immunotherapy resistance

Abstract Obesity is linked to an increased risk of various cancers, including renal cell carcinoma (RCC). Many RCC patients have obesity at diagnosis and treatment initiation, and our lab has found that this significantly impairs immunotherapy outcomes. Both preclinical and clinical reports, from our lab and others, have demonstrated that obesity reduces the efficacy of CD8+ T cell-dependent immunotherapy by increasing pro-tumorigenic IL-1β. Combining anti-PD-1 based therapy with anti-IL-1β triggers the recruitment of CD8+ T cells and improves the efficacy of anti-PD-1 based immunotherapy. However, the mechanistic links between obesity and increased IL-1β production remains unknown. Our objective is to identify mechanisms promoting IL-1 β-driven immunosuppression within renal tumors of obese mice. In our in vivo studies, we utilized a BALB/c mouse model of diet-induced obesity (DIO) and lean controls in combination with the Renca-Luc RCC cell line. Using flow cytometry and western blot, we respectively assessed leukocyte populations producing IL-1β and tumor energetics. Flow cytometry revealed that intra-tumoral IL-1β is produced primarily by tumor associated macrophages (TAMS). Immunoblotting demonstrated that increased IL-1β production is linked to altered mitochondrial function and ATP production. These early findings support the hypothesis that obesity driven IL-1β expression is mediated by tumor-associated macrophages and that mitochondrial dysfunction drives immune suppression. Understanding these molecular and immune-related mechanisms may pave the way for novel strategies to reduce immunosuppression in obese RCC patients, thus improving immunotherapeutic efficacy and overall clinical outcomes. Citation Format: Henry Nnaemeka Ogbonna, Zachary Roberts, Haley Kvarnberg, Francesca Dempsey, Patrick N. Song, Anna G. Sorace, Lyse Norian. Investigating the role of host obesity in promoting immunotherapy resistance [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 3980.

Effects of Empagliflozin-Induced Glycosuria on Weight Gain, Food Intake and Metabolic Indicators in Mice Fed a High-Fat Diet.

Sodium glucose-linked transporter 2 (SGLT2) inhibitors promote glucose, and therefore calorie, excretion in the urine. Patients taking SGLT2 inhibitors typically experience mild weight loss, but the amount of weight loss falls short of what is expected based on caloric loss. Understanding the mechanisms responsible for this weight loss discrepancy is imperative, as strategies to improve weight loss could markedly improve type 2 diabetes management and overall metabolic health. Two mouse models of diet-induced obesity were administered the SGLT2 inhibitor empagliflozin in the food for 3 months. Urine glucose excretion, body weight, food intake and activity levels were monitored. In addition, serum hormone measurements were taken, and gene expression analyses were conducted. In both mouse models, mice receiving empagliflozin gained the same amount of body weight as their diet-matched controls despite marked glucose loss in the urine. No changes in food intake, serum ghrelin concentrations or activity levels were observed, but serum levels of fibroblast growth factor 21 (FGF21) decreased after treatment. A decrease in the levels of deiodinase 2 (Dio2) was also observed in the white adipose tissue, a primary target tissue of FGF21. These findings suggest that compensatory metabolic adaptations, other than increased food intake or decreased physical activity, occur in response to SGLT2 inhibitor-induced glycosuria that combats weight loss, and that reductions in FGF21, along with subsequent reductions in peripheral Dio2, may play a role.

Sipyimigwanjung-tang, a traditional herbal medication, alleviates weight gain in a high-fat diet-induced obese mice model

Obesity leads to the development of metabolic syndrome and comorbidities. Overweight and obesity continue to be a relentless global issue. Sipyimigwanjung-tang (SGT), a traditional herbal medication, was first mentioned in Dongui Sasang Shinpyun and has been used to treat edema, meteorism, and jaundice, which are common findings associated with obesity. The main physiological feature of obesity is expanded adipose tissue, which causes several impairments in liver metabolism. Therefore, this study aimed to investigate the anti-obesity effects of SGT in the epididymal white adipose tissue (eWAT) and livers of high-fat diet (HFD)-induced obese mice. SGT significantly blocked HFD-induced weight gain in C57BL/6N mice. In addition, SGT effectively reduced the increased weight and adipocyte size in eWAT of HFD-induced obese C57BL/6 N mice. Moreover, SGT significantly decreased the elevated gene expression of Peroxisome proliferator-activated receptor γ, CCAAT/enhancer-binding protein α, and Sterol regulatory element-binding protein 1 in the eWAT of HFD-induced obese mice. Furthermore, SGT significantly decreased lipid accumulation in the livers of HFD-induced obese mice and differentiated 3T3-L1 adipocytes. Hence, the present study provides substantial evidence that SGT has potential therapeutic effects on obesity.

In situ combinatorial synthesis of degradable branched lipidoids for systemic delivery of mRNA therapeutics and gene editors

The ionizable lipidoid is a key component of lipid nanoparticles (LNPs). Degradable lipidoids containing extended alkyl branches have received tremendous attention, yet their optimization and investigation are underappreciated. Here, we devise an in situ construction method for the combinatorial synthesis of degradable branched (DB) lipidoids. We find that appending branch tails to inefficacious lipidoids via degradable linkers boosts mRNA delivery efficiency up to three orders of magnitude. Combinatorial screening and systematic investigation of two libraries of DB-lipidoids reveal important structural criteria that govern their in vivo potency. The lead DB-LNP demonstrates robust delivery of mRNA therapeutics and gene editors into the liver. In a diet-induced obese mouse model, we show that repeated administration of DB-LNP encapsulating mRNA encoding human fibroblast growth factor 21 alleviates obesity and fatty liver. Together, we offer a construction strategy for high-throughput and cost-efficient synthesis of DB-lipidoids. This study provides insights into branched lipidoids for efficient mRNA delivery.

Notch signaling in adipose tissue macrophages prevents diet-induced inflammation and metabolic dysregulation.

The importance of macrophages in adipose tissue (AT) homeostasis and inflammation is well established. However, the potential cues that regulate their function remain incompletely understood. To bridge this important gap, we sought to characterize novel pathways involved using a mouse model of diet-induced obesity. By performing transcriptomics analysis of AT macrophages (ATMs), we found that late-stage ATMs from high-fat diet mice presented with perturbed Notch signaling accompanied by robust proinflammatory and metabolic changes. To explore the hypothesis that the deregulated Notch pathway contributes to the development of AT inflammation and diet-induced obesity, we employed a genetic approach to abrogate myeloid Notch1 and Notch2 receptors. Our results revealed that the combined loss of Notch1 and Notch2 worsened obesity-related metabolic dysregulation. Body and AT weight gain was higher, blood glucose levels increased and metabolic parameters were substantially worsened in deficient mice fed high-fat diet. Moreover, serum insulin and leptin were elevated as were triglycerides. Molecular analysis of ATMs showed that deletion of Notch receptors escalated inflammation through the induction of an M1-like pro-inflammatory phenotype. Our findings thus support a protective role of myeloid Notch signaling in adipose tissue inflammation and metabolic dysregulation.

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.

Rebaudioside D decreases adiposity and hepatic lipid accumulation in a mouse model of obesity

Overconsumption of added sugars has been pointed out as a major culprit in the increasing rates of obesity worldwide, contributing to the rising popularity of non-caloric sweeteners. In order to satisfy the growing demand, industrial efforts have been made to purify the sweet-tasting molecules found in the natural sweetener stevia, which are characterized by a sweet taste free of unpleasant aftertaste. Although the use of artificial sweeteners has raised many concerns regarding metabolic health, the impact of purified stevia components on the latter remains poorly studied. The objective of this project was to evaluate the impact of two purified sweet-tasting components of stevia, rebaudioside A and D (RebA and RebD), on the development of obesity, insulin resistance, hepatic health, bile acid profile, and gut microbiota in a mouse model of diet-induced obesity. Male C57BL/6 J mice were fed an obesogenic high-fat/high-sucrose (HFHS) diet and orally treated with 50 mg/kg of RebA, RebD or vehicle (water) for 12 weeks. An additional group of chow-fed mice treated with the vehicle was included as a healthy reference. At weeks 10 and 12, insulin and oral glucose tolerance tests were performed. Liver lipids content was analyzed. Whole-genome shotgun sequencing was performed to profile the gut microbiota. Bile acids were measured in the feces, plasma, and liver. Liver lipid content and gene expression were analyzed. As compared to the HFHS-vehicle treatment group, mice administered RebD showed a reduced weight gain, as evidenced by decreased visceral adipose tissue weight. Liver triglycerides and cholesterol from RebD-treated mice were lower and lipid peroxidation was decreased. Interestingly, administration of RebD was associated with a significant enrichment of Faecalibaculum rodentium in the gut microbiota and an increased secondary bile acid metabolism. Moreover, RebD decreased the level of lipopolysaccharide-binding protein (LBP). Neither RebA nor RebD treatments were found to impact glucose homeostasis. The daily consumption of two stevia components has no detrimental effects on metabolic health. In contrast, RebD treatment was found to reduce adiposity, alleviate hepatic steatosis and lipid peroxidation, and decrease LBP, a marker of metabolic endotoxemia in a mouse model of diet-induced obesity.

The Hepatokine Orosomucoid 2 Mediates Beneficial Metabolic Effects of Bile Acids.

Bile acids (BAs) are pleiotropic regulators of metabolism. Elevated levels of hepatic and circulating BAs improve energy metabolism in peripheral organs, but the precise mechanisms underlying the metabolic benefits and harm still need to be fully understood. In the present study, we identified orosomucoid 2 (ORM2) as a liver-secreted hormone (i.e., hepatokine) induced by BAs and investigated its role in BA-induced metabolic improvements in mouse models of dietinduced obesity. Contrary to our expectation, under a high-fat diet (HFD), our Orm2 knockout (Orm2-KO) exhibited a lean phenotype compared to C57BL/6J control, partly due to the increased energy expenditure. However, when challenged with HFD supplemented with cholic acid (HFDCA), Orm2-KO eliminated the anti-obesity effect of BAs, indicating that ORM2 governs BA-induced metabolic improvements. Moreover, hepatic ORM2 overexpression partially replicated BA effects by enhancing insulin sensitivity. Mechanistically, ORM2 suppressed IFNγ/STAT1 activities in inguinal WAT (iWAT) depots, forming the basis for anti-inflammatory effects of BAs and improving glucose homeostasis. In conclusion, our study provides new insights into the molecular mechanisms of BA-induced liver-adipose crosstalk through ORM2 induction.

Targeting the PDK/PDH axis to reverse metabolic abnormalities by structure-based virtual screening with in vitro and in vivo experiments

In humans and animals, the pyruvate dehydrogenase kinase (PDK) family proteins (PDKs 1–4) are excessively activated in metabolic disorders such as obesity, diabetes, and cancer, inhibiting the activity of pyruvate dehydrogenase (PDH) which plays a crucial role in energy and fatty acid metabolism and impairing its function. Intervention and regulation of PDH activity have become important research approaches for the treatment of various metabolic disorders.In this study, a small molecule (g25) targeting PDKs and activating PDH, was identified through multi-level computational screening methods. In vivo and in vitro experiments have shown that g25 activated the activity of PDH and reduced plasma lactate and triglyceride level. Besides, g25 significantly decreased hepatic fat deposition in a diet-induced obesity mouse model. Furthermore, g25 enhanced the tumor-inhibiting activity of cisplatin when used in combination. Molecular dynamics simulations and in vitro kinase assay also revealed the specificity of g25 towards PDK2.Overall, these findings emphasize the importance of targeting the PDK/PDH axis to regulate PDH enzyme activity in the treatment of metabolic disorders, providing directions for future related research. This study provides a possible lead compound for the PDK/PDH axis related diseases and offers insights into the regulatory mechanisms of this pathway in diseases.

Dietary intervention reverses molecular markers of hepatocellular senescence in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH.

Hepatocellular senescence may be a causal factor in the development and progression of non-alcoholic steatohepatitis (NASH). The most effective currently available treatment for NASH is lifestyle intervention, including dietary modification. This study aimed to evaluate the effects of dietary intervention on hallmarks of NASH and molecular signatures of hepatocellular senescence in the Gubra-Amylin NASH (GAN) diet-induced obese (DIO) and biopsy-confirmed mouse model of NASH. GAN DIO-NASH mice with liver biopsy-confirmed NASH and fibrosis received dietary intervention by switching to chow feeding (chow reversal) for 8, 16 or 24 weeks. Untreated GAN DIO-NASH mice and chow-fed C57BL/6J mice served as controls. Pre-to-post liver biopsy histology was performed for within-subject evaluation of NAFLD Activity Score and fibrosis stage. Terminal endpoints included blood/liver biochemistry, quantitative liver histology, mitochondrial respiration and RNA sequencing. Chow-reversal promoted substantial benefits on metabolic outcomes and liver histology, as demonstrated by robust weight loss, complete resolution of hepatomegaly, hypercholesterolemia, elevated transaminase levels and hepatic steatosis in addition to attenuation of inflammatory markers. Notably, all DIO-NASH mice demonstrated ≥ 2 point significant improvement in NAFLD Activity Score following dietary intervention. While not improving fibrosis stage, chow-reversal reduced quantitative fibrosis markers (PSR, collagen 1a1, α-SMA), concurrent with improved liver mitochondrial respiration, complete reversal of p21 overexpression, lowered γ-H2AX levels and widespread suppression of gene expression markers of hepatocellular senescence. Dietary intervention (chow reversal) substantially improves metabolic, biochemical and histological hallmarks of NASH and fibrosis in GAN DIO-NASH mice. These benefits were reflected by progressive clearance of senescent hepatocellular cells, making the model suitable for profiling potential senotherapeutics in preclinical drug discovery for NASH.

ACOD1 deficiency offers protection in a mouse model of diet-induced obesity by maintaining a healthy gut microbiota

Aconitate decarboxylase 1 (ACOD1) is the enzyme synthesizing itaconate, an immuno-regulatory metabolite tuning host-pathogen interactions. Such functions are achieved by affecting metabolic pathways regulating inflammation and microbe survival. However, at the whole-body level, metabolic roles of itaconate remain largely unresolved. By using multiomics-integrated approaches, here we show that ACOD1 responds to high-fat diet consumption in mice by promoting gut microbiota alterations supporting metabolic disease. Genetic disruption of itaconate biosynthesis protects mice against obesity, alterations in glucose homeostasis and liver metabolic dysfunctions by decreasing meta-inflammatory responses to dietary lipid overload. Mechanistically, fecal metagenomics and microbiota transplantation experiments demonstrate such effects are dependent on an amelioration of the intestinal ecosystem composition, skewed by high-fat diet feeding towards obesogenic phenotype. In particular, unbiased fecal microbiota profiling and axenic culture experiments point towards a primary role for itaconate in inhibiting growth of Bacteroidaceae and Bacteroides, family and genus of Bacteroidetes phylum, the major gut microbial taxon associated with metabolic health. Specularly to the effects imposed by Acod1 deficiency on fecal microbiota, oral itaconate consumption enhances diet-induced gut dysbiosis and associated obesogenic responses in mice. Unveiling an unrecognized role of itaconate, either endogenously produced or exogenously administered, in supporting microbiota alterations underlying diet-induced obesity in mice, our study points ACOD1 as a target against inflammatory consequences of overnutrition.

Biomarkers of Metabolic Adaptation to High Dietary Fats in a Mouse Model of Obesity Resistance.

Obesity-resistant (non-responder, NR) phenotypes that exhibit reduced susceptibility to developing obesity despite being exposed to high dietary fat are crucial in exploring the metabolic responses that protect against obesity. Although several efforts have been made to study them in mice and humans, the individual protective mechanisms are poorly understood. In this exploratory study, we used a polygenic C57BL/6J mouse model of diet-induced obesity to show that NR mice developed healthier fat/lean body mass ratios (0.43 ± 0.05) versus the obesity-prone (super-responder, SR) phenotypes (0.69 ± 0.07, p < 0.0001) by upregulating gene expression networks that promote the accumulation of type 2a, fast-twitch, oxidative muscle tissues. This was achieved in part by a metabolic adaptation in the form of blood glucose sparing, thus aggravating glucose tolerance. Resistance to obesity in NR mice was associated with 4.9-fold upregulated mitoferrin 1 (Slc25a37), an essential mitochondrial iron importer. SR mice also showed fecal volatile metabolite signatures of enhanced short-chain fatty acid metabolism, including increases in detrimental methyl formate and ethyl propionate, and these effects were reversed in NR mice. Continued research into obesity-resistant phenotypes can offer valuable insights into the underlying mechanisms of obesity and metabolic health, potentially leading to more personalized and effective approaches for managing weight and related health issues.

TAAR1 agonists improve glycemic control, reduce body weight and modulate neurocircuits governing energy balance and feeding

ObjectiveMetabolic Syndrome, which can be induced or exacerbated by current antipsychotic drugs (APDs), is highly prevalent in schizophrenia patients. Recent preclinical and clinical evidence suggest that agonists at trace amine-associated receptor 1 (TAAR1) have potential as a new treatment option for schizophrenia. Intriguingly, preclinical tudies have also identified TAAR1 as a novel regulator of metabolic control. Here we evaluated the effects of three TAAR1 agonists, including the clinical development candidate ulotaront, on body weight, metabolic parameters and modulation of neurocircuits implicated in homeostatic and hedonic feeding. MethodsEffects of TAAR1 agonists (ulotaront, RO5166017 and/or RO5263397) on body weight, food intake and/or metabolic parameters were investigated in rats fed a high-fat diet (HFD) and in a mouse model of diet-induced obesity (DIO). Body weight effects were also determined in a rat and mouse model of olanzapine-, and corticosterone-induced body weight gain, respectively. Glucose tolerance was assessed in lean and diabetic db/db mice and fasting plasma glucose and insulin examined in DIO mice. Effects on gastric emptying were evaluated in lean mice and rats. Drug-induced neurocircuit modulation was evaluated in mice using whole-brain imaging of c-fos protein expression. ResultsTAAR1 agonists improved oral glucose tolerance by inhibiting gastric emptying. Sub-chronic administration of ulotaront in rats fed a HFD produced a dose-dependent reduction in body weight, food intake and liver triglycerides compared to vehicle controls. In addition, a more rapid reversal of olanzapine-induced weight gain and food intake was observed in HFD rats switched to ulotaront or RO5263397 treatment compared to those switched to vehicle. Chronic ulotaront administration also reduced body weight and improved glycemic control in DIO mice, and normalized corticosterone-induced body weight gain in mice. TAAR1 activation increased neuronal activity in discrete homeostatic and hedonic feeding centers located in the dorsal vagal complex and hypothalamus with concurrent activation of several limbic structures. ConclusionThe current data demonstrate that TAAR1 agonists, as a class, not only lack APD-induced metabolic liabilities but can reduce body weight and improve glycemic control in rodent models. The underlying mechanisms likely include TAAR1-mediated peripheral effects on glucose homeostasis and gastric emptying as well as central regulation of energy balance and food intake.

Antidiabetic features of AdipoAI, a novel AdipoR agonist.

Adiponectin is an antidiabetic endogenous adipokine that plays a protective role against the unfavorable metabolic sequelae of obesity. Recent evidence suggests a sinister link between hypoadiponectinemia and development of insulin resistance/type 2 diabetes (T2D). Adiponectin's insulin-sensitizing property is mediated through the specific adiponectin receptors R1 and R2, which activate the AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor (PPAR) α pathways. AdipoAI is a novel synthetic analogue of endogenous adiponectin with possibly similar pharmacological effects. Thus, there is a need of orally active small molecules that activate Adipoq subunits, and their downstream signaling, which could ameliorate obesity related type 2 diabetes. In the study we aim to investigate the effects of AdipoAI on obesity and T2D. Through in-vitro and in-vivo analyses, we investigated the antidiabetic potentials of AdipoAI and compared it with AdipoRON, another orally active adiponectin receptors agonist. Our results showed that in-vitro treatment of AdipoAI (0-5 µM) increased adiponectin receptor subunits AdipoR1/R2 with increase in AMPK and APPL1 protein expression in C2C12 myotubes. Similarly, in-vivo, oral administration of AdipoAI (25 mg/kg) observed similar effects as that of AdipoRON (50 mg/kg) with improved control of blood glucose and insulin sensitivity in diet-induced obesity (DIO) mice models. Further, AdipoAI significantly reduced epididymal fat content with decrease in inflammatory markers and increase in PPAR-α and AMPK levels and exhibited hepatoprotective effects in liver. Further, AdipoAI and AdipoRON also observed similar results in adipose tissue. Thus, our results suggest that low doses of orally active small molecule agonist of adiponectin AdipoAI can be a promising therapeutic target for obesity and T2D.

Semaglutide reduces tumor burden in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH-HCC with advanced fibrosis

Non-alcoholic steatohepatitis (NASH) is emerging as a major cause of hepatocellular carcinoma (HCC), however, it is not resolved if compounds in late-stage clinical development for NASH may have additional therapeutic benefits in NASH-driven HCC (NASH-HCC). Here, we profiled monotherapy with semaglutide (glucagon-like-receptor-1 receptor agonist) and lanifibranor (pan-peroxisome proliferator-activated receptor agonist) in a diet-induced obese (DIO) mouse model of NASH-HCC. Disease progression was characterized in male C57BL/6 J mice fed the GAN (Gubra Amylin NASH) diet high in fat, fructose and cholesterol for 12–72 weeks (n = 15 per group). Other GAN DIO-NASH-HCC mice fed the GAN diet for 54 weeks and with biopsy-confirmed NASH (NAFLD Activity Score ≥ 5) and advanced fibrosis (stage F3) received vehicle (n = 16), semaglutide (30 nmol/kg, s.c., n = 15), or lanifibranor (30 mg/kg, p.o., n = 15) once daily for 14 weeks. GAN DIO-NASH-HCC mice demonstrated progressive NASH, fibrosis and HCC burden. Tumors presented with histological and molecular signatures of poor prognostic HCC. Consistent with clinical trial outcomes in NASH patients, both lanifibranor and semaglutide improved NASH while only lanifibranor reduced fibrosis in GAN DIO-NASH-HCC mice. Notably, only semaglutide reduced tumor burden in GAN DIO-NASH-HCC mice. In conclusion, the GAN DIO-NASH-HCC mouse is a clinical translational model of NASH-HCC. Semaglutide improves both NASH and tumor burden in GAN DIO-NASH-HCC mice, highlighting the suitability of this preclinical model for profiling novel drug therapies targeting NASH-HCC.

Vertical sleeve gastrectomy improves glucose-insulin homeostasis by enhancing β-cell function and survival via FGF15/19.

Vertical sleeve gastrectomy (VSG) restores glucose homeostasis in obese mice and humans. In addition, the increased fibroblast growth factor (FGF)15/19 circulating level postsurgery has been implicated in this effect. However, the impact of FGF15/19 on pancreatic islets remains unclear. Using a diet-induced obese mice model, we demonstrate that VSG attenuates insulin hypersecretion in isolated pancreatic islets, likely due to morphological alterations in the endocrine pancreas such as reduction in islet, β-cell, and α-cell mass. In addition, VSG relieves gene expression of endoplasmic reticulum (ER) stress and inflammation markers in islets from obese mice. Incubation of INS-1E β-cells with serum from obese mice induced dysfunction and cell death, whereas these conditions were not induced with serum from obese mice submitted to VSG, implicating the involvement of a humoral factor. Indeed, VSG increased FGF15 circulating levels in obese mice, as well as the expression of FGF receptor 1 (Fgfr1) and its coreceptor β-klotho (Klb), both in pancreatic islets from VSG mice and in INS-1E cells treated with the serum from these mice. Moreover, exposing INS-1E cells to an FGFR inhibitor abolished the effects of VSG serum on insulin secretion and cell death. Also, recombinant FGF19 prevents INS-1E cells from dysfunction and death induced by serum from obese mice. These findings indicate that the amelioration of glucose-insulin homeostasis promoted by VSG is mediated, at least in part, by FGF15/19. Therefore, approaches promoting FGF15/19 release or action may restore pancreatic islet function in obesity.NEW & NOTEWORTHY Vertical sleeve gastrectomy (VSG) decreases insulin secretion, endoplasmic reticulum (ER) stress, and inflammation in pancreatic islets from obese mice. In addition, VSG increased fibroblast growth factor (FGF)15 circulating levels in obese mice, as well as the expression of FGF receptor 1 (Fgfr1) and its coreceptor β-klotho (Klb), both in pancreatic islets from VSG mice and in INS-1E β-cells treated with the serum from these mice. Serum from operated mice protects INS-1E cells from dysfunction and apoptosis, which was mediated by FGF15/19.