Diet-induced Insulin Resistance Research Articles

Dietary caloric input and tumor growth accelerate senescence and modulate liver and adipose tissue crosstalk

Metabolic alterations are related to tumorigenesis and other age-related diseases that are accelerated by “Westernized” diets. In fact, hypercaloric nutrition is associated with an increased incidence of cancers and faster aging. Conversely, lifespan-extending strategies, such as caloric restriction, impose beneficial effects on both processes. Here, we investigated the metabolic consequences of hypercaloric-induced aging on tumor growth in female mice. Our findings indicate that a high-fat high-sucrose diet increases tumor growth mainly due to the boosted oxidation of glucose and fatty acids. Consequently, through an increased expression of lactate, IGFBP3, and PTHLH, tumors modulate liver and white adipose tissue metabolism. In the liver, the induced tumor increases fibrosis and accelerates the senescence process, despite the lower systemic pro-inflammatory state. Importantly, the induced tumor induces the wasting and browning of white adipose tissue, thereby reversing diet-induced insulin resistance. Finally, we suggest that tumor growth alters liver-adipose tissue crosstalk that upregulates Fgf21, induces senescence, and negatively modulates lipids and carbohydrates metabolism even in caloric-restricted-fed mice.

Ablation of PI3Kγ in neurons protects mice from diet-induced obesity MASLD and insulin resistance.

Mice with genetic ablation of PI3Kγ are protected from diet-induced obesity. However, the cell type responsible for PI3Kγ action in obesity remains unknown. We generated mice with conditional deletion of PI3Kγ in neurons using the nestin promoter to drive the expression of the Cre recombinase (PI3KγNest mice) and investigated their metabolic phenotype in a model of diet-induced obesity. On a chow diet, lean PI3KγNest mice display reduced linear growth and a normal metabolic phenotype. PI3KγNest mice were largely protected from diet-induced obesity and liver steatosis and showed improved glucose tolerance and insulin sensitivity. This phenotype was associated with increased phosphorylation of hormone-sensitive lipase (HSL) at protein kinase A (PKA) sites in white fat. It is concluded that PI3Kγ action in diet-induced obesity depends on its activity in neurons controlling adipose tissue lipolysis. Future clinical studies on PI3Kγ inhibitors capable of crossing the brain-blood barrier will reveal the relevance of these findings to humans.

LXR regulation of adipose tissue inflammation during obesity is associated with dysregulated macrophage function.

Liver X receptors (LXRs) play essential roles in cholesterol homeostasis and immune response. In obesity, elevated cholesterol levels trigger proinflammatory responses; however, the specific contributions of LXRs to adipose tissue (AT) macrophage (ATM) phenotype and metabolic programming are not fully understood. In this study, we determine the role of LXR isoforms in diet-induced obesity AT inflammation and insulin resistance. For in vivo studies, to evaluate the effects of LXR activation on AT inflammation, obese and insulin-resistant wild-type mice were treated with 10 mg/kg of the LXR modulator naringenin (NAR) for 4 weeks, and systemic insulin sensitivity and AT inflammation were assessed. To evaluate the effects of LXR deficiency on AT inflammation, we used LXRα, LXRβ, and LXRαβ knockout (KO) mice. For in vitro studies, to assess the role of LXRs specifically in macrophages, bone marrow-derived macrophages from wild-type, LXRαKO, LXRβKO, and LXRαβKO mice were treated with 0.5μM NAR 1 h prior to lipopolysaccharide (LPS) stimulation (100 ng/mL), and the effects on macrophage function and metabolism were evaluated 24 h after LPS stimulation. We found that LXR deletion intensifies AT inflammation in an LXRβ-dependent manner. LXR deficiency in immune cells exacerbates obesity-induced AT inflammation, increasing the numbers of CD11c+, TNF-α+, and IL-1β+ ATMs. We also identified NAR as a novel LXR agonist in macrophages that reduces proinflammatory cytokine secretion by mitigating glycolysis and mitochondrial dysfunction in LPS - and LPS + IFNγ-activated macrophages. Furthermore, NAR-treated obese mice display reduced AT inflammation, characterized by decreased CD11c+, IL-1β+, and TNF-α+ ATM numbers and monocyte infiltration compared with vehicle-treated obese mice. Our study highlights distinct roles for each LXR isoform in AT inflammation regulation, with LXRβ being crucial for maintaining the anti- and proinflammatory balance in ATMs. Thus, LXRβ holds therapeutic potential as a target to treat AT inflammation and insulin resistance.

α -lipoic acid supplementation reduces oxidative stress and inflammation in red skeletal muscle of insulin-resistant rats

α -lipoic acid (ALA) is an eight-carbon saturated fatty acid with strong antioxidant activity. Despite previous reports of ALA's protective properties in treating cardiovascular and metabolic diseases (including insulin resistance and diabetes), little is known about the compound's effects on skeletal muscle metabolism. In particular, the effect of ALA on glycooxidative and nitrosative damage in red muscles during insulin resistance is unknown. This study investigated the therapeutic potential of ALA on the antioxidant barrier as well as oxidative, nitrosative and carbonyl stress in the red skeletal muscle of rats with high-fat diet-induced insulin resistance. Male Wistar cmdb/outbred rats were divided into four equal groups: control diet (CTRL), high fat diet (HFD), CTRL+ALA (30 mg/kg body weight for 4 weeks; intragastrically) and HFD+ALA. Enzymatic and nonenzymatic antioxidant systems, protein and lipid glycoxidation, nitrosative stress, and selected inflammatory/apoptosis parameters were assessed using colorimetric, fluorimetric, and immune-enzymatic methods. ALA lowered body weight and glucose metabolism parameters in insulin-resistant rats. ALA not only strengthened enzymatic antioxidant defense (by increasing superoxide dismutase, catalase and glutathione peroxidase activity) but also stimulated the synthesis of non-enzymatic GSH. ALA supplementation inhibited lipid peroxidation (decreased lipid hydroperoxides and malondialdehyde content) and prevented protein oxidation (by lowering advanced oxidation protein products concentration) in red muscle. ALA's multifactorial actions on muscle tissue also included inhibition of inflammation and apoptosis, requiring further research to elucidate its effects in metabolic diseases.

Impact of vitamin A on the risk of mild cognitive impairment and Alzheimer's disease pathology in high‐fat‐diet–treated APP/PS1 mice

AbstractAbnormal glucose metabolism and vitamin A (VA) nutritional status promote the occurrence of cognitive impairment and Alzheimer's disease (AD). However, the effects of low VA intake, insulin resistance, and their interaction on the promoting cognitive impairment remain unclear. This population‐based study was conducted to explore the relationship between circulating VA levels with cognitive performance in T2DM subjects. Moreover, APP/PS1 mice were treated with a low VA diet to investigate the effect and mechanism of VA deficiency on glucose and Aβ metabolism in the brain. Low blood VA levels correlated with an increased risk of mild cognitive impairment in both non‐T2DM and T2DM subjects, and T2DM patients need much higher circulating VA levels to maintain normal cognitive function. High‐fat diet induced insulin resistance in APP/PS1 mice, and this impact was further enhanced by a low VA diet. A synergistic deteriorated impact of a high‐fat diet and low VA intake on AD‐like pathology was observed in APP/PS1 mice, which was demonstrated by increased cortical BACE1 expression and Aβ level and decreased IRS1 expression. Our results suggest that the nutritional status of VA is associated with cognitive performance in the elderly and synergistically enhances the pathological phenotypic changes in APP/PS1 mice treated with a high‐fat diet.

Efficacy of red algae and artichoke extracts in disrupting antioxidant/PI3K/RBP-4 pathway in high-fat diet-induced metabolic disorders in rats

BackgroundInsulin resistance (IR) leads to various metabolic abnormalities, including diabetes mellitus, obesity, nonalcoholic steatohepatitis, and neurodegenerative disorders. Natural products rich in nontoxic phytochemicals are cost-effective and widely used to manage insulin resistance, reducing drug interactions. Artichoke stems and red algae contain several phytochemical compounds that exert antioxidant and anti-inflammatory effects.AimThis study aims to explore and compare the preventive and therapeutic effects of red algae and artichoke stem extracts against high-fat diet-induced insulin resistance and then compare their impacts with those of the reference drug metformin, which is commonly used for treating type 2 diabetes.MethodsThe animals were fed a high-fat diet for eight weeks to induce insulin resistance. The plants were then treated orally with 100 mg/kg body weight red algae, artichoke extracts, or metformin per day for 14 days. The protective rat groups received the extracts at the same dose for 14 days before being fed the high-fat diet for eight weeks. Commercial kits and standardized methods were used to measure blood diabetic profiles (glucose, insulin, lipid profile, fructosamine, and retinol-binding protein-4 (RBP-4)) and liver oxidative stress parameters, nuclear factor-κβ (NF-κβ), peroxisome proliferator-activated receptor gamma (PPAR-γ), phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K), retinol-binding protein-4 (RBP-4), and phosphatase and tensin homolog (PTEN).ResultsOur results showed that both extracts inhibited NF-κB and PTEN while enhancing PI3K, RPB-4, and PPAR-γ due to their potent antioxidant properties. They also increased insulin sensitivity, as reflected by reduced blood glucose and lipid profile levels and normalized fructosamine and RBP-4. Additionally, these extracts prevent oxidative stress-induced hepatic and nephric cell dysfunction, as confirmed by improved blood, liver, and kidney parameters.ConclusionTherefore, both extracts could be good antioxidant treatments for oxidative stress-related insulin resistance because they restore the balance of the PI3K/PPAR-γ/RBP-4 pathway. This pathway increases glucose uptake, stops gluconeogenesis, speeds up lipid metabolism, and stops the inflammation pathway.

Rice Kefiran Ameliorates Obesity and Hepatic Steatosis Through the Change in Gut Microbiota

Obesity is a global epidemic and a significant risk factor for various diseases. Obesity and dysbiosis are associated, drawing attention to the mechanisms that regulate the gut microbiota. In this study, we focused on the postbiotic effects of rice kefiran (Kef), a functional product of Lactobacillus kefiranofaciens cultured in a rice-based medium, on obesity and its complications. Although Kef has the potential to improve obesity, the underlying mechanisms remain unknown. Therefore, we aimed to elucidate the mechanisms underlying changes in gut microbiota. The administration of Kef significantly suppressed diet-induced body weight gain, reduced liver fat accumulation, and modestly improved insulin resistance. Among the gut bacteria, Lachnospiraceae and Lachnoclostridium, which were positively correlated with obesity, decreased in mice administered Kef. In contrast, Bacteroides and Alistipes, both reported to ameliorate obesity, were increased. Consistent with the changes in the gut microbiota, Kef increased fecal acetate levels, which ameliorated obesity and hepatic steatosis. Predictive metagenomic analysis suggested that Kef administration increased the abundance of KEGG orthologs, associated with carbohydrate metabolism and improvements in insulin resistance. In conclusion, Kef improves diet-induced obesity, hepatic steatosis, and insulin resistance by regulating the gut microbiota’s composition.

OM-85 attenuates high-fat diet-induced obesity, insulin resistance, gut dysbiosis and nonalcoholic steatohepatitis in a murine model

BackgroundObesity is a global epidemic that is tied to a wide range of human disorders. Chronic consumption of a high-fat diet is linked to disruption of the intestinal microbiome, which drives obesity-related pathophysiology. Broncho-Vaxom® (OM-85), a bacterial lysate used for prophylaxis of recurrent respiratory tract infections, has both immunostimulatory and immunomodulatory functions. MethodsMale C57Bl/6 mice were maintained on normal control vs. high-fat diets for 8 weeks and treated or untreated with OM-85 or with the probiotic Lactobacillus plantarum, as a positive control. Mice were evaluated for weight gain, glucose tolerance, insulin tolerance, gut microbiome composition and non-alcoholic steatohepatitis (NASH). ResultsHigh-fat diet mice developed obesity, insulin resistance, NASH and gut dysbiosis with a shift from the Bacteroidetes phylum, such as Bacteroidales order and Muribaculaceae family organisms to Firmicutes groups, such as the Clostridium and Blautia genuses. Treatment with OM-85 led to 1) prevention of obesity, 2) prevention of insulin resistance, 3) attenuation of NASH and 4) attenuation of gut dysbiosis, with decreased levels of the organisms mentioned above and increases in Verrucomicrobiae phylum organisms such as Akkermansia family microbes as well as Muribaculaceae organisms. These shifts in the gut microbiome predict favorable effects on the short chain fatty acid profile in the gut and increased integrity of the intestinal barrier. Pathway analysis showed that OM-85 decreases rates of carbohydrate metabolism, providing an additional mechanism whereby OM-85 prevents obesity. ConclusionImmune modulators such as OM-85 should be investigated for their potential therapeutic effects on metabolism.

Porcine transient receptor potential channel 1 promotes adipogenesis and lipid deposition

Adipose tissue, an important organ involved in energy metabolism and endocrine, is closely related to animal meat quality and human health. Transient receptor potential channel 1 (TRPC1), an ion transporter, is adipocytes’ major Ca2+ entry channel. However, its function in fat deposition is poorly understood, particularly in pigs, which are both an ideal model for human obesity research and a primary meat source for human diets. In the present investigation, our findings demonstrate a prominent expression of TRPC1 within the adipose tissue of pigs with a strong fat deposition ability. Functional analysis showed that TRPC1 promotes primary preadipocyte proliferation and adipogenic differentiation. In vivo, transgenic mice expressing porcine TRPC1 (Tg-pTRPC1) exhibited aggravated high-fat diet-induced obesity, hepatic steatosis, and insulin resistance. Moreover, TRPC1 may facilitate adipogenesis via activating PI3K/AKT and β-catenin signaling pathways. Our research underscores the pivotal role of porcine TRPC1 as a positive regulator in adipogenesis and lipid accumulation processes, providing a potential target for improving animal meat quality and treating obesity-related diseases in humans.

A double knockout for zinc transporter 8 and somatostatin in mice reveals their distinct roles in regulation of insulin secretion and obesity

BackgroundBoth zinc transporter 8 (ZnT8) and somatostatin (Sst) play crucial roles in the regulation of insulin and glucagon secretion. However, the interaction between them in controlling glucose metabolism was not well understood. The aim of this study was to explore the interactive effects of a double knockout of Znt8 and Sst on insulin and glucose metabolism in mice.MethodsCo-expression of ZnT8 with hormones secreted from gastrointestinal endocrine cells of mice was determined using immunofluorescence. Male Znt8 knockout (Znt8KO), Sst knockout (SstKO), double knockout for Sst and Znt8 (DKO), and the wild-type (WT) mice were fed a regular chow diet (CD) or a high-fat diet (HFD) at 3 weeks old for 15 weeks. Weights and fasting or fed glucose levels were determined. Glucose and insulin tolerance tests were performed; metabolic-relevant hormone levels including insulin, glucagon, glucagon-like peptide 1, Pyy, and leptin were determined.ResultsZnT8 is co-expressed with Sst in a subpopulation of endocrine D cells in the gastrointestinal tract. The absence of ZnT8 expression resulted in an increased density of the dense cores in the secretory granules of the D cell. DKO mice had reduced weight compared to WT when maintained on the CD. Compared to Znt8KO and SstKO, DKO mice did not show significant differences in fed or fasting blood glucose level regardless of dietary conditions. However, the CD-fed DKO mice had impaired insulin secretion without alterations in islet morphology or numbers. Moreover, DKO mice displayed diet-induced insulin resistance and disrupted secretion of metabolic-related hormones.ConclusionsSomatostatin as well as a normal insulin sensitivity are required for normalizing glucose metabolism in Znt8KO mice. ZnT8 may play a role in regulating fat mass and leptin secretion. These findings shed light on the multifaceted nature of Znt8 and Sst interactions, opening new avenues to understand their roles in controlling glucose metabolism and fat mass.

Liver adrenoceptor alpha-1b plays a key role in energy and glucose homeostasis in female mice.

The liver plays a major role in glucose and lipid homeostasis and acts as a key organ in the pathophysiology of metabolic diseases. Intriguingly, increased sympathetic nervous system (SNS) activity to the liver has been associated with the development and progression of type 2 diabetes and obesity. However, the precise mechanisms by which the SNS regulates hepatic metabolism remain to be defined. Although liver α1-adrenoceptors were suggested to play a role in glucose homeostasis, the specific subtypes involved are unknown mainly because of the limitations of pharmacological tools. Here, we generated and validated a novel mouse model allowing tissue-specific deletion of α-1b adrenoceptor (Adra1b) in hepatocytes to investigate the role of liver ADRA1B in energy and glucose metabolism. We found that selective deletion of Adra1b in mouse liver has limited metabolic impact in lean mice. However, loss of Adra1b in hepatocytes exacerbated diet-induced obesity, insulin resistance, and glucose intolerance in female, but not in male mice. In obese females, this was accompanied by reduced hepatic gluconeogenic capacity and reprogramming of gonadal adipose tissue with hyperleptinemia. Our data highlight sex-dependent mechanisms by which the SNS regulates energy and glucose homeostasis through liver ADRA1B.NEW & NOTEWORTHY The sympathetic nervous system plays an important role in regulating hepatic physiology and metabolism. However, the identity of the adrenoceptors involved in these effects is still elusive. Using CRISPR-Cas9, we developed a novel transgenic tool to study the role of liver α-1b adrenoceptor (ADRA1B). We show that ADRA1B plays a key role in mediating the effects of the sympathetic nervous system on hepatic metabolism, particularly in female mice.

9227 Haptoglobin-related protein (HPR) new role as insulin secretion enhancer

Abstract Disclosure: Carlos Viesi, Ph.D.[1], Ian Tamburini, BS[1], Hosung Bae, Ph.D[1]., Erwin Ilegems, Ph.D.[2], Leandro Velez, Ph.D. [1], Mingqi Zhou, BS[1], Christy Nguyen, Ph.D.[1], Casey Johnson, Ph.D.[1], Cholsoon Jang, Ph.D[1]., Erika Nishimura[2] and Marcus Seldin, Ph.D.[1]. [1]Department of Biological Chemistry, Center for Epigenetics and Metabolism, University of California, Irvine, CA, USA, [2]Departments of Diabetes Protein Engineering, Diabetes Biology & Pharmacology, Medicinal Chemistry, Protein Engineering, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark. Type 2 Diabetes (T2D) affects over 530 million people around the globe. Insulin resistance, encompassing tissues such as muscle, adipose, and liver, is the initial step hallmarked by hyperinsulinemia. Coupled with β-cell failure, these coordinated responses progress to T2D, becoming irreversible and medically challenging. Despite the well-established requirement for communication between pancreas and peripheral tissues in T2D progression, this area remains almost entirely unexplored. Here, we performed a human population genetic screening across 310 individuals to search for new endocrine regulators of pancreas function. Specifically, global gene expression from 18 peripheral tissues was analyzed to identify potential endocrine regulators of insulin secretion. This analysis prioritized liver-specific Haptoglobin-related protein (HPR) as genetically-enriched with islet insulin responses. Mouse models using AAV technology and acute protein administration of HPR showed that this newly secreted protein is sufficient to prevent diet-induced insulin resistance through enhanced beta-cell respiration. When mice were administered soluble HPR, then pancreatic tissue subjected to global RNA-sequencing, enhanced respiration pathways were observed. Next, we generated hepatocyte-specific overexpression models using AAV, which were sufficient to rescue whole-body glucose disposal profiles and weight gain in diet-induced insulin-resistant mice. Altogether, these findings highlight HPR as a novel soluble protein which signals from liver to pancreatic islets. Presentation: 6/3/2024

8258 Haptoglobin-related protein (HPR) new role as insulin secretion enhancer

Abstract Disclosure: C. Viesi: None. Type 2 Diabetes (T2D) affects over 530 million people around the globe. Insulin resistance, encompassing tissues such as muscle, adipose, and liver, is the initial step hallmarked by hyperinsulinemia. Coupled with β-cell failure, these coordinated responses progress to T2D, becoming irreversible and medically challenging. Despite the well-established requirement for communication between pancreas and peripheral tissues in T2D progression, this area remains almost entirely unexplored. Here, we performed a human population genetic screening across 310 individuals to search for new endocrine regulators of pancreas function. Specifically, global gene expression from 18 peripheral tissues was analyzed to identify potential endocrine regulators of insulin secretion. This analysis prioritized liver-specific Haptoglobin-related protein (HPR) as genetically-enriched with islet insulin responses. Mouse models using AAV technology and acute protein administration of HPR showed that this newly secreted protein is sufficient to prevent diet-induced insulin resistance through enhanced beta-cell respiration. When mice were administered soluble HPR, then pancreatic tissue subjected to global RNA-sequencing, enhanced respiration pathways were observed. Next, we generated hepatocyte-specific overexpression models using AAV, which were sufficient to rescue whole-body glucose disposal profiles and weight gain in diet-induced insulin-resistant mice. Altogether, these findings highlight HPR as a novel soluble protein which signals from liver to pancreatic islets. Presentation: 6/3/2024

Hypoxanthine ameliorates diet-induced insulin resistance by improving hepatic lipid metabolism and gluconeogenesis via AMPK/mTOR/PPARα pathway

AimInsulin resistance (IR) is a pivotal metabolic disorder associated with type 2 diabetes and metabolic syndrome. This study investigated the potential of hypoxanthine (Hx), a purine metabolite and uric acid precursor, in ameliorating IR and regulating hepatic glucose and lipid metabolism. MethodsWe utilized both in vitro IR-HepG2 cells and in vivo diet-induced IR mice to investigate the impact of Hx. The HepG2 cells were treated with Hx to evaluate its effects on glucose production and lipid deposition. Activity-based protein profiling (ABPP) was applied to identify Hx-target proteins and the underlying pathways. In vivo studies involved administration of Hx to IR mice, followed by assessments of IR-associated indices, with explores on the potential regulating mechanisms on hepatic glucose and lipid metabolism. Key findingsHx intervention significantly reduced glucose production and lipid deposition in a dose-dependent manner without affecting cell viability in IR-HepG2 cells. ABPP identified key Hx-target proteins engaged in fatty acid and pyruvate metabolism. In vivo, Hx treatment reduced IR severities, as evidenced by decreased HOMA-IR, fasting blood glucose, and serum lipid profiles. Histological assessments confirmed reduced liver lipid deposition. Mechanistic insights revealed that Hx suppresses hepatic gluconeogenesis and fatty acid synthesis, and promotes fatty acid oxidation via the AMPK/mTOR/PPARα pathway. SignificanceThis study delineates a novel role of Hx in regulating hepatic metabolism, offering a potential therapeutic strategy for IR and associated metabolic disorders. The findings provide a foundation for further investigation into the role of purine metabolites in metabolic regulation and their clinical implications.

Glibenclamide reverses cardiac damage and NLRP3 inflammasome activation associated with a high refined sugar diet

Increased energy intake from carbohydrates has been associated with major cardiovascular outcomes. Mice fed a highly-refined carbohydrate (HC) diet develop cardiac hypertrophy and inflammation. During cardiac injury, NLRP3 inflammasome is activated which results in a local inflammatory response. In this study, we hypothesized that a nom-hypoglycemic dose of glibenclamide may reverses sugar diet-induced cardiac damage by NRLP3 inflammasome inhibition. Mice were fed the HC diet for eight weeks and divided into a group treated with glibenclamide (20 mg/kg, gavage) and another with vehicle for four weeks. Afterward, hearts were excised for morphometric analysis and ex vivo function determination. NLRP3 inflammasome activation was investigated by western blotting and in situ fluorescent detection of reactive oxygen species (ROS) and active caspase-1. The HC diet promotes heart hypertrophy and collagen deposition, which were reverted by glibenclamide without ameliorating HC diet-induced insulin resistance. Changes in cardiac performance were observed in vivo by invasive catheterization and in Langendorff-perfused hearts due to the HC diet, which were prevented by glibenclamide. Hearts from HC diet mice had increased levels of NLRP3 and cleaved IL-1β. Glibenclamide reversed ROS production and caspase-1 activity induced by HC diet. These findings suggest glibenclamide's cardioprotective effects on heart damage caused by the HC diet are related to its inhibitory action on the NLRP3 inflammasome.

8449 A Chronic Treatment of Interleukin-12 Restores Diet-Induced Hepatic Insulin Resistance and Liver Fibrosis in Mice with Interferon-gamma Signaling Deficient Macrophages

8449 A Chronic Treatment of Interleukin-12 Restores Diet-Induced Hepatic Insulin Resistance and Liver Fibrosis in Mice with Interferon-gamma Signaling Deficient Macrophages

Actein ameliorates diet-induced obesity through the activation of AMPK-mediated white fat browning

BackgroundTargeting white adipose tissue (WAT) browning to increase systemic energy expenditure is a promising therapeutic strategy to combat obesity. Actein from Actaea cimicifuga L. has recently been reported to ameliorate high fat-induced hepatic steatosis. However, the effect of actein on diet-induced obesity merits more and further investigation. PurposeWe aimed to examine the anti-obesity potential of actein and unravel its actions on WAT browning. MethodsThe effect of actein on diet-induced obesity was evaluated using a high-fat diet model in C57BL/6 mice. Systemic energy expenditure of mice was measured with a combined indirect calorimetry system. Quantitative real-time PCR analyses were performed to investigate the mRNA levels of genes involved in thermogenesis, browning, and lipolysis. The protein levels were assessed by Western blot. Moreover, WAT explants and a transwell co-culture system consisting of SVFs and adipocytes were constructed to study the mechanisms of actein on promoting WAT browning and lipolysis. ResultsAt a dosage of 5 mg/kg/d, actein not only protected mice against diet-induced obesity and insulin resistance, but also reversed pre-established obesity and glucose intolerance in mice. Meanwhile, actein facilitated systemic energy expenditure by activating WAT lipolysis and browning. Further, mechanistic studies revealed that actein indirectly induced epididymal adipocyte lipolysis and directly promoted a white-to-beige conversion of subcutaneous adipocytes by activating the AMPK signaling. ConclusionActein ameliorated diet-induced obesity and was discovered as a natural lead compound directly targeting white-to-beige conversion of subcutaneous adipocytes, suggesting the potential of developing new therapies for obesity and associated metabolic disorders.

Enhanced ECCD36 signaling promotes skeletal muscle insulin resistance in female mice.

Consumption of a Western diet (WD) increases CD36 expression in vascular, hepatic, and skeletal muscle tissues promoting lipid metabolic disorders and insulin resistance. We further examined the role of endothelial cell-specific CD36 (ECCD36) signaling in contributing to skeletal muscle lipid metabolic disorders, insulin resistance, and their underlying molecular mechanisms. Female ECCD36 wild-type (ECCD36+/+) and knock-out (ECCD36-/-) mice, aged 6 wk, were provided with either a WD or a standard chow diet for a duration of 16 wk. ECCD36+/+ WD mice were characterized by elevated fasting plasma glucose and insulin levels, increased homeostatic model assessment for insulin resistance, and glucose intolerance that was blunted in ECCD36-/- mice. Improved insulin sensitivity in ECCD36-/- mice was characterized by increased phosphoinositide 3-kinases/protein kinase B signaling that further augmented glucose transporter type 4 expression and glucose uptake. Meanwhile, 16 wk of WD feeding also increased skeletal muscle free fatty acid (FFA) and lipid accumulation, without any observed changes in plasma FFA levels. These lipid metabolic disorders were blunted in ECCD36-/- mice. Moreover, ECCD36 also mediated in vitro palmitic acid-induced lipid accumulation in cultured ECs, subsequently leading to the release of FFAs into the culture media. Furthermore, consumption of a WD increased FFA oxidation, mitochondrial dysfunction, impaired mitochondrial respiratory, skeletal muscle fiber type transition, and fibrosis. These WD-induced abnormalities were blunted in ECCD36-/- mice. These findings demonstrate that endothelial-specific ECCD36 signaling participates in skeletal muscle FFA uptake, ectopic lipid accumulation, mitochondrial dysfunction, insulin resistance, and associated skeletal muscle dysfunction in diet-induced obesity.NEW & NOTEWORTHY ECCD36 exerts "extra endothelial cell" actions in skeletal muscle insulin resistance. ECCD36 is a major mediator of Western diet-induced lipid metabolic disorders and insulin resistance in skeletal muscle. Mitochondrial dysfunction is associated with diet-induced CD36 activation and related skeletal muscle insulin resistance.

The microbiota-dependent tryptophan metabolite alleviates high-fat diet–induced insulin resistance through the hepatic AhR/TSC2/mTORC1 axis

Type 2 diabetes (T2D) is potentially linked to disordered tryptophan metabolism that attributes to the intricate interplay among diet, gut microbiota, and host physiology. However, underlying mechanisms are substantially unknown. Comparing the gut microbiome and metabolome differences in mice fed a normal diet (ND) and high-fat diet (HFD), we uncover that the gut microbiota-dependent tryptophan metabolite 5-hydroxyindole-3-acetic acid (5-HIAA) is present at lower concentrations in mice with versus without insulin resistance. We further demonstrate that the microbial transformation of tryptophan into 5-HIAA is mediated by Burkholderia spp. Additionally, we show that the administration of 5-HIAA improves glucose intolerance and obesity in HFD-fed mice, while preserving hepatic insulin sensitivity. Mechanistically, 5-HIAA promotes hepatic insulin signaling by directly activating AhR, which stimulates TSC2 transcription and thus inhibits mTORC1 signaling. Moreover, T2D patients exhibit decreased fecal levels of 5-HIAA. Our findings identify a noncanonical pathway of microbially producing 5-HIAA from tryptophan and indicate that 5-HIAA might alleviate the pathogenesis of T2D.

Amelioration of nonalcoholic fatty liver disease by inhibiting the deubiquitylating enzyme RPN11

Nonalcoholic fatty liver disease (NAFLD), including its more severe manifestation nonalcoholic steatohepatitis (NASH), is a global public health challenge. Here, we explore the role of deubiquitinating enzyme RPN11 in NAFLD and NASH. Hepatocyte-specific RPN11 knockout mice are protected from diet-induced liver steatosis, insulin resistance, and steatohepatitis. Mechanistically, RPN11 deubiquitinates and stabilizes METTL3 to enhance the m6A modification and expression of acyl-coenzyme A (CoA) synthetase short-chain family member 3 (ACSS3), which generates propionyl-CoA to upregulate lipid metabolism genes via histone propionylation. The RPN11-METTL3-ACSS3-histone propionylation pathway is activated in the livers of patients with NAFLD. Pharmacological inhibition of RPN11 by Capzimin ameliorated NAFLD, NASH, and related metabolic disorders in mice and reduced lipid contents in human hepatocytes cultured in 2D and 3D. These results demonstrate that RPN11 is a novel regulator of NAFLD/NASH and that suppressing RPN11 has therapeutic potential for the treatment.