Insulin Resistance In Obese Mice Research Articles

Marine algae oils from Phaeodactylum tricornutum and Laminaria japonica alleviate obesity, insulin resistance, and gut microbiota dysbiosis in high-fat diet-fed mice

The present study was aimed to investigate the effects of Phaeodactylum tricornutum oil (PO) and Laminaria japonica oil (LO) against obesity and other metabolic disorders in a high-fat diet (HFD) induced obese mouse model. The results revealed that PO or LO supplementation significantly reduced HFD-induced body weight gain, hyperlipemia, and fat accumulation in mice. PO or LO supplementation also inhibited SREBP-1-mediated de novo lipogenesis and PPARγ-mediated adipogenesis, as well as enhanced PPARα-mediated fatty acid β-oxidation in the WAT and liver of HFD-fed mice. Moreover, PO or LO supplementation attenuated low-grade chronic inflammation, hyperglycemia and insulin resistance in obese mice. Furthermore, Dietary PO or LO also modulated HFD-induced gut microbiota dysbiosis and increased the SCFAs production. More importantly, our results also manifested that the ameliorative effect of PO and LO against HFD-induced obesity, IR and gut microbiota dysbiosis was comparable, but was superior than that of krill oil and fish oil.

The therapeutic effects of traditional Chinese medicine on insulin resistance in obese mice by modulating intestinal functions

IntroductionObesity, mainly caused by excessive accumulation of visceral fat, excessive fat metabolism will cause hormone secretion imbalance and inflammation and other diseases. is extremely detrimental to human health. Although many treatments are available for obesity, most treatments fail to exert a radical effect or are associated with several side effects. Traditional Chinese medicine (TCM) for regulating the intestinal flora, lipid content and inflammation is considered effective. Based on previous studies, Artemisia capillaris, Astragalus propinquus, Phellodendron amurense, Salvia miltiorrhiza, Poria cocos, and Anemarrhena asphodeloides were selected to prepare an innovative herbal formula. MethodsTCM was characterized by UHPLC-Q-Orbitrap-MS. The anti-inflammatory and lipid-lowering effects of the TCM formula prepared were evaluated in a high-fat diet-fed obese mouse model. The effects of the TCM formula on the intestinal flora were also investigated. ResultsWeights and insulin resistance, as well as inflammation, decreased in the mice after treatment. At the same time, lipid metabolism increased after the mice were gavaged with the TCM formula for 2 weeks. The intestinal motility of the drug administration group was enhanced, with partial restoration of the intestinal flora. ConclusionIn summary, our innovative Chinese herbal formula significantly reduced weight, reduced intestinal inflammation, improved intestinal motility, and improved lipid metabolism in obese mice. Furthermore, the innovative formula effectively prevented relevant obesity-induced metastatic diseases in the mice.

Alleviative effects of the parthenolide derivative ACT001 on insulin resistance induced by sodium propionate combined with a high-fat diet and its potential mechanisms

The increasing side effects of traditional medications used to treat type II diabetes have made research into the development of safer and more effective natural medications necessary. ACT001, a derivative of parthenolide, has been shown to have good anti-inflammatory and antitumor effects; however, its role in diabetes is unclear. The short-chain fatty acid propionate is a common food preservative that has been found to cause disturbances in glucose metabolism in mice and humans. This study aimed to investigate whether sodium propionate could aggravate insulin resistance in obese mice and cause diabetes and to study the alleviative effects and potential mechanisms of action of ACT001 on insulin resistance in diabetic mice. Type II diabetic mice were adminietered sodium propionate combined with a high-fat diet (HFD + propionate) by gavage daily for four weeks. Biochemical analysis showed that ACT001 significantly affected blood glucose concentration in diabetic mice, mainly by downregulating the expression of phosphoenolpyruvate carboxykinase 2 and glucose-6-phosphatase. Meanwhile, the level of fatty acid-binding protein 4 in the liver was significantly decreased. ACT001 has a protective effect on the liver and adipose tissue of mice. In addition, the results of the running wheel experiment indicated that ACT001 alleviated the circadian rhythm disorder caused by insulin resistance to a certain extent. This study revealed the potential mechanism by which ACT001 alleviates insulin resistance and provides ideas for developing natural antidiabetic drugs.

Inhibition of HSP20 Ameliorates Steatotic Liver Disease by Stimulating ERK2-Dependent Autophagy.

Heat shock protein 20 (HSP20) emerges as a novel regulator of autophagy in the heart. Nonetheless, the detailed function of HSP20 in liver and its effect on autophagy remain unknown. Here, we observed that HSP20 expression is increased in liver tissues from mice and patients with metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD). Liver-specific downregulation of HSP20 mitigates hepatic steatosis and insulin resistance in obese mice, while upregulating HSP20 promotes lipid deposition and hepatocyte cell death. Mechanistically, Liquid chromatography tandem mass spectrometry (LC-MS/MS) revealed that HSP20 interacts with phosphorylated extracellular regulated protein kinases 2 (ERK2) and prevents its dephosphorylation by dual specificity phosphatase 6 (DUSP6), leading to ERK2-mediated repression of autophagy, resulting in aggravated saturated fatty acid (SFA)-triggered hepatocyte death. Importantly, such adverse effects could be ameliorated by ERK inhibitor. Our data reveals a framework of how HSP20 increases susceptibility of SFA-induced liver injury through enhancing ERK2 phosphorylation, which represents a plausible therapeutic intervention to combat MASLD.

Divergent roles of the regulatory subunits of class IA PI3K.

The regulatory subunit of phosphatidylinositol 3-kinase (PI3K), known as p85, is a critical component in the insulin signaling pathway. Extensive research has shed light on the diverse roles played by the two isoforms of p85, namely p85α and p85β. The gene pik3r1 encodes p85α and its variants, p55α and p50α, while pik3r2 encodes p85β. These isoforms exhibit various activities depending on tissue types, nutrient availability, and cellular stoichiometry. Whole-body or liver-specific deletion of pik3r1 have shown to display increased insulin sensitivity and improved glucose homeostasis; however, skeletal muscle-specific deletion of p85α does not exhibit any significant effects on glucose homeostasis. On the other hand, whole-body deletion of pik3r2 shows improved insulin sensitivity with no significant impact on glucose tolerance. Meanwhile, liver-specific double knockout of pik3r1 and pik3r2 leads to reduced insulin sensitivity and glucose tolerance. In the context of obesity, upregulation of hepatic p85α or p85β has been shown to improve glucose homeostasis. However, hepatic overexpression of p85α in the absence of p50α and p55α results in increased insulin resistance in obese mice. p85α and p85β have distinctive roles in cancer development. p85α acts as a tumor suppressor, but p85β promotes tumor progression. In the immune system, p85α facilitates B cell development, while p85β regulates T cell differentiation and maturation. This review provides a comprehensive overview of the distinct functions attributed to p85α and p85β, highlighting their significance in various physiological processes, including insulin signaling, cancer development, and immune system regulation.

Exerkine β-aminoisobutyric acid protects against atrial structural remodeling and atrial fibrillation in obesity via activating AMPK signaling and improving insulin sensitivity

Moderate exercise decreases the risk for atrial fibrillation (AF), an effect which is probably mediated via exercise-stimulated release of exerkines. β-Aminoisobutyric acid (BAIBA), a novel exerkine, has been reported to provide protective benefits against many cardiovascular diseases, yet its role in AF remains elusive. Herein, using a mouse model of obesity-related AF through high-fat diet (HFD) feeding, we found that 12-week drinking administration of BAIBA (170 mg/kg/day) decreased AF susceptibility in obese mice. Atrial remodeling assessment showed that BAIBA attenuated obesity-induced atrial hypertrophy and interstitial fibrosis, thereby ablating the substrate for AF. Of note, to our knowledge, this is the first report of the direct association of BAIBA and hypertrophy. BAIBA has been reported to be a key regulator of glucose and lipid metabolism, and we found that BAIBA alleviated insulin resistance in obese mice. Transcriptional analysis of metabolism-related genes showed that BAIBA increased the transcription of fatty acids metabolism-related genes in the atria of lean mice but not in that of obese mice. Mechanistic investigation showed that BAIBA stimulated AMP-activated protein kinase (AMPK) signaling in the atria of obese mice and palmitic acid (PA)-treated neonatal rat cardiomyocytes (NRCM), whereas inhibition of AMPK via Compound C attenuated BAIBA-conferred cardioprotection against hypertrophy and insulin resistance in PA-treated NRCM. Collectively, BAIBA attenuates AF susceptibility in obese mice via activated AMPK signaling and resultant improvement of insulin sensitivity, thereby providing perspectives on the potential therapeutic role of BAIBA in AF treatment.

The P2Y2 receptor mediates terminal adipocyte differentiation and insulin resistance: Evidence for a dual G-protein coupling mode

Several P2Y nucleotide receptors have been shown to be involved in the early stage of adipocyte differentiation in vitro and insulin resistance in obese mice; however, the exact receptor subtype(s) and its underlying molecular mechanism in relevant human cells are unclear. Here, using human primary visceral preadipocytes as a model, we found that during preadipocyte-to-mature adipocyte differentiation, the P2Y2 nucleotide receptor (P2Y2R) was the most upregulated subtype among the eight known P2Y receptors and the only one further dramatically upregulated after inflammatory TNFα treatment. Functional studies indicated that the P2Y2R induced intracellular Ca2+, ERK1/2, and JNK signaling but not the p38 pathway. In addition, stimulation of the P2Y2R suppressed basal and insulin-induced phosphorylation of AKT, accompanied by decreased GLUT4 membrane translocation and glucose uptake in mature adipocytes, suggesting a role of P2Y2R in insulin resistance. Mechanistically, we found that activation of P2Y2R did not increase lipolysis but suppressed PIP3 generation. Interestingly, activation of P2Y2R triggered Gi-protein coupling, and pertussis toxin pretreatment largely inhibited P2Y2R-mediated ERK1/2 signaling and cAMP suppression. Further, treatment of the cells with AR-C 118925XX, a selective P2Y2R antagonist, significantly inhibited adipogenesis, and P2Y2R knockout decreased mouse body weight gain with smaller eWAT mass infiltrated with fewer macrophages as compared to wild-type mice in response to a Western diet. Thus, we revealed that terminal adipocyte differentiation and inflammation selectively upregulate P2Y2R expression and that P2Y2R mediates insulin resistance by suppressing the AKT signaling pathway, highlighting P2Y2R as a potential new drug target to combat obesity and type-2 diabetes.

GIPR Agonism Enhances TZD-Induced Insulin Sensitivity in Obese IR Mice.

Recent studies have found that GIPR agonism can enhance the metabolic efficacy of GLP-1R agonist treatment by promoting both weight-dependent and -independent improvements on systemic insulin sensitivity. These findings have prompted new investigations aimed at better understanding the broad metabolic benefit of GIPR activation. Herein, we determined whether GIPR agonism favorably influenced the pharmacologic efficacy of the insulin sensitizing thiazolidinedione, rosiglitazone in obese insulin resistant (IR) mice. Genetic and pharmacological approaches were employed to examine the role of GIPR signaling on rosiglitazone-induced weight gain, hyperphagia, and glycemic control. RNA-sequencing was conducted to uncover potential mechanisms by which GIPR activation influences energy balance and insulin sensitivity. In line with previous findings, treatment with rosiglitazone induced the mRNA expression of the GIPR in white and brown fat. However, obese GIPR null mice dosed with rosiglitazone displayed equivalent weight gain to that of wild-type (WT) animals. Strikingly, chronic treatment of obese IR WT animals with a long-acting GIPR agonist (LAGIPRA) prevented rosiglitazone-induced weight-gain and hyperphagia, and it enhanced the insulin-sensitivity effect of this thiazolidinedione. The systemic insulin sensitization was accompanied by increased glucose disposal in brown adipose tissue (BAT), which was underlined by the recruitment of metabolic and thermogenic genes. These findings suggest that GIPR agonism can counter the negative consequences of rosiglitazone treatment on body weight and adiposity, while at the same time improving its insulin sensitizing efficacy.

Effects of diallyl disulfide administration on insulin resistance in high-fat diet-fed mice

ObjectivesDiallyl disulfide (DADS) is a natural organosulfur compound found in garlic and related plants with various pharmacologic effects. However, whether DADS improves obesity-induced insulin resistance (IR) and its underlying mechanisms remain unclear. The aim of this study was to investigate the effects of DADS on systemic IR in high-fat diet-induced obese mice. MethodsTo induce obesity, 8-wk-old male C57BL/6J mice were fed a high-fat diet (60% fat/kcal). The mice were assigned to three weight-matched groups: control (CON, n = 8), low-dose DADS (DADS-L, n = 8), and high-dose DADS (DADS-H, n = 9). The treated mice were orally administered DADS (25 or 100 mg/kg) 5 d/wk for 8 wk. At 15 wk of age, an intraperitoneal glucose tolerance test (GTT) and insulin tolerance test (ITT) were performed. Twenty-four hours after the final administration of DADS, epididymal fat and the liver were sampled after a 5-h fast. ResultsDADS administration significantly attenuated body and fat weight gains during the experimental period. Additionally, systemic IR, as evaluated by ITT, was significantly improved by DADS administration in a dose-dependent manner. High-dose DADS administration significantly decreased liver triacylglycerol levels. Moreover, high-dose DADS administration decreased the c-Jun N-terminal kinase (JNK) phosphorylation and significantly increased heat shock protein 72 expression in the liver. ConclusionsThe results of this study suggested that DADS administration alleviated systemic IR in obese mice. This may be associated with decreased hepatic fat accumulation and a heat shock protein 72-mediated decrease in JNK activity in the liver.

Hepatic DDAH1 mitigates hepatic steatosis and insulin resistance in obese mice: Involvement of reduced S100A11 expression.

Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is an important regulator of plasma asymmetric dimethylarginine (ADMA) levels, which are associated with insulin resistance in patients with nonalcoholic fatty liver disease (NAFLD). To elucidate the role of hepatic DDAH1 in the pathogenesis of NAFLD, we used hepatocyte-specific Ddah1-knockout mice (Ddah1HKO) to examine the progress of high-fat diet (HFD)-induced NAFLD. Compared to diet-matched flox/flox littermates (Ddah1f/f), Ddah1HKO mice exhibited higher serum ADMA levels. After HFD feeding for 16 weeks, Ddah1HKO mice developed more severe liver steatosis and worse insulin resistance than Ddah1f/f mice. On the contrary, overexpression of DDAH1 attenuated the NAFLD-like phenotype in HFD-fed mice and ob/ob mice. RNA-seq analysis showed that DDAH1 affects NF-κB signaling, lipid metabolic processes, and immune system processes in fatty livers. Furthermore, DDAH1 reduces S100 calcium-binding protein A11 (S100A11) possibly via NF-κB, JNK and oxidative stress-dependent manner in fatty livers. Knockdown of hepatic S100a11 by an AAV8-shS100a11 vector alleviated hepatic steatosis and insulin resistance in HFD-fed Ddah1HKO mice. In summary, our results suggested that the liver DDAH1/S100A11 axis has a marked effect on liver lipid metabolism in obese mice. Strategies to increase liver DDAH1 activity or decrease S100A11 expression could be a valuable approach for NAFLD therapy.

Role of Oxidative Stress on Insulin Resistance in Diet-Induced Obesity Mice.

Insulin resistance is the link between obesity and type 2 diabetes mellitus. The molecular mechanism by which obese individuals develop insulin resistance has not yet been fully elucidated; however, inconclusive and contradictory studies have shown that oxidative stress may be involved in the process. Thus, this study aimed to evaluate the effect of reactive species on the mechanism of insulin resistance in diet-induced obese mice. Obese insulin-resistant mice were treated with N-acetylcysteine (NAC; 50 mg/kg per day, for 15 days) by means of oral gavage. Twenty-four hours after the last NAC administration, the animals were euthanized and their tissues were extracted for biochemical and molecular analyses. NAC supplementation induced improved insulin resistance and fasting glycemia, without modifications in food intake, body weight, and adiposity. Obese mice showed increased dichlorofluorescein (DCF) oxidation, reduced catalase (CAT) activity, and reduced glutathione levels (GSH). However, treatment with NAC increased GSH and CAT activity and reduced DCF oxidation. The gastrocnemius muscle of obese mice showed an increase in nuclear factor kappa B (NFκB) and protein tyrosine phosphatase (PTP1B) levels, as well as c-Jun N-terminal kinase (JNK) phosphorylation compared to the control group; however, NAC treatment reversed these changes. Considering the molecules involved in insulin signaling, there was a reduction in insulin receptor substrate (IRS) and protein kinase B (Akt) phosphorylation. However, NAC administration increased IRS and Akt phosphorylation and IRS/PI3k (phosphoinositide 3-kinase) association. The results demonstrated that oxidative stress-associated obesity could be a mechanism involved in insulin resistance, at least in this animal model.

Red ginseng extracts ameliorate high-fat diet-induced obesity and insulin resistance by activating the intestinal TGR5-mediated bile acids signaling pathway

BackgroundObesity has emerged as a worldwide metabolic disease, given its rapid growth in global prevalence. Red ginseng extracts (RGS), one of the traditional processed products of ginseng, show the potential to improve the metabolic phenotype of obesity. However, the RGS mechanism for regulating obesity and late insulin resistance remains to be clarified. PurposeThis study aimed to emphasize the potential use of RGS in treatment of obesity and insulin resistance (IR) and explore the underlying mechanism affecting glucose and lipid metabolism improvements. MethodsThe role of RGS was evaluated in a high-fat diet (HFD) rodent model. Glucose tolerance test (GTT) and insulin tolerance test (ITT) were performed to characterize the glucose metabolism level. The expression of lipolysis proteins and uncoupling protein-1 (UCP-1) were investigated by western blot. Glucagon-like peptide-1 (GLP-1) and apical sodium-dependent bile acid transporter (ASBT) protein expression in the intestine were determined via immunofluorescence. UPLC-Q-TOF-MS were used to detect the alterations in bile acids (BAs) levels in serum, ileum, and inguinal white adipose tissue (iWAT). In addition, intestine-specific Tgr5 knockout mice were employed to verify the efficacy of RGS in improving obesity. ResultsRGS treatment alleviated dietary-induced dyslipidemia and IR in obese mice in a dose-dependent manner and improved glucose and insulin tolerance, and energy expenditure. RGS treatment significantly reduced lipid deposition and induced GLP-1 secretion in the intestine of wild-type mice but not in Tgr5ΔIN obese mice. Furthermore, RGS intervention increased BA levels in serum, ileum, and iWAT. The increase of circulating BAs in mice was related to the activation of ileal TGR5 and the promotion of ASBT translocation to the plasma membrane, thus affecting BA transport. Next, the increased level of circulating BAs entered the periphery, which might facilitate lipolysis and energy consumption by activating TGR5 in iWAT. ConclusionOur results demonstrated that RGS significantly alleviated HFD-induced obesity and insulin resistance in mice. RGS intervention improved glucose metabolism, promoted lipolysis, and energy metabolism by activating TGR5 in the intestine. In addition, we found that activating intestinal TGR5 facilitated the localization of ASBT to the plasma membrane, which ultimately promoted the transport of BAs to regulate metabolic phenotype.

363-OR: Brown Adipose Tissue m6A mRNA Methylation Regulates Systemic Insulin Sensitivity via a Prostaglandin Interorgan Axis

Brown adipose tissue (BAT) has the capacity to regulate peripheral insulin sensitivity via the secretion of signaling lipids. N6-methyladenosine (m6A) is among the most prevalent and abundant post-transcriptional RNA modifications in eukaryotes. Recently, m6A has been shown to regulate islet and hepatic metabolism as well as BAT adipogenesis and energy expenditure. Here, we demonstrate that deficiency of m6A methyltransferase-like 14 (M14) in BAT positively regulates BAT-secretory function to improve systemic insulin sensitivity through inter-organ communication. Using lipidomic approaches, we identified prostaglandin E2 (PGE2) and prostaglandin F2a (PGF2a) as M14KOBAT-secreted insulin sensitizers. Notably, circulatory PGE2 and PGF2a showed significant inverse correlation with HOMA-IR in humans. Furthermore, in vivo administration of PGE2 and PGF2a in HFD-induced insulin resistant obese mice recapitulated the phenotypes of M14KO mice. Exogenous PGE2 or PGF2a significantly improved insulin stimulated-pAKT by suppressing expression of specific phosphatases in human hepatocyte cell line. Mechanistically, M14-mediated m6A installation destabilizes transcripts encoding PGE2 and PGF2a synthases in brown adipocytes in an YTHDF2/3-dependent manner. Collectively, these results unveil a new mechanism by which m6A-facilitated BAT-secretory function enables the regulation of whole body insulin sensitivity. Disclosure L.Xiao: None. J.Pihlajamaki: None. Y.Tseng: Consultant; Cellarity, LyGenesis. R.Kulkarni: Advisory Panel; Novo Nordisk, Inversago, Biomea Fusion, Inc., REDD Pharma, Research Support; Inversago. D.F.De jesus: None. C.Ju: None. J.Wei: None. J.Hu: None. T.Tsuji: None. C.Cero: None. D.Kaminska: None. A.M.Cypess: None.

Post-Effects of Time-Restricted Feeding against Adipose Tissue Inflammation and Insulin Resistance in Obese Mice.

Time-restricted feeding (TRF) has been shown to improve the disordered metabolic and immunologic functions associated with obesity, however little is known about its post-effects after the cessation of TRF practice. In the current study, we determined how long the effects of TRF persist, and whether the effects are tissue-dependent. There were four groups of mice in this study: overweight and obese mice were randomized into (1) TRF group (TRF for 6 weeks), (2) post-TRF group (TRF for 4 weeks and later ad libitum), (3) continuous ad libitum of high-fat diet (HFD-AL), and (4) the lean control-fed low-fat diet ad libitum. Blood, liver, and adipose tissues were collected to measure the metabolic, inflammatory, and immune cell parameters. The results showed that TRF withdrawal quickly led to increased body weight/adiposity and reversed fasting blood glucose. However, fasting insulin and insulin resistance index HOMA-IR remained lower in the post-TRF than in the HFD-AL group. In addition, TRF-induced reduction in blood monocytes waned in the post-TRF group, but the TRF effects on mRNA levels of proinflammatory immune cells (macrophages Adgre1 and Itgax) and cytokine (Tnf) in adipose tissue remained lower in the post-TRF group than in the HFD-AL group. Furthermore, the TRF group was protected from the down-regulation of Pparg mRNA expression in adipose tissue, which was also observed in the post-TRF group to a lesser extent. The post-TRF animals displayed liver mass similar to those in the TRF group, but the TRF effects on the mRNA of inflammation markers in the liver vanished completely. Together, these results indicate that, although the lasting effects of TRF may differ by tissues and genes, the impact of TRF on adipose tissue inflammation and immune cell infiltration could last a couple of weeks, which may, in part, contribute to the maintenance of insulin sensitivity even after the cessation of TRF.

Visualizing increased uptake of [18F]FDG and [18F]FTHA in kidneys from obese high-fat diet fed C57BL/6J mice using PET/CT ex vivo.

It is known that high-fat diet (HFD) and/or diabetes may influence substrate preferences and energy demands in the heart preceding diabetic cardiomyopathy. They may also induce structural glomerular changes causing diabetic nephropathy. PET/CT has been utilized to examine uptake of energy substrates, and to study metabolic changes or shifts before onset of metabolic disorders. However, conventional PET/CT scanning of organs with relatively low uptake, such as the kidney, in small animals in vivo may render technical difficulties. To address this issue, we developed a PET/CT ex vivo protocol with radiolabeled glucose and fatty acid analouges, [18F]FDG and [18F]FTHA,to study substrate uptake in mouse kidneys. We also aimed to detect a possible energy substrate shift before onset of diabetic nephropathy. The ex vivo protocol reduced interfering background as well as interindividual variances. We found increased uptake of [18F]FDG and [18F]FTHA in kidneys after HFD, compared to kidneys from young mice on standard chow. Levels of kidney triglycerides also increased on HFD. Lipoprotein lipase (LPL) activity, the enzyme responsible for release of fatty acids from circulating lipoproteins, is normally increased in postprandial mice kidneys. After long-term HFD, we found that LPL activity was suppressed, and could therefore not explain the increased levels of stored triglycerides. Suppressed LPL activity was associated with increased expression of angiopoietin-like protein4, an inhibitor of LPL. HFD did not alter the transcriptional control of some common glucose and fatty acid transporters that may mediate uptake of [18F]FDG and [18F]FTHA. Performing PET/CT ex vivo reduced interfering background and interindividual variances. Obesity and insulin resistance induced by HFD increased the uptake of [18F]FDG and [18F]FTHA and triglyceride accumulation in mouse kidneys. Increased levels of [18F]FDG and [18F]FTHA in obese insulin resistant mice could be used clinically as an indicator of poor metabolic control, and a complementary test for incipient diabetic nephropathy.

Effects of neutral polysaccharide from Platycodon grandiflorum on high-fat diet-induced obesity via the regulation of gut microbiota and metabolites.

The obesity epidemic has become a global problem with far-reaching health and economic impact. Despite the numerous therapeutic efficacies of Platycodon grandiflorum, its role in modulating obesity-related metabolic disorders has not been clarified. In this study, a purified neutral polysaccharide, PGNP, was obtained from Platycodon grandiflorum. Based on methylation and NMR analyses, PGNP was found to be composed of 2,1-β-D-Fruf residues ending with a (1→2)-bonded α-D-Glcp. The protective effects of PGNP on high-fat HFD-induced obesity were assessed. According to our results, PGNP effectively alleviated the signs of metabolic syndrome, as demonstrated by reductions in body weight, hepatic steatosis, lipid profile, inflammatory response, and insulin resistance in obese mice. Under PGNP treatment, intestinal histomorphology and the tight junction protein, ZO-1, were well maintained. To elucidate the underlying mechanism, 16S rRNA gene sequencing and LC-MS were employed to assess the positive influence of PGNP on the gut microbiota and metabolites. PGNP effectively increased species diversity of gut microbiota and reversed the HFD-induced imbalance in the gut microbiota by decreasing the Firmicutes to Bacteroidetes ratio. The abundance of Bacteroides and Blautia were increased after PGNP treatment, while the relative abundance of Rikenella, Helicobacter were reduced. Furthermore, PGNP notably influenced the levels of microbial metabolites, including the increased levels of cholic and gamma-linolenic acid. Overall, PGNP might be a potential supplement for the regulation of gut microbiota and metabolites, further affecting obesity.

Yogurt Supplementation Attenuates Insulin Resistance in Obese Mice by Reducing Metabolic Endotoxemia and Inflammation

BackgroundInflammation is an underlying mechanism for the development of obesity-related health complications. Yogurt consumption inhibits obesity-associated inflammation, but the tissue-specific mechanisms have not been adequately described. ObjectivesWe aimed to determine the tissue-specific responses by which yogurt supplementation inhibits inflammation. MethodsC57BL/6 male mice (5 wk old) were fed a Teklad Global 14% Protein Rodent Maintenance diet as a control or a high-fat diet (60% calories from fat) to induce obesity for 11 wk, followed by feeding a Western diet (WD; 43% carbohydrate and 42% fat) or WD supplemented with 5.6% lyophilized yogurt powder for 3 wk to test for the impact of yogurt supplementation. Markers of metabolic endotoxemia and inflammation were assessed in plasma and tissues. Cecal and fecal microbiota were profiled by 16S rRNA sequencing. ResultsIn obese mice, relative to the WD control group, yogurt supplementation attenuated HOMA-IR by 57% (P = 0.020), plasma TNF-α by 31% (P < 0.05) and colonic IFN-γ by 46% (P = 0.0034), which were accompanied by a 40% reduction in plasma LPS binding protein (LBP) (P = 0.0019) and 45% less colonic Lbp expression (P = 0.037), as well as alteration in the beta diversity of cecal microbiota (P = 0.0090) and relative abundance of certain cecal microbes (e.g., Lachnospiraceae Dorea longicatena with P = 0.049). There were no differences in the LBP, Lbp, and Cd14 levels in the liver and small intestine between obese mice with and without yogurt supplementation (P > 0.05). ConclusionsYogurt consumption inhibits obesity-induced inflammation in mice by modulating colonic endotoxin detoxification, changing the gut microbiota, and improving glucose metabolism. This work helps to establish the underlying mechanisms by which yogurt consumption affects markers of metabolic and immune health.

Treatment with EV-miRNAs Alleviates Obesity-Associated Metabolic Dysfunction in Mice

Most cells release extracellular vesicles (EVs) that can be detected circulating in blood. We and others have shown that the microRNA contents of these vesicles induce transcriptomic changes in acceptor cells, contributing to the adjustment of metabolic homeostasis in response to environmental demands. Here, we explore the potential for modulating obesity- and exercise-derived EV-microRNAs to treat the metabolic dysfunction associated with obesity in mice. Treatment with EV-miRNAs alleviated glucose intolerance and insulin resistance in obese mice to an extent similar to that of high-intensity interval training, although only exercise improved cardiorespiratory fitness and decreased body weight. Mechanistically, EV-miRNAs decreased fatty acid and cholesterol biosynthesis pathways in the liver, reducing hepatic steatosis and increasing insulin sensitivity, resulting in decreased glycemia and triglyceridemia. Our data suggest that manipulation of EV-miRNAs may be a viable strategy to alleviate metabolic dysfunction in obese and diabetic patients who are unable to exercise, although actual physical activity is needed to improve cardiorespiratory fitness.

The nitrone 5,5-dimethyl-1-pyrroline N-oxide improves adipogenesis and reduces insulin resistance in obese mice

The nitrone 5,5-dimethyl-1-pyrroline N-oxide improves adipogenesis and reduces insulin resistance in obese mice

Interferon gamma mediates the reduction of adipose tissue regulatory T cells in human obesity

Decreased adipose tissue regulatory T cells contribute to insulin resistance in obese mice, however, little is known about the mechanisms regulating adipose tissue regulatory T cells numbers in humans. Here we obtain adipose tissue from obese and lean volunteers. Regulatory T cell abundance is lower in obese vs. lean visceral and subcutaneous adipose tissue and associates with reduced insulin sensitivity and altered adipocyte metabolic gene expression. Regulatory T cells numbers decline following high-fat diet induction in lean volunteers. We see alteration in major histocompatibility complex II pathway in adipocytes from obese patients and after high fat ingestion, which increases T helper 1 cell numbers and decreases regulatory T cell differentiation. We also observe increased expression of inhibitory co-receptors including programmed cell death protein 1 and OX40 in visceral adipose tissue regulatory T cells from patients with obesity. In human obesity, these global effects of interferon gamma to reduce regulatory T cells and diminish their function appear to instigate adipose inflammation and suppress adipocyte metabolism, leading to insulin resistance.