Insulin Resistance In High-fat Diet Research Articles

Specific Knockout of Notch-1 in Macrophages Modulate the Progression of Hepatic Insulin Resistance in HFD Fed Mice via Regulating IRE1α-XBP1 Signals.

To develop an intervention based on Notch-1 signalling pathway blockade by investigating the potential application of the neurogenic locus notch homologue protein 1(Notch-1) signalling pathway as a key regulator of chronic inflammation and adipogenesis in the treatment of hepatic insulin resistance (HIR). Experimental study. Place and Duration of the Study: Animal Laboratory of the Fourth Hospital of Hebei Medical University, Shijiazhuang, China, from April 2021 to June 2022. HIR models were established in Notch-1WT and Notch-1MAC-KO mice by high fat diet (HFD) for 16 weeks. Haematoxylin and eosin (HE) staining and oil red O (ORO) staining were used to detect inflammatory infiltration and lipid accumulation in each group. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of TNF-α and IL-6. Free fatty acid (FFA) and total cholesterol (TC) were measured with relevant kits. Moreover, real-time quantitative polymerase chain reaction (PCR) was performed to detect the relative expressions of F4/80, Mcp1, and CD11b in hepatic tissues. Mass spectrometry was used to analyse the levels of triglyceride (TG), diacylglycerol (DAG) and conformite europeenne (CE) in liver tissue. Western blotting was used to detect the expression of related proteins. Specific knockdown of Notch-1 in macrophages decreases the relative fluorescence intensity of CD68 and attenuates inflammatory infiltration and lipid degeneration. There was no difference in plasma levels of FFA and TG. Specific knockdown of Notch-1 in macrophages decreases the expression of F4/80, Mcp1, and CD11b, as well as the levels of TG, DAG, CE, IL-6, and TNF-α. Specific knockout of Notch-1 in macrophages may reduce HIR by inhibiting the IRE1α-XBP1 signalling pathway. Hepatic insulin resistance, Macrophages, Notch-1, IRE1α, XBP1.

Branched-chain amino acid supplementation drives dynamic changes in gut microbiota without impairing glucose and lipid homeostasis at the different stages of insulin resistance in mice on a high-fat diet

ObjectiveThe potential role of dietary branched-chain amino acids on circulating branched-chain amino acid levels and their relationship with metabolic health are complex, and the literature is inconsistent. We aimed to explore the dynamic effects of branched-chain amino acid supplementation on glucose and lipid homeostasis at different stages of insulin resistance in high-fat diet–fed mice. MethodsMale C57BL/6J mice were fed with a normal chow diet, high-fat diet, or high-fat diet supplemented with 100% branched-chain amino acids for 12 or 24 wk. Metabolic parameters and gut microbiota profiling were performed at these two time points. ResultsHigh-fat diet feeding caused varying degrees of branched-chain amino acid metabolic disorders in two different stages of insulin resistance. Supplementing with branched-chain amino acids further exacerbated branched-chain amino acid accumulation in the early stage of insulin resistance (12 wk), while adding branched-chain amino acids did not further elevate branched-chain amino acid levels in the hyperglycemia and hyperinsulinemia stage (24 wk). Compared with the high-fat diet group, branched-chain amino acid supplementation did not affect body weight; liver total cholesterol and triacylglycerol levels; and serum glucose, insulin, total cholesterol, triacylglycerol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels as well as glucose tolerance at these two time points but triggered dynamic changes in the gut bacterial diversity and gut microbiota composition and abundance, especially in the genus associated with obesity and related metabolic disorders. ConclusionDietary branched-chain amino acid supplementation drives dynamic changes in circulating branched-chain amino acid levels and gut microbiome without subsequent effects on glucose and lipid homeostasis in high-fat diet–induced obese mice within the parameters of our study.

Genistein in combination with Chlorogenic acid ameliorates insulin resistance and oxidative stress in skeletal muscle of high-fat diet fed mice

Objectives: Increasing evidence has demonstrated that oxidative stress plays a significant role in the pathogenesis of muscle insulin resistance. The beneficial impacts of genistein (GEN) and chlorogenic acid (CGA) on insulin resistance have already been revealed. However, their combined effects on skeletal muscle oxidative stress and insulin resistance have not been completely understood. The aim of the present study was to determine the effect of GEN in combination with CGA on skeletal muscle insulin resistance in high-fat diet (HFD) fed C57BL/6 mice.
 Methods: C57BL/6 male mice were fed an HFD for 15 weeks. The mice were then divided into five groups: standard chow diet (SCD), HFD, HFD + GEN, HFD + CGA, and HFD + GEN + CGA for 10 weeks.
 Results: The findings indicated that single treatment with GEN or CGA, and with a stronger effect of GEN+CGA combined treatment, decreased body weight gain and improved glucose intolerance. Moreover, following treatment with GEN and CGA alone or in combination with further effect, the level of plasma and muscle triglyceride (TG) were reduced. Furthermore, the combination therapy of GEN and CGA with greater efficacy than the single treatments, could decrease several oxidative stress markers in the skeletal muscle. Treatment with GEN and CGA alone or in combination could increase the expression of NF-E2–related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NAD(P): Quinone Oxidoreductase 1 (NQO1).
 Conclusion: The data of this study suggest that the combination of GEN and CGA might ameliorate insulin resistance and reduce oxidative stress in the skeletal muscle of mice fed HFD.

Identification of novel SCD1 inhibitor alleviates nonalcoholic fatty liver disease: critical role of liver-adipose axis

Due to the complexity and incomplete understanding of the crosstalk between liver and adipose tissue, especially the processes of hepatic lipogenesis and adipogenic differentiation, there are currently no effective drugs for the treatment of nonalcoholic fatty liver disease (NAFLD). Stearoyl-coenzyme A desaturase 1 (SCD1), which is abundantly expressed in liver and adipose tissue, may mediate the cross-talk between liver and adipose tissue. Thus, it is essential to develop specific SCD1 inhibitors that target the liver-adipose axis. Herein, we identified a novel SCD1 inhibitor, E6446, through a high-throughput virtual screen. E6646 significantly inhibited adipogenic differentiation and hepatic lipogenesis via SCD1-ATF3 signaling. The SPR results showed that E6446 had a strong interaction ability with SCD1 (KD:4.61 μM). Additionally, E6646 significantly decreased hepatic steatosis, hepatic lipid droplet accumulation and insulin resistance in high-fat diet (HFD)-fed mice. Taken together, our findings not only suggest that E6446 can serve as a new, safe and highly effective anti-NAFLD agent for future clinical use but also provide a molecular basis for the future development of SCD1 inhibitors that inhibit both adipogenic differentiation and hepatic lipogenesis.-_fLbJcbqbtKciFUEE_QdNVideo

Ascorbic acid reduces insulin resistance and pancreatic steatosis by regulating adipocyte hypertrophy in obese ovariectomized mice.

Ascorbic acid has been suggested to regulate obesity in obese male rodents.Moreover, increased adipocyte size has been associated with metabolic disease. Thus, we investigated the effects of ascorbic acid on adipocyte hypertrophy and insulin resistance in high-fat diet (HFD)-induced obese ovariectomized (OVX) C57BL/6J mice, an animal model of obese postmenopausal women. Administration of ascorbic acid (5%w/w in diet for 18 weeks) reduced the size of visceral adipocytes without changes in body weight and adipose tissue mass in HFD-fed obese OVX mice compared with obese OVX mice that did not receive ascorbic acid. Ascorbic acid inhibited adipose tissue inflammation, as shown by the decreased number of crown-like structures and CD68-positive macrophages in visceral adipose tissues. Ascorbic acid-treated mice exhibited improved hyperglycemia, hyperinsulinemia, and glucose and insulin tolerance compared with nontreated obese mice. Pancreatic islet size and insulin-positive β-cell area in ascorbic acid-treated obese OVX mice decreased to the levels observed in low-fat diet-fed lean mice. Ascorbic acid also suppressed pancreatic triglyceride accumulation in obese mice. These results suggest that ascorbic acid may reduce insulin resistance and pancreatic steatosis partly by suppressing visceral adipocyte hypertrophy and adipose tissue inflammation in obese OVX mice.

5-Heptadecylresorcinol alleviated high-fat diet induced obesity and insulin resistance by activating brown adipose tissue.

The whitening and loss of brown adipose tissue (BAT) during obesity and aging are associated with a higher risk of metabolic syndrome and chronic diseases. 5-Heptadecylresorcinol (AR-C17), the specific biomarker of whole-grain wheat and rye intake, has been proved to have notable health promoting effects, whereas whether AR-C17 could modulate BAT function and the potential mechanism of action remains unclear. In this study, we found that AR-C17 could significantly inhibit body weight gain and insulin resistance in high-fat diet (HFD) induced obese mice. Moreover, AR-C17 treatment improved whole body energy metabolism and alleviated the whitening and loss of BAT compared with the HFD group. RNA sequencing and western-blot analysis indicated that expression of genes and proteins related to BAT energy metabolism was upregulated by AR-C17 administration, including AMPK, UCP-1, ACSL1, CPT1A, and SIRT3. These results suggested that brown adipose tissue might be the target of AR-C17 to prevent obesity and its associated insulin resistance.

Cistanche tubulosa phenylethanoid glycosides suppressed adipogenesis in 3T3-L1 adipocytes and improved obesity and insulin resistance in high-fat diet induced obese mice

BackgroundCistanche tubulosa is an editable and medicinal traditional Chinese herb and phenylethanoid glycosides are its major components, which have shown various beneficial effects such as anti-tumor, anti-oxidant and neuroprotective activities. However, the anti-obesity effect of C. tubulosa phenylethanoid glycosides (CTPG) and their regulatory effect on gut microbiota are still unclear. In the present study, we investigated its anti-obesity effect and regulatory effect on gut microbiota by 3T3-L1 cell model and obesity mouse model.Methods3T3-L1 adipocytes were used to evaluate CTPG effects on adipogenesis and lipids accumulation. Insulin resistant 3T3-L1 cells were induced and used to measure CTPG effects on glucose consumption and insulin sensitivity. High-fat diet (HFD)-induced C57BL/6 obese mice were used to investigate CTPG effects on fat deposition, glucose and lipid metabolism, insulin resistance and intestinal microorganism.ResultsIn vitro data showed that CTPG significantly decreased the triglyceride (TG) and non-esterified fatty acid (NEFA) contents of the differentiated 3T3-L1 adipocytes in a concentration-dependent manner without cytotoxicity, and high concentration (100 µg/ml) of CTPG treatment dramatically suppressed the level of monocyte chemoattractant protein-1 (MCP-1) in 3T3-L1 mature adipocytes. Meanwhile, CTPG increased glucose consumption and decreased NEFA level in insulin resistant 3T3-L1 cells. We further found that CTPG protected mice from the development of obesity by inhibiting the expansion of adipose tissue and adipocyte hypertrophy, and improved hepatic steatosis by activating AMPKα to reduce hepatic fat accumulation. CTPG ameliorated HFD-induced hyperinsulinemia, hyperglycemia, inflammation and insulin resistance by activating IRS1/Akt/GLUT4 insulin signaling pathway in white adipose tissue. Moreover, gut microbiota structure and metabolic functions in HFD-induced obese mice was changed by CTPG, especially short chain fatty acids-producing bacteria including Blautia, Roseburia, Butyrivibrio and Bacteriodes were significantly increased by CTPG treatment.ConclusionsCTPG effectively suppressed adipogenesis and lipid accumulation in 3T3-L1 adipocytes and ameliorated HFD-induced obesity and insulin resistance through activating AMPKα and IRS1/AKT/GLUT4 signaling pathway and regulating the composition and metabolic functions of gut microbiota.

Berberrubine, a Main Metabolite of Berberine, Alleviates Non-Alcoholic Fatty Liver Disease via Modulating Glucose and Lipid Metabolism and Restoring Gut Microbiota.

Non-alcoholic fatty liver disease (NAFLD) is a major public health problem in many countries. Berberine (BBR) is an effective therapeutic agent in alleviating NAFLD. Berberrubine (BRB) is one of the main active metabolites of BBR, which shows significant anti-obesity and antihypoglycemic effects. However, whether BRB is responsible for the in vivo therapeutic effect and the underlying mechanism of BRB on NAFLD have not been elucidated. In this study, the ability of BRB to ameliorate NAFLD, together with its molecular mechanism, was investigated. The results showed that BRB treatments could significantly improve hepatic steatosis and insulin resistance in high-fat diet (HFD)–fed mice and oleic acid (OA)–treated HepG2 cells. Meanwhile, BBR and BRB treatment similarly prevented lipid accumulation by regulating the protein expression of ATGL, GK, PPARα, CPT-1, ACC1, FAS, and CD36. In addition, compared with BBR, BRB could maintain glucose homeostasis via GLUT2, GSK3β, and G6Pase in HFD-fed mice. Furthermore, the components of the gut microbiota in mice were analyzed by 16S rRNA gene sequencing. BBR and BRB treatment could greatly modify the structure and composition of gut microbiota. At the genus level, BBR and BRB treatment decreased Lactobacillus and Romboutsia, while BBR increased beneficial bacteria, such as Akkermansia and Bacteroides, and BRB increased beneficial bacteria, such as Ileibacterium and Mucispirillum. Altogether, both BRB and BBR were active in alleviating NAFLD in vivo and BRB might be used as a functional material to treat NAFLD clinically.

Berberine reduces hepatic ceramide levels to improve insulin resistance in HFD-fed mice by inhibiting HIF-2α

Several studies have documented the effects of hypoxia and ceramides on lipid and glucose metabolism, resulting in insulin resistance. However, the roles of ceramide in hepatic hypoxia and hepatic insulin resistance remain to be clarified. This study aimed to explore the relationship between hypoxia, ceramide synthesis, and hepatic insulin resistance in high-fat diet (HFD)-fed mice. Given the interaction of hypoxia-inducible factors 2α(HIF-2α) and berberine determined using molecular docking, this study also assessed the pharmacological effects of berberine on the HIF-2α-ceramide-insulin resistance pathway. In the preliminary phase of the study, gradually aggravated hepatic hypoxia and varying levels of ceramides were observed with the development of type 2 diabetes mellitus (T2DM) due to increasing HIF-2α accumulation. Lipidomic analyses of animal and cell models revealed that berberine reduced hypoxia-induced ceramide production and attenuated ceramide-induced insulin resistance. This research provides timely and necessary evidence for the role of ceramide in hypoxia and insulin resistance in the liver. It also contributes to a better understanding of the pharmacological effects of berberine on ameliorating hypoxia and insulin resistance in T2DM therapy.

IL-37 isoform D acts as an inhibitor of soluble ST2 to boost type 2 immune homeostasis in white adipose tissue

White adipose tissue (WAT) homeostasis substantiated by type 2 immunity is indispensable to counteract obesity and metabolic disorders. IL-33/suppression of tumorigenicity (ST) 2 signaling promotes type 2 response in WAT, while potential regulators remain to be discovered. We identified human IL-37 isoform D (IL-37D) as an effective trigger for ST2-mediated type 2 immune homeostasis in WAT. IL-37D transgene amplified ST2+ immune cells, promoted M2 macrophage polarization and type 2 cytokine secretion in WAT that mediate beiging and inflammation resolution, thereby increasing energy expenditure, reducing obesity and insulin resistance in high-fat diet (HFD)-fed mice. Mechanistically, either endogenous or exogenous IL-37D inhibited soluble ST2 (sST2) production from WAT challenged with HFD or TNF-α. Recombinant sST2 impaired the beneficial effects of IL-37D transgene in HFD-fed mice, characterized by damaged weight loss, insulin action, and type 2 cytokine secretion from WAT. In adipose-derived stem cells, IL-37D inhibited TNF-α-stimulated sST2 expression through IL-1 receptor 8 (IL-1R8)-dependent NF-κB inactivation. Collectively, human IL-37D suppresses sST2 to boost type 2 immune homeostasis in WAT, which may be a promising therapy target for obesity and metabolic disorders.

Effect of parthenolide, an NLRP3 inflammasome inhibitor, on insulin resistance in high-fat diet-obese mice.

The activation of Nod-like receptor proteins (NLRP3) containing the pyrin domain inflammasome is a hallmark of the pathogenesis of metabolic disorders. Inhibition of the NLRP3 inflammasome by phytoconstituents has been attempted as a strategy to mitigate these disorders. Therefore, the present study aimed to evaluate the efficacy of an NLRP3 inflammasome inhibitor, parthenolide (PN; 5mg/kg i.p.) against inflammation and insulin resistance in high-fat diet (HFD) - obese mice. Treatment with PN and pioglitazone (PIO; 30mg/kg p.o.) attenuated lipopolysaccharide (LPS; 1 ng/ml) - induced elevation of tumor necrosis factor-α and interleukin-1β in mouse peritoneal macrophages in a dose-dependent manner. Sixty days of PN and PIO treatment marginally reduced obesity-induced insulin resistance in HFD-obese mice. PN treatment also decreased blood glucose from 14th to 60th day, supporting the hypothesis of simultaneous attenuation of inflammation and insulin resistance in obese mice. Thus, PN treatment was also evident with significant improvement in glucose tolerance and peripheral insulin resistance validated through the respective tolerance tests. Therefore, the present study suggests that PN, an NLRP3 inflammasome inhibitor, could be a possible therapeutic agent for attenuating obesity-induced insulin resistance.

Exercise does not improve insulin resistance and mitochondrial characteristics together.

The aim of this study was to investigate the relationship between mitochondrial content and respiratory function and whole-body insulin resistance in high-fat diet (HFD) fed rats. Male Wistar rats were given either a chow diet or an HFD for 12 weeks. After 4 weeks of the dietary intervention, half of the rats in each group began 8 weeks of interval training. In vivo glucose and insulin tolerance were assessed. Mitochondrial respiratory function was assessed in permeabilised soleus and white gastrocnemius (WG) muscles. Mitochondrial content was determined by the measurement of citrate synthase (CS) activity and protein expression of components of the electron transport system (ETS). We found HFD rats had impaired glucose and insulin tolerance but increased mitochondrial respiratory function and increased protein expression of components of the ETS. This was accompanied by an increase in CS activity in WG. Exercise training improved glucose and insulin tolerance in the HFD rats. Mitochondrial respiratory function was increased with exercise training in the chow-fed animals in soleus muscle. This exercise effect was absent in the HFD animals. In conclusion, exercise training improved insulin resistance in HFD rats but without changes in mitochondrial respiratory function and content. The lack of an association between mitochondrial characteristics and whole-body insulin resistance was reinforced by the absence of strong correlations between these measures. Our results suggest that improvements in mitochondrial respiratory function and content are not responsible for improvements in whole-body insulin resistance in HFD rats.

Apigenin Alleviates Obesity-Associated Metabolic Syndrome by Regulating the Composition of the Gut Microbiome

The gut microbiota, often viewed as a “digestive organ,” can influence the development of obesity and related metabolic disorders. Diet is significantly important in shaping the structure and modulating the function of the gut microbiota. Apigenin (Api) widely exists in fruits and vegetables as a naturally occurring flavonoid and has anti-obesogenic, anti-inflammatory, and anti-carcinogenic properties. Its low bioavailability means it has enough time to interact with the intestine thus becomes a potential substrate for the gut intestine; thus, contributing to gut health. Here, we show that Api reduces whole-body weight, low-grade inflammation, and insulin resistance in high-fat diet (HFD)-induced obese mice. Our results reflect that Api supplementation can substantially improve intestinal dysbiosis triggered by HFD and restores gut barrier damage by alleviating metabolic endotoxemia. Augmentation of Akkermansia and Incertae_Sedis along with reduction of Faecalibaculum and Dubosiella at the genus level potentially mediated the protective effects of Api on metabolic syndrome. Furthermore, we show that the impact of Api on the reduction of body weight and the modification of gut microbiota could be transferred from Api-administered mice to HFD-feeding mice via horizontal fecal microbiota transplantation. Taken together, our data highlight the prebiotic role of Api and show its contribution to the restraint of gut dysbiosis and metabolic deterioration associated with obesity in mice.

The protective effects of Aster yomena (Kitam.) Honda on high-fat diet-induced obese C57BL/6J mice.

BACKGROUND/OBJECTIVESAster yomena (Kitam.) Honda (AY) has remarkable bioactivities, such as antioxidant, anti-inflammation, and anti-cancer activities. On the other hand, the effects of AY against obesity-induced insulin resistance have not been reported. Therefore, this study examined the potential of AY against obesity-associated insulin resistance in high-fat diet (HFD)-fed mice.MATERIALS/METHODSAn obesity model was established by feeding C57BL/6J mice a 60% HFD for 16 weeks. The C57BL6/When ethyl acetate fraction from AY (EFAY) at doses of 100 and 200 mg/kg/day was administered orally to mice fed a HFD for the last 4 weeks. Normal and control groups were administered water orally. The body weight and fasting blood glucose were measured every week. Dietary intake was measured every other day. After dissection, blood and tissues were collected from the mice.RESULTSThe administration of EFAY reduced body and organ weights significantly compared to HFD-fed control mice. The EFAY-administered groups also improved the serum lipid profile by decreasing the triglyceride, total cholesterol, and low-density lipoprotein compared to the control group. In addition, EFAY ameliorated the insulin resistance-related metabolic dysfunctions, including the fasting blood glucose and serum insulin level, compared to the HFD-fed control mice. The EFAY inhibited lipid synthesis and insulin resistance by down-regulation of hepatic fatty acid synthase and up-regulation of the AMP-activated protein kinase pathway. EFAY also reduced lipid peroxidation in the liver, indicating that EFAY protected hepatic injury induced by obesity.CONCLUSIONSThese results suggest that EFAY improved obesity-associated insulin resistance by regulating the lipid and glucose metabolism, suggesting that AY could be used as a functional food to prevent obesity and insulin resistance.

Deletion of ABCB10 in beta-cells protects from high-fat diet induced insulin resistance

ObjectiveThe contribution of beta-cell dysfunction to type 2 diabetes (T2D) is not restricted to insulinopenia in the late stages of the disease. Elevated fasting insulinemia in normoglycemic humans is a major factor predicting the onset of insulin resistance and T2D, demonstrating an early alteration of beta-cell function in T2D. Moreover, an early and chronic increase in fasting insulinemia contributes to insulin resistance in high-fat diet (HFD)-fed mice. However, whether there are genetic factors that promote beta-cell-initiated insulin resistance remains undefined. Human variants of the mitochondrial transporter ABCB10, which regulates redox by increasing bilirubin synthesis, have been associated with an elevated risk of T2D. The effects of T2D ABCB10 variants on ABCB10 expression and the actions of ABCB10 in beta-cells are unknown. MethodsThe expression of beta-cell ABCB10 was analyzed in published transcriptome datasets from human beta-cells carrying the T2D-risk ABCB10 variant. Insulin sensitivity, beta-cell proliferation, and secretory function were measured in beta-cell-specific ABCB10 KO mice (Ins1Cre-Abcb10flox/flox). The short-term role of beta-cell ABCB10 activity on glucose-stimulated insulin secretion (GSIS) was determined in isolated islets. ResultsCarrying the T2Drisk allele G of ABCB10 rs348330 variant was associated with increased ABCB10 expression in human beta-cells. Constitutive deletion of Abcb10 in beta-cells protected mice from hyperinsulinemia and insulin resistance by limiting HFD-induced beta-cell expansion. An early limitation in GSIS and H2O2-mediated signaling caused by elevated ABCB10 activity can initiate an over-compensatory expansion of beta-cell mass in response to HFD. Accordingly, increasing ABCB10 expression was sufficient to limit GSIS capacity. In health, ABCB10 protein was decreased during islet maturation, with maturation restricting beta-cell proliferation and elevating GSIS. Finally, ex-vivo and short-term deletion of ABCB10 in islets isolated from HFD-fed mice increased H2O2 and GSIS, which was reversed by bilirubin treatments. ConclusionsBeta-cell ABCB10 is required for HFD to induce insulin resistance in mice by amplifying beta-cell mass expansion to maladaptive levels that cause fasting hyperinsulinemia.

Skeletal muscle-targeted delivery of Fgf6 protects mice from diet-induced obesity and insulin resistance.

Obesity, a major health care issue, is characterized by metabolic abnormalities in multiple tissues, including the skeletal muscle. Although dysregulation of skeletal muscle metabolism can strongly influence the homeostasis of systemic energy, the underlying mechanism remains unclear. We found promoter hypermethylation and decreased gene expression of fibroblast growth factor 6 (FGF6) in the skeletal muscle of individuals with obesity using high-throughput sequencing. Reduced binding of the cyclic AMP responsive element binding protein-1 (CREB1) to the hypermethylated cyclic AMP response element, which is a regulatory element upstream of the transcription initiation site, partially contributed to the downregulation of FGF6 in patients with obesity. Overexpression of Fgf6 in mouse skeletal muscle stimulated protein synthesis, activating the mammalian target of rapamycin pathway, and prevented the increase in weight and the development of insulin resistance in high-fat diet–fed mice. Thus, our findings highlight the role played by Fgf6 in regulating skeletal muscle hypertrophy and whole-body metabolism, indicating its potential in strategies aimed at preventing and treating metabolic diseases.

Augmentation of RBP4/STRA6 signaling leads to insulin resistance and inflammation and the plausible therapeutic role of vildagliptin and metformin.

A role of Retinol Binding Protein-4 (RBP4) in insulin resistance is widely studied. However, there is paucity of information on its receptor viz., Stimulated by Retinoic Acid-6 (STRA6) with insulin resistance. To address this, we investigated the regulation of RBP4/STRA6 expression in 3T3-L1 adipocytes exposed to glucolipotoxicity (GLT) and in visceral adipose tissue (VAT) from high fat diet (HFD) fed insulin-resistant rats. 3T3-L1 adipocytes were subjected to GLT and other experimental maneuvers with and without vildagliptin or metformin. Real-time PCR and western-blot experiments were performed to analyze RBP4, STRA6, PPARγ gene and protein expression. Adipored staining and glucose uptake assay were performed to evaluate lipid and glucose metabolism. Oral glucose tolerance test (OGTT) and Insulin Tolerance Test (ITT) were performed to determine the extent of insulin resistance in HFD fed male Wistar rats. Total serum RBP4 was measured by quantitative sandwich enzyme-linked immunosorbent assay kit. Adipocytes under GLT exhibited significantly increased RBP4/STRA6 expressions and decreased insulin sensitivity/glucose uptake. Vildagliptin and metformin not only restored the above but also decreased the expression of IL-6, NFκB, SOCS-3 along with lipid accumulation. Furthermore, HFD fed rats exhibited significantly increased serum levels of RBP4 along with VAT expression of RBP4, STRA6, PPARγ, IL-6. These molecules were significantly altered by the vildagliptin/ metformin treatment. We conclude that RBP4/STRA6 pathway is primarily involved in mediating inflammation and insulin resistance in adipocytes and visceral adipose tissues under glucolipotoxicity and in insulin resistant rats.

Effective and safe delivery of GLP-1AR and FGF-21 plasmids using amino-functionalized dual-mesoporous silica nanoparticles in vitro and in vivo

Nanomaterials have attracted increased attention because of their excellent drug-carrying capacity. However, these nanomaterials are rarely used in the treatment of metabolic diseases. Liraglutide, a glucagon-like peptide-1 receptor agonist, has been widely used in the treatment of type 2 diabetes mellitus (T2DM). Furthermore, fibroblast growth factor 21 (FGF-21) has been found to improve glucose metabolism and insulin resistance (IR). To investigate whether these two molecules have synergistic effects in vivo, we developed a novel drug delivery system using amino-functionalized and embedded dual-mesoporous silica nanoparticles (N-EDMSNs) to simultaneously carry liraglutide and FGF-21, and observed their biological effects. The resultant N-EDMSNs possessed unique hierarchical porous structures consisting of open large pores (>10 nm) and small mesopores (~2.5 nm) in the silica framework, highly positively charged surfaces and good disperisity in aqueous solution. We found that N-EDMSNs had a high loading capacity for exogenous genes and low toxicity to Hepa1-6 cells. Moreover, N-EDMSNs can simultaneously carry FGF-21 plasmids and liraglutide and successfully transfect them into Hepa1-6 cells. The transfection efficiency of N-EDMSNs was higher than that of Lipofectamine 2000 in vitro. In mice experiments, N-EDMSNs/pFGF21 treatment resulted in higher FGF-21 expression in the liver than pFGF21 treatment with hydrodynamic delivery. Compared with both pFGF21 and liraglutide, N-EDMSNs/pFGF21/Lira treatment significantly reduced the food intake, body weight, and blood glucose; increased the energy expenditure and improved hepatic IR in high-fat diet (HFD)-fed mice. Our results demonstrated that the biological effects of N-EDMSNs/pFGF21/Lira complexes were better than those of pFGF21 combined with liraglutide in vivo.

Multiple antisense oligonucleotides targeted against monoacylglycerol acyltransferase 1 (Mogat1) improve glucose metabolism independently of Mogat1

ObjectiveMonoacylglycerol acyltransferase (MGAT) enzymes catalyze the synthesis of diacylglycerol from monoacylglycerol. Previous work has suggested the importance of MGAT activity in the development of obesity-related hepatic insulin resistance. Indeed, antisense oligonucleotide (ASO)-mediated knockdown of Mogat1 mRNA, which encodes MGAT1, reduced hepatic MGAT activity and improved glucose tolerance and insulin resistance in high-fat diet (HFD)-fed mice. However, recent work has suggested that some ASOs may have off-target effects on body weight and metabolic parameters via activation of the interferon alpha/beta receptor 1 (IFNAR-1) pathway. MethodsMice with whole-body Mogat1 knockout or a floxed allele for Mogat1 to allow for liver-specific Mogat1-knockout (by either a liver-specific transgenic or adeno-associated virus-driven Cre recombinase) were generated. These mice were placed on an HFD, and glucose metabolism and insulin sensitivity were assessed after 16 weeks on diet. In some experiments, mice were treated with control scramble or Mogat1 ASOs in the presence or absence of IFNAR-1 neutralizing antibody. ResultsGenetic deletion of hepatic Mogat1, either acutely or chronically, did not improve hepatic steatosis, glucose tolerance, or insulin sensitivity in HFD-fed mice. Furthermore, constitutive Mogat1 knockout in all tissues actually exacerbated HFD-induced obesity, insulin sensitivity, and glucose intolerance on an HFD. Despite markedly reduced Mogat1 expression, liver MGAT activity was unaffected in all knockout mouse models. Mogat1 overexpression in hepatocytes increased liver MGAT activity and TAG content in low-fat-fed mice but did not cause insulin resistance. Multiple Mogat1 ASO sequences improved glucose tolerance in both wild-type and Mogat1 null mice, suggesting an off-target effect. Hepatic IFNAR-1 signaling was activated by multiple Mogat1 ASOs, but its blockade did not prevent the effects of either Mogat1 ASO on glucose homeostasis. ConclusionThese results indicate that genetic loss of Mogat1 does not affect hepatic MGAT activity or metabolic homeostasis on HFD and show that multiple Mogat1 ASOs improve glucose metabolism through effects independent of targeting Mogat1 or activation of IFNAR-1 signaling.

Swertiamarin supplementation prevents obesity-related chronic inflammation and insulin resistance in mice fed a high-fat diet

ABSTRACT Obesity is characterized by low-grade chronic inflammation, which underlies insulin resistance and non-alcoholic fatty liver disease (NAFLD). Swertiamarin is a secoiridoid glycoside that has been reported to ameliorate diabetes and NAFLD in animal models. However, the effects of swertiamarin on obesity-related inflammation and insulin resistance have not been fully elucidated. Thus, this study investigated the effects of swertiamarin on inflammation and insulin resistance in high-fat diet (HFD)-induced obese mice. C57BL/6 mice were fed a HFD or HFD containing swertiamarin for 8 weeks. Obesity-induced insulin resistance and inflammation were assessed in the epididymal white adipose tissue (eWAT) and livers of the mice. Swertiamarin attenuated HFD-induced weight gain, glucose intolerance, oxidative stress, and insulin resistance, and enhanced insulin signalling in mice. Compared to HFD-fed mice, the swertiamarin-treated mice exhibited increased lipolysis and reduced adipocyte hypertrophy and macrophage infiltration in eWAT. Moreover, swertiamarin alleviated HFD-mediated hepatic steatosis and inflammation by suppressing activation of the p38 MAPK and NF-κB pathways within the eWAT and liver of obese mice. In conclusion, supplementation with swertiamarin attenuated weight gain and hepatic steatosis, and alleviated obesity-associated inflammation and insulin resistance, in obese mice.