Regulation Of Insulin Sensitivity Research Articles

Anti-Obese Effect of Cinnamon Extracts Dietary Supplementation on Serum Lipids and Body Weight Gain in High-Fat-Diet Induced Obese Mice Model

ObjectivesCinnamon is one of the oldest spices widely used in traditional medicine and also currently used by people all around the world. Cinnamon has been known for modulating metabolic disorders by regulating insulin sensitivity. The aim of this study was to investigate the anti-obese effects of cinnamon extracts in high-fat-diet induced obese mice model. MethodsAfter a week of adaptation period, the 6-week-old male C57BL/6J mice were randomly divided into 4 groups (n = 11 for each group) of the normal diet group (ND), the high-fat-diet group (HF), the normal diet with 1% cinnamon extracts (NC), and the high-fat diet with 1% cinnamon extracts (HC). All groups were treated for 14 weeks. ResultsIn final body weight and body weight gain, NC group was significantly lower than ND group and HC group was significantly lower than HF group (P = 0.000). In serum TG (Triglyceride) levels and TC (Total cholesterol) levels, NC group showed significantly decreased level compared to that of ND group and HC group represented significantly decreased level compared to that of HF group (P = 0.000). ConclusionsThe present data showed NC group and HC group showed lower final body weight and body weight gain than ND group and HF group. Also, NC group and HC group showed the decreased level of TG (Triglyceride) and TC (Total cholesterol) compared to ND group and HF group. The further indicators of insulin-related factors are in progress. Funding SourcesThis study received no external funding.

Increased Expression of Retinol-Binding Protein 4 in Ovarian Endometrioma and Its Possible Role in the Pathogenesis of Endometriosis.

Although endometriosis is a benign disease characterized by the presence of endometrial tissues outside the uterus, ectopic endometrial cells can exhibit malignant biological behaviors. Retinol-binding protein4 (RBP4) is a novel adipocyte-derived cytokine, which has important roles in regulating insulin sensitivity and energy metabolism. RBP4 is a potent modulator of gene transcription, and acts by directly controlling cell growth, invasiveness, proliferation and differentiation. Here, we evaluated the possible role of RBP4 in the pathogenesis of endometriosis. We compared the levels of RBP4 in the tissues and peritoneal fluid (PF) of women with and without endometriosis and evaluated the in vitro effects of RBP4 on the viability, invasiveness, and proliferation of endometrial stromal cells (ESCs). RBP4 levels were significantly higher in the PF of the women in the endometriosis group than in the controls. RBP4 immunoreactivity was significantly higher in the ovarian endometriomas of women with advanced stage endometriosis than those of controls. In vitro treatment with human recombinant-RBP4 significantly increased the viability, bromodeoxyuridine expression, and invasiveness of ESCs. Transfection with RBP4 siRNA significantly reduced ESC viability and invasiveness. These findings suggest that RBP4 partakes in the pathogenesis of endometriosis by increasing the viability, proliferation and invasion of endometrial cells.

Associations Among Adipose Tissue Immunology, Inflammation, Exosomes and Insulin Sensitivity in People With Obesity and Nonalcoholic Fatty Liver Disease

Insulin resistance is a key factor in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). We evaluated the importance of subcutaneous abdominal adipose tissue (SAAT) inflammation and both plasma and SAAT-derived exosomes in regulating insulin sensitivity in people with obesity and NAFLD. Adipose tissue inflammation (macrophage and T-cell content and expression of proinflammatory cytokines), liver and whole-body insulin sensitivity (assessed using a hyperinsulinemic-euglycemic clamp and glucose tracer infusion), and 24-hour serial plasma cytokine concentrations were evaluated in 3 groups stratified by adiposity and intrahepatic triglyceride (IHTG) content: (1) lean with normal IHTG content (LEAN; N= 14); (2) obese with normal IHTG content (OB-NL; N= 28); and (3) obese with NAFLD (OB-NAFLD; N= 28). The effect of plasma and SAAT-derived exosomes on insulin-stimulated Akt phosphorylation in human skeletal muscle myotubes and mouse primary hepatocytes was assessed in a subset of participants. Proinflammatory macrophages, proinflammatory CD4 and CD8 T-cell populations, and gene expression of several cytokines in SAAT were greater in the OB-NAFLD than the OB-NL and LEAN groups. However, with the exception of PAI-1, which was greater in the OB-NAFLD than the LEAN and OB-NL groups, 24-hour plasma cytokine concentration areas-under-the-curve were not different between groups. The percentage of proinflammatory macrophages and plasma PAI-1 concentration areas-under-the-curve were inversely correlated with both hepatic and whole-body insulin sensitivity. Compared with exosomes from OB-NL participants, plasma and SAAT-derived exosomes from the OB-NAFLD group decreased insulin signaling in myotubes and hepatocytes. Systemic insulin resistance in people with obesity and NAFLD is associated with increased plasma PAI-1 concentrations and both plasma and SAAT-derived exosomes. ClinicalTrials.gov number: NCT02706262 (https://clinicaltrials.gov/ct2/show/NCT02706262).

Developmental Programming: Prenatal Bisphenol A Induces Non-Monotonic Changes in Epigenetic Modulators in Metabolic Tissues of Female Sheep

Developmental exposure to endocrine disruptor bisphenol A (BPA) is associated \\with metabolic defects during adulthood in the female sheep. These are characterized by peripheral insulin resistance and increase in negative mediators of insulin sensitivity such as oxidative stress in metabolic tissues, lipotoxicity in liver and muscle and adipocyte hypertrophy in visceral (VAT) and subcutaneous (SAT) adipose tissue. Conceivably, developmental impact of BPA on regulators of insulin sensitivity involves changes in epigenetic machinery and mediated via changes in expression of enzymes that induce covalent modifications of DNA and histone. To determine the impact of prenatal BPA exposure on epigenetic enzymes [DNA methyltransferases (DNMT), histone deacetylases (HDAC), histone acetyl transferase EP300, histone methylases (SUV39H1, SMYD3 and EZH2) and histone demethylase KDM1A], metabolic tissues (liver, muscle, VAT and SAT) were collected from 21-month-old female offspring born to mothers treated with 0, 0.05, 0.5, or 5 mg/kg/day of BPA from days 30-90 of gestation. Data were analyzed by Cohen’s effect size analysis and large magnitude differences (Cohens d>0.8) discussed. In liver, prenatal BPA induced: 1) a decrease in DNMT1 and 3B at all doses and DNMT3A at the highest dose, 2) a decrease in histone deacetylase HDAC3 as opposed to increase in acetylase EP300 at the highest dose, 3) a decrease in SUV39H1 at the two higher doses, and 4) an increase in EZH2 only with 0.5 mg dose. The prenatal BPA-induced changes in muscle include: 1) increases in expression of DNMTs and EP300 at all doses, 2) an increase in SUV39H1 at 0.5 mg dose and EZH2 at 0.05 and 0.5 mg doses, and 3) decreases in SMYD3 at the lowest dose and KDM1A with 0.05 and 5 mg doses. Prenatal BPA treatment also induced depot-specific changes at the adipose tissue level. In the VAT prenatal BPA induced: 1) increases in expression of all DNMTs examined 2) increases in HDAC2 at all doses except HDAC3 only at 0.05 and 0.5mg dose and 3) increases in histone acetylase EP300 at all doses. In SAT BPA induced: 1) decrease in DNMT3A at 0.5mg and increase at 5 mg, 2) decreases in HDAC1 and HDAC2 at the lowest dose, 3) an increase in HDAC3 at the medium dose, and 4) a decrease in EP300 at the lowest dose. Contrasting changes in histone methylation modifying enzymes were also evident between VAT and SAT manifested as increases in SUV39H1 at the two higher doses and SMYD3 at all three doses in the VAT as opposed to decrease in SUV39H1 and SMYD3 at 0.05 and 0.5 mg doses and EZH2 and KDM1A at the lowest dose in the SAT. These findings indicating developmental exposure to BPA induces non-monotonic dose responses in epigenetic modifying enzymes are consistent with the premise that changes in epigenetic machinery underlie the metabolic disruptions induced by prenatal BPA treatment likely accounting for the tissue specific changes in insulin sensitivity. (support by R01-ES-016541)

The possible role of Interleukin-6 as a regulator of insulin sensitivity in patients with neuromyelitis optica spectrum disorder

BackgroundNeuromyelitis optica spectrum disorder (NMOSD) is associated with inflammatory mediators that may also trigger downstream signaling pathways leading to reduce insulin sensitivity.MethodsWe aimed to determine the risk association of hyperinsulinemia in NMOSD patients with seropositive AQP4-IgG and the serum levels of interleukin (IL)-6 and IL-17A compared with the control group.Serum levels of metabolic (Insulin, Fasting Blood Sugar (FBS), lipid profile) and inflammatory (IL-6 and IL-17) markers were assessed in 56 NMOSD patients and 100 controls.ResultsHyperinsulinemia was more prevalent in NMOSD patients independent of age, sex and body mass index (BMI) (48.2% vs. 26%, p = 0.005) compared to control group. After adjusting age, sex and BMI, there was significant association between lower insulin sensitivity (IS) and NMOSD risk (95% CI: Beta = 0.73, 0.62 to 0.86, p = 0.0001).Circulating levels of IL-6 and IL-17 were higher in NMOSD patients, and only IL-6 had an effect modifier for the association between lower insulin sensitivity and NMOSD risk.ConclusionsOur data suggests that inflammatory pathogenesis of NMOSD leads to hyperinsulinemia and increases the risk of insulin resistance.

Exendin-4 improves long-term potentiation and neuronal dendritic growth in vivo and in vitro obesity condition

Metabolic syndrome, which increases the risk of obesity and type 2 diabetes has emerged as a significant issue worldwide. Recent studies have highlighted the relationship between metabolic imbalance and neurological pathologies such as memory loss. Glucagon-like peptide 1 (GLP-1) secreted from gut L-cells and specific brain nuclei plays multiple roles including regulation of insulin sensitivity, inflammation and synaptic plasticity. Although GLP-1 and GLP-1 receptor agonists appear to have neuroprotective function, the specific mechanism of their action in brain remains unclear. We investigated whether exendin-4, as a GLP-1RA, improves cognitive function and brain insulin resistance in metabolic-imbalanced mice fed a high-fat diet. Considering the result of electrophysiological experiments, exendin-4 inhibits the reduction of long term potentiation (LTP) in high fat diet mouse brain. Further, we identified the neuroprotective effect of exendin-4 in primary cultured hippocampal and cortical neurons in in vitro metabolic imbalanced condition. Our results showed the improvement of IRS-1 phosphorylation, neuronal complexity, and the mature of dendritic spine shape by exendin-4 treatment in metabolic imbalanced in vitro condition. Here, we provides significant evidences on the effect of exendin-4 on synaptic plasticity, long-term potentiation, and neural structure. We suggest that GLP-1 is important to treat neuropathology caused by metabolic syndrome.

Effect of Sitagliptin on Serum Irisin Levels in Patients with Newly Diagnosed Type 2 Diabetes Mellitus.

IntroductionIrisin is a unique myokine with striking effects on regulating insulin sensitivity and energy metabolism. This study aimed to investigate the changes in serum irisin in patients with newly diagnosed type 2 diabetes mellitus (T2DM) following sitagliptin treatment.MethodsThirty-two patients with T2DM were treated with 100 mg/day sitagliptin for 16 weeks. Twenty age-, sex- and body mass index (BMI)-matched healthy subjects were enrolled as the control group. Irisin and metabolic parameters were measured at baseline and after treatment.ResultsPatients with T2DM had lower irisin levels than the controls (10.03 ± 2.06 vs. 13.06 ± 3.10 ng/ml, P < 0.01). Sitagliptin treatment significantly increased serum irisin levels in T2DM patients compared to baseline (11.18 ± 1.91 vs. 10.03 ± 2.06 ng/ml, P < 0.01). Increased irisin levels were associated with decreased fasting blood glucose (FBG) (β = − 0.24, P < 0.05) and glycosylated hemoglobin (HbA1c) (β = − 0.15, P < 0.05).ConclusionsSitagliptin treatment significantly increased serum irisin levels in patients with T2DM, and the increase of the irisin level was associated with decreases of FBG and HbA1c levels. These results suggest that irisin might be involved in the antidiabetic mechanisms of sitagliptin.Trial RegistrationClinicalTrials.gov identifier NCT04495881.

Gene set enrichment analysis of PPAR-γ regulators from Murraya odorata Blanco.

Peroxisome proliferator-activated receptor gamma (PPAR-γ) is reported to regulate insulin sensitivity and progression of Type 2 diabetes mellitus (T2DM). Hence the present study is aimed to identify PPAR-γ regulators from Murraya odorata Blanco and predict their role to manage T2DM. Multiple in-silico tools and databases like SwissTargetPrediction, ADVERPred, PubChem, and MolSoft, were used to retrieve the information related to bioactives, targets, druglikeness character, and probable side effects as applicable. Similarly, the Kyoto Encyclopedia of Genes and Genomes (KEGG) database was used to identify the regulated pathways. Further, the bioactives-protein-pathways network interaction was constructed using Cytoscape. Finally, molecular docking was performed using Autodock4. Twenty-five bioactives were shortlistedin which six were predicted as PPAR-γ modulators. Among them, stigmasterol was predicted to possess the best binding affinity towards PPAR-γ and possessed no side effects. Similarly, n-hexadecanoic acid was predicted to modulate the highest number of proteins, and protein CD14 was targeted by the highest number of bioactives. Further, the PI3K-Akt pathway was predicted as the maximum modulated genes. The anti-diabetic property of theMurraya odorata Blanco offruit pulp may be due to the presence of n-hexadecanoic acid and stigmasterol; may also involve in the regulation of the PI3K-Akt pathway which needs further investigated by in-vitro and in-vivo protocols.

Adenosine monophosphate activated protein kinase (AMPK) is essential for the memory improving effect of adiponectin

Adiponectin (APN) plays a major role in the regulation of insulin sensitivity and glucose homeostasis. Insulin and APN have a positive effect on memory. In this study, we examined whether the inhibition of AMPK could block the memory improving effect of APN or affect the IRS1 expression.Animal model of AD was developed by intracerebroventricular (icv) injection of 3 mg/kg streptozotocin (STZ), in 12 weeks old Wistar rats, on days 1 and 3 after cannulation. Dorsomorphin (DM) and APN (600 nM) were injected 30 and 20 min before the acquisition phase, respectively. DM was applied in 3 different doses (0.2, 2 and 20 μM). All behavioral tests were performed on days 15 and 16; the Preference Index (PI) was calculated for novel object recognition (NOR) test, while the step through latency (STL) and total time in dark compartment (TDC) were recorded and analyzed for the passive avoidance task. Relative expression of insulin receptor substrate-1 (IRS-1) protein in the hippocampus was measured by western blotting.In early retrieval test, STZ + APN treatment increased STL (P < 0.0001) and decreased TDC (P < 0.05) in comparison to STZ group, while STZ + APN + DM (2μM) caused a decrease in STL (P < 0.05) and increase in TDC (0.2μM and 2μM DM; P < 0.05). Icv injection of DM (0.2μM and 2μM) before APN decreased the PI significantly (P < 0.05) in comparison to STZ + APN group. APN treatment raised the IRS-1 expression and DM reversed this increment, significantly (P < 0.0001).It is concluded that the memory improving effect of APN is mediated, at least in part, by the AMPK pathway. APN is also able to boost insulin signaling by overexpression of IRS-1 in the hippocampus.

MiR-467 regulates inflammation and blood insulin and glucose.

Obesity is associated with inflammation and insulin resistance (IR), but the regulation of insulin sensitivity (IS) and connections between IS and inflammation remain unclear. We investigated the role of miR‐467a‐5p, a miRNA induced by hyperglycaemia, in regulating inflammation and blood glucose handling. We previously demonstrated that miR‐467a‐5p is induced by hyperglycaemia and inhibits the production of thrombospondin‐1 (TSP‐1), a protein implicated in regulating inflammation. To investigate the role of miR‐467 in blood glucose handling and tissue inflammation, WT C57BL/6 mice were fed chow or Western diet from 5 to 32 weeks of age and injected weekly with miR‐467a‐5p antagonist. Inhibiting miR‐467a‐5p resulted in 47% increase in macrophage infiltration and increased Il6 levels in adipose tissue, higher plasma insulin levels (98 ng/mL vs 63 ng/mL), and 17% decrease in glucose clearance without increase in weight or HDL/LDL. The antagonist effect was lost in mice on Western diet. Mice lacking TSP‐1 lost some but not all of the miR‐467 effects, suggesting Thbs1 (and other unknown transcripts) are targeted by miR‐467 to regulate inflammation. miR‐467a‐5p provides a physiological feedback when blood glucose is elevated to avoid inflammation and increased blood glucose and insulin levels, which may prevent IR.

N1‑methylnicotinamide ameliorates insulin resistance in skeletal muscle of type2 diabetic mice by activating the SIRT1/PGC‑1α signaling pathway.

Insulin resistance is one of important factors causing type2 diabetes; therefore, regulating insulin sensitivity is considered a beneficial therapeutic approach against type2 diabetes. The present study aimed to determine the effects of N1‑methylnicotinamide (MNAM) on insulin resistance(IR) in skeletal muscle from a mouse model of type2 diabetes mellitus(T2DM), and to investigate the regulatory mechanisms of the sirtuin1 (SIRT1)/peroxisome proliferator‑activated receptor γcoactivator‑1α (PGC‑1α) signaling pathway. C57BL/6 mice were fed a normal diet with or without 1%MNAM and ob/ob mice were also fed a normal diet with or without 0.3or 1%MNAM. Blood glucose, insulin levels, insulin resistance(IR), sensitivity indices and triglyceride(TG) content were detected using ELISAs. The expression of gluconeogenesis‑related, insulin signaling‑related and SIRT1/PGC‑1α pathway‑related proteins was analyzed using reverse transcription‑quantitative PCR (RT‑qPCR) and western blotting. Invitro, C2C12 cells were used to establish an IR muscle cell model by 0.75mM palmitic acid (PA) treatment (PAgroup). The IRcell model was subsequently supplemented with 1mM MNAM (PMgroup) or 1mM MNAM+30µM SIRT1 inhibitor, EX527 (PMEgroup). After treatment the glucose levels and insulin signaling‑related proteins were detected by ELISAs and western blotting, respectively. Furthermore, the expression levels of SIRT1/PGC‑1α signaling pathway‑related mRNA and proteins under MNAM treatment were detected by RT‑qPCR and western blotting. MNAM reduced body weight gain in T2DM mice, decreased fasting blood glucose and fasting insulin levels, and inhibited IR. MNAM also regulated insulin signal transduction and promoted glucose utilization in skeletal muscle, and reduced lipid deposition. Thus, MNAM improved IR in the skeletal muscle of T2DM mice. Following application of a SIRT1 inhibitor, the effects of MNAM on the increased glucose utilization in insulin‑resistant myocytes and the insulin signaling pathway were suppressed. The mechanism of action was associated with activation of the SIRT1/PGC‑1α signaling pathway, which promoted the activation of the insulin receptor substrate IRS1/PI3K/AKT pathway.

An Update to the WISP-1/CCN4 Role in Obesity, Insulin Resistance and Diabetes.

Insulin resistance refers to the diminished response of peripheral tissues to insulin and is considered the major risk factor for type 2 diabetes. Although many possible mechanisms have been reported to develop insulin resistance, the exact underlying processes remain unclear. In recent years, the role of adipose tissue as a highly active metabolic and endocrine organ, producing proteins called adipokines and their multidirectional activities has gained interest. The physiological effects of adipokines include energy homeostasis and insulin sensitivity regulation. In addition, an excess of adipose tissue is followed by proinflammatory state which results in dysregulation of secreted cytokines contributing to insulin resistance. Wingless-type (Wnt) inducible signalling pathway protein-1 (WISP-1), also known as CCN4, has recently been described as a novel adipokine, whose circulating levels are elevated in obese and insulin resistant individuals. Growing evidence suggests that WISP-1 may participate in the impaired glucose homeostasis. In this review, we characterize WISP-1 and summarize the latest reports on the role of WISP-1 in obesity, insulin resistance and type 2 diabetes.

Serum sclerostin is negatively associated with insulin sensitivity in obese but not lean women.

ObjectiveThe mechanisms underlying the development of peripheral insulin resistance are complex. Several studies have linked sclerostin, an osteocyte-derived inhibitor of the Wnt/β-catenin pathway, to obesity and insulin resistance. The aim of this study was to investigate (1) whether serum sclerostin is associated with insulin sensitivity in lean and/or obese women; and (2) whether hyperinsulinaemia affects serum sclerostin concentrations.DesignA cross-sectional study.MethodsInsulin sensitivity was measured in lean (BMI < 25 kg/m2) and obese (BMI > 30 kg/m2) women using a hyperinsulinaemic–euglycaemic clamp. Serum sclerostin was measured at baseline and during the clamp procedure.ResultsWe studied 21 lean and 22 obese women with a median age of 40 and 43 years and a median BMI of 22.4 and 33.5 kg/m2, respectively. Obese women had higher serum sclerostin than lean women (122 ± 33 vs 93 ± 33 nmol/L, P < 0.01). Higher serum sclerostin was associated with lower insulin sensitivity in obese, but not in lean individuals (difference in M-value between highest and lowest quartile: −7.02 mg/kg/min, P = 0.03 and 1.59 mg/kg/min, P = 0.50, respectively). Hyperinsulinaemia did not affect serum sclerostin in lean nor obese women (P > 0.5).ConclusionSerum sclerostin is negatively associated with insulin sensitivity as measured with the hyperinsulinaemic–euglycaemic clamp in obese, but not lean women. This indicates a potential role of the Wnt/β-catenin pathway in regulating insulin sensitivity particularly in obese individuals. Our findings remain hypothesis-generating and should be confirmed by additional studies.

Lipocalin-2: a role in hepatic gluconeogenesis via AMP-activated protein kinase (AMPK).

Evidence is accumulating that lipocalin2 (LCN2) is implicated in insulin resistance and glucose homeostasis, but the underlying possible mechanisms remain unclear. This study is to investigate the possible linkage between LCN2 and AMP-activated protein kinase (AMPK) or forkhead transcription factor O1 (FoxO1), which influences insulin sensitivity and gluconeogenesis in liver. LCN2 knockout (LCN2KO) mice and wild-type littermates were used to evaluate the effect of LCN2 on insulin sensitivity and hepatic gluconeogenesis through pyruvate tolerance test (PTT), glucose tolerance test (ipGTT), insulin tolerance test (ITT), and hyperinsulinemic-euglycemic clamps, respectively. LCN2KO mice and WT mice in vivo, and in vitro HepG2 cells were co-transfected with adenoviral FoxO1-siRNA (Ad-FoxO1-siRNA) or adenovirus expressing constitutively active form of AMPK (Ad-CA-AMPK), or dominant negative adenovirus AMPK (Ad-DN-AMPK), the relative mRNA and protein levels of two key gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6P) were measured. Improved insulin sensitivity and inhibited gluconeogenesis in the LCN2KO mice were confirmed by pyruvate tolerance tests and hyperinsulinemic-euglycemic clamps. Nuclear FoxO1 and its downstream genes PEECK and G6P were decreased in the livers of the LCN2KO mice, and AMPK activity was stimulated and directly phosphorylated FoxO1. In vitro, AMPK activity was inhibited in HepG2 cells overexpressing LCN2 leading to a decrease in phosphorylated FoxO1 and an increase in nuclear FoxO1. The present study demonstrates that LCN2 regulates insulin sensitivity and glucose metabolism through inhibiting AMPK activity, and regulating FoxO1 and its downstream genes PEPCK/G6P, which regulate hepatic gluconeogenesis.

Active integrins regulate white adipose tissue insulin sensitivity and brown fat thermogenesis

ObjectiveReorganization of the extracellular matrix is a prerequisite for healthy adipose tissue expansion, whereas fibrosis is a key feature of adipose dysfunction and inflammation. However, very little is known about the direct effects of impaired cell–matrix interaction in adipocyte function and insulin sensitivity. The objective of this study was to determine whether integrin activity can regulate insulin sensitivity in adipocytes and thereby systemic metabolism. MethodsWe characterized integrin activity in adipose tissue and its consequences on whole-body metabolism using adipose-selective deletion of β1 integrin (Itgb1adipo-cre) and Kindlin-2 (Kind2adipo-cre) in mice. ResultsWe demonstrate that integrin signaling regulates white adipocyte insulin action and systemic metabolism. Consequently, loss of adipose integrin activity, similar to loss of adipose insulin receptors, results in a lipodystrophy-like phenotype and systemic insulin resistance. However, brown adipose tissue of Kind2adipo-cre and Itgb1adipo-cre mice is chronically hyperactivated and has increased substrate delivery, reduced endothelial basement membrane thickness, and increased endothelial vesicular transport. ConclusionsThus, we establish integrin-extracellular matrix interactions as key regulators of white and brown adipose tissue function and whole-body metabolism.

SENP2 is vital for optimal insulin signaling and insulin-stimulated glycogen synthesis in human skeletal muscle cells

Sentrin-specific protease (SENP) 2 has been suggested as a possible novel drug target for the treatment of obesity and type 2 diabetes mellitus after observations of a palmitate-induced increase in SENP2 that lead to increased fatty acid oxidation and improved insulin sensitivity in skeletal muscle cells from mice. However, no precedent research has examined the role of SENP2 in human skeletal muscle cells. In the present work, we have investigated the impact of SENP2 on fatty acid and glucose metabolism as well as insulin sensitivity in human skeletal muscle using cultured primary human myotubes. Acute (4 ​h) oleic acid oxidation was reduced in SENP2-knockdown (SENP2-KD) cells compared to control cells, with no difference in uptake. After prelabeling (24 ​h) with oleic acid, total lipid content and incorporation into triacylglycerol was decreased, while incorporation into other lipids, as well as complete oxidation and β-oxidation was increased in SENP2-KD cells. Basal glucose uptake (i.e., not under insulin-stimulated conditions) was higher in SENP2-KD cells, whereas oxidation was similar to control myotubes. Further, basal glycogen synthesis was not different in SENP2-KD myotubes, but both insulin-stimulated glycogen synthesis and AktSer473 phosphorylation was completely blunted in SENP2-KD cells. In conclusion, SENP2 plays an important role in fatty acid and glucose metabolism in human myotubes. Interestingly, it also appears to have a pivotal role in regulating myotube insulin sensitivity. Future studies should examine the role of SENP2 in regulation of insulin sensitivity in other tissues and in vivo, defining the potential for SENP2 as a drug target.

Activation of N-methyl-D-aspartate receptor regulates insulin sensitivity and lipid metabolism.

Rationale: Although significant progress has been made in understanding the mechanisms of steatosis and insulin resistance, the physiological functions of regulators in these processes remain largely elusive. Evidence has suggested that the glutamate/N-methyl-D-aspartic acid receptor (NMDAR) axis contributes to acute lung injury, pulmonary arterial hypertension, and diabetes, but the specific metabolic contribution of the glutamate/NMDAR axis is not clear. Here we provide data at the animal, cellular, and molecular levels to support the role of the glutamate/NMDAR axis as a therapeutic target for metabolic syndrome in obesity.Methods: We examined the glutamate level in the obese mouse induced by a high-fat diet (HFD) for 12 weeks. To assess the role of NMDAR in insulin sensitivity and lipid metabolism, we tested the effects of Memantine (an NMDAR antagonist) and NMDA (an NMDAR agonist) on mice fed with HFD or standard chow diet. The in vitros NMDAR roles were analyzed in hepatocytes and potential mechanisms involved in regulating lipid metabolism were investigated.Results: Glutamate was increased in the serum of HFD-treated mice. The NMDAR blockade by Memantine decreased the susceptibility to insulin resistance and hepatic steatosis in obese mice. NMDA treatment for 6 months induced obesity in mice, characterized by hyperglycemia, hyperlipidemia, insulin resistance, and pathological changes in the liver. We provided in vitro evidence demonstrating that NMDAR activation facilitated metabolic syndrome in obesity through promoting lipid accumulation. NMDAR inhibition attenuated lipid accumulation induced by palmitic acid. Mechanistically, NMDAR activation impaired fatty acid oxidation by reducing PPARα phosphorylation and activity. The PPARα activity reduction induced by NMDAR activation was reversibly mediated by ERK1/2 signaling.Conclusion: These findings revealed that targeting NMDAR might be a promising therapeutic strategy for metabolic syndrome in obesity.

An Integrated Analysis of miRNA and Gene Expression Changes in Response to an Obesogenic Diet to Explore the Impact of Transgenerational Supplementation with Omega 3 Fatty Acids.

Insulin resistance decreases the ability of insulin to inhibit hepatic gluconeogenesis, a key step in the development of metabolic syndrome. Metabolic alterations, fat accumulation, and fibrosis in the liver are closely related and contribute to the progression of comorbidities, such as hypertension, type 2 diabetes, or cancer. Omega 3 (n-3) polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA), were identified as potent positive regulators of insulin sensitivity in vitro and in animal models. In the current study, we explored the effects of a transgenerational supplementation with EPA in mice exposed to an obesogenic diet on the regulation of microRNAs (miRNAs) and gene expression in the liver using high-throughput techniques. We implemented a comprehensive molecular systems biology approach, combining statistical tools, such as MicroRNA Master Regulator Analysis pipeline and Boolean modeling to integrate these biochemical processes. We demonstrated that EPA mediated molecular adaptations, leading to the inhibition of miR-34a-5p, a negative regulator of Irs2 as a master regulatory event leading to the inhibition of gluconeogenesis by insulin during the fasting–feeding transition. Omics data integration provided greater biological insight and a better understanding of the relationships between biological variables. Such an approach may be useful for deriving innovative data-driven hypotheses and for the discovery of molecular–biochemical mechanistic links.

SESTRINs: Emerging Dynamic Stress-Sensors in Metabolic and Environmental Health.

Proper timely management of various external and internal stresses is critical for metabolic and redox homeostasis in mammals. In particular, dysregulation of mechanistic target of rapamycin complex (mTORC) triggered from metabolic stress and accumulation of reactive oxygen species (ROS) generated from environmental and genotoxic stress are well-known culprits leading to chronic metabolic disease conditions in humans. Sestrins are one of the metabolic and environmental stress-responsive groups of proteins, which solely have the ability to regulate both mTORC activity and ROS levels in cells, tissues and organs. While Sestrins are originally reported as one of several p53 target genes, recent studies have further delineated the roles of this group of stress-sensing proteins in the regulation of insulin sensitivity, glucose and fat metabolism, and redox-function in metabolic disease and aging. In this review, we discuss recent studies that investigated and manipulated Sestrins-mediated stress signaling pathways in metabolic and environmental health. Sestrins as an emerging dynamic group of stress-sensor proteins are drawing a spotlight as a preventive or therapeutic mechanism in both metabolic stress-associated pathologies and aging processes at the same time.

MiR-146a regulates insulin sensitivity via NPR3

The pathogenesis of obesity-related metabolic diseases has been linked to the inflammation of white adipose tissue (WAT), but the molecular interconnections are still not fully understood. MiR-146a controls inflammatory processes by suppressing pro-inflammatory signaling pathways. The aim of this study was to characterize the role of miR-146a in obesity and insulin resistance. MiR-146a−/− mice were subjected to a high-fat diet followed by metabolic tests and WAT transcriptomics. Gain- and loss-of-function studies were performed using human Simpson–Golabi–Behmel syndrome (SGBS) adipocytes. Compared to controls, miR-146a−/− mice gained significantly more body weight on a high-fat diet with increased fat mass and adipocyte hypertrophy. This was accompanied by exacerbated liver steatosis, insulin resistance, and glucose intolerance. Likewise, adipocytes transfected with an inhibitor of miR-146a displayed a decrease in insulin-stimulated glucose uptake, while transfecting miR-146a mimics caused the opposite effect. Natriuretic peptide receptor 3 (NPR3) was identified as a direct target gene of miR-146a in adipocytes and CRISPR/Cas9-mediated knockout of NPR3 increased insulin-stimulated glucose uptake and enhanced de novo lipogenesis. In summary, miR-146a regulates systemic and adipocyte insulin sensitivity via downregulation of NPR3.