Obesity-induced Hyperglycemia Research Articles

Coreopsis tinctoria improves energy metabolism in obese hyperglycemic mice

Coreopsis tinctoria (CT) improves energy metabolism. However, the role of CT in alleviating obesity-induced hyperglycemia by targeting the liver remains unknown. Therefore, this article aims to explore the mechanism by which CT improves energy metabolism and resists hyperglycemia. The water and ethanol extracts of CT were administered to high-fat diet-induced (HFD) obese C57BL/6J mice at a dose of 4 g/kg.bw (low-dose water extract, WL; low-dose ethanol extract, EL) or 10 g/kg.bw (high-dose water extract, WH; high-dose ethanol extract, EH). Mice that consumed a maintenance diet (LFD) were included as blank controls. Network pharmacology, liquid chromatography-mass spectrometry (LC-MS), L02 cell cultivation, and liver transcriptomics were used to examine the mechanism and functional components of CT against obesity-induced hyperglycemia. The results indicated that WL significantly (p < 0.05) alleviated glucose intolerance and insulin resistance in obesity-induced hyperglycemia. Kaempferol is the main active compound of CT, which demonstrated significant (p < 0.05) anti-hyperglycemic effects in obese mice and L02 cells. Finally, kaempferol significantly (p < 0.05; fold change >1.2) shifted the genes involved in carbon metabolism, glycolysis/gluconeogenesis, and the mitogen-activated protein kinase (MAPK) pathways toward the trend of LFD, indicating that it exerts an anti-hyperglycemic effect through these molecular mechanisms. Overall, oral intake of CT lowers blood glucose and improves insulin sensitivity in mice with obesity-induced hyperglycemia. Kaempferol is the primary functional component of CT.

Effect of Semaglutide and Empagliflozin on Pulmonary Structure and Proteomics in Obese Mice.

This study utilized proteomics to investigate changes in protein expression associated with lung health in obese mice exposed to semaglutide and empagliflozin through a high-fat diet. Twenty-eight male C57BL/6JC mice were randomly assigned to two groups: a control diet group (n = 7) and a high-fat diet group (n = 21). The HFD group was further divided into three groups: HFD group (n = 7), Sema group (n = 7), and Empa group (n = 7). Post-treatment, mice underwent assessments including glucose tolerance, lipids, oxidative stress markers, body weight, lung weight, and structure. Proteomics identified differentially expressed proteins (DEPs) in lung tissue, and bioinformatics analyzed the biological processes and functions of these proteins. Semaglutide and empagliflozin significantly attenuated obesity-induced hyperglycemia, abnormal lipid metabolism, oxidative stress response, and can decrease alveolar wall thickness, enlarge alveolar lumen, and reduce collagen content in lung tissue. Both medications also attenuated lung elastic fibre cracking and disintegration. In the HFD/NCD group, there were 66 DEPs, comprising 30 proteins that were increased and 36 that were decreased. Twenty-three DEPs overlapped between Sema/HFD and Empa/HFD, with 11 up-regulated and 12 down-regulated simultaneously. After analysing DEPs in different groups, four proteins - LYVE1, BRAF, RGCC, and CHMP5 - were all downregulated in the HFD group and upregulated by semaglutide and empagliflozin treatment. This study demonstrates that obesity induced by a high-fat diet causes a reduction in the expression of LYVE1, BRAF, RGCC, and CHMP5 proteins, potentially affecting lung function and structure in mice. Significantly, the administration of semaglutide and empagliflozin elevates the levels of these proteins, potentially offering therapeutic benefits against lung injury caused by obesity. Merging semaglutide with empagliflozin may exert a more pronounced impact.

Dopamine D2 receptor antagonist counteracts hyperglycemia and insulin resistance in diet-induced obese male mice.

Obesity leads to insulin resistance (IR) and type 2 diabetes. In humans, low levels of the hormone prolactin (PRL) correlate with IR, adipose tissue (AT) dysfunction, and increased prevalence of T2D. In obese rats, PRL treatment promotes insulin sensitivity and reduces visceral AT adipocyte hypertrophy. Here, we tested whether elevating PRL levels with the prokinetic and antipsychotic drug sulpiride, an antagonist of dopamine D2 receptors, improves metabolism in high fat diet (HFD)-induced obese male mice. Sulpiride treatment (30 days) reduced hyperglycemia, IR, and the serum and pancreatic levels of triglycerides in obese mice, reduced visceral and subcutaneous AT adipocyte hypertrophy, normalized markers of visceral AT function (PRL receptor, Glut4, insulin receptor and Hif-1α), and increased glycogen stores in skeletal muscle. However, the effects of sulpiride reducing hyperglycemia were also observed in obese prolactin receptor null mice. We conclude that sulpiride reduces obesity-induced hyperglycemia by mechanisms that are independent of prolactin/prolactin receptor activity. These findings support the therapeutic potential of sulpiride against metabolic dysfunction in obesity.

Apolipoprotein E (ApoE) orchestrates adipose tissue inflammation and metabolic disorders through NLRP3 inflammasome

Obesity is a metabolic disorder characterized by the hypertrophy expansion of adipose tissue, resulting in dysregulated energy metabolism, and accompanied by chronic low-grade inflammation. Adipose tissue macrophages (ATMs), a principal component of inflammation, respond to microenvironment signals and modulate adipose tissue remodeling and metabolic processes situation-specific. However, the mechanisms governing how the organism maintains equilibrium between its chronic inflammation and metabolism still need to be understood. Here, we describe a novel role of apolipoprotein E (ApoE), which associated with lipid particles, in maintaining fat deposition and system metabolic inflammation. Using human samples and mouse models, we show that ApoE is robustly downregulated in obese individuals, db/db mice, and mice of high-fat diet (HFD) feeding and increased in obese subjects with diabetes. Furthermore, we found that ApoE deficiency mice globally prevented obesity by restraining adipose tissue expansion and improved systemic glucose tolerance and insulin sensitivity. However, macrophage contributed to metabolic inflammation due to increased IL-1β production in adipose tissue from ApoE-/- mice induced by HFD. Our results suggest that the role of ApoE in regulating obesity and obesity-associated glucose dysregulation is inconsistent. Mechanistically, ApoE modulates of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome priming and activation step. Thus, our studies might provide new sights into ApoE, which is required for obesity-induced hyperglycemia, hyperinsulinism, and adaptive inflammation responses but diminishes the tolerance towards a subsequent metabolic inflammatory challenge. Our study shed new light on the integral role of apolipoprotein APOE in immunometabolism and adipose tissue homeostasis.

Obesity-Induced Hyperglycemia and Heart Failure Preserved Ejection Fraction: Uncharted Territories to Remission.

Until the end of World War II, food security was a global challenge. Consequently, in 1948, type 2 diabetes was relatively uncommon, with the majority of cases being type 1 diabetes requiring insulin therapy. Since then, food has become increasingly palatable and readily available, leading to a rise in obesity across all age groups. Understanding the impact of obesity on our health has become crucial for optimizing healthcare. In this context, we draw attention to two significant, yet relatively uncharted pathogenic effects associated with obesity: Hyperglycemia and Heart Failure with Preserved Ejection Fraction (HFpEF). Thorough pathophysiologic, hemodynamic, and echocardiographic characterization have revealed the existence of a distinct phenotypeknown as "obese HFpEF" within the broader HFpEF population, and "obesity-induced hyperglycemia" within the diabetes population. In these phenotypes, patients often present with higher Body Mass Index and experience clinical symptoms decades earlier. Recent insights have enhanced our understanding of the mechanisms underlying obesity-mediated heart failure preserved ejection fraction and hyperglycemia. Early detection offers the potential for reversibility of many pathologies associated with obesity through adequate weight reduction. The objective of this review is to provide a deeper insight into these uncharted territories and explore the potential for improved outcomes by reframing these two narratives toward achieving remission. Such a shift has the potential to positively impact individual engagement with healthier lifestyles.

Targeting Neutrophil α9 Improves Functional Outcomes After Stroke in Mice With Obesity-Induced Hyperglycemia.

Obesity-induced hyperglycemia is a significant risk factor for stroke. Integrin α9β1 is expressed on neutrophils and stabilizes adhesion to the endothelium via ligands, including Fn-EDA (fibronectin containing extra domain A) and tenascin C. Although myeloid deletion of α9 reduces susceptibility to ischemic stroke, it is unclear whether this is mediated by neutrophil-derived α9. We determined the role of neutrophil-specific α9 in stroke outcomes in a mice model with obesity-induced hyperglycemia. α9Neu-KO (α9fl/flMRP8Cre+) and littermate control α9WT (α9fl/flMRP8Cre-) mice were fed on a 60% high-fat diet for 20 weeks to induce obesity-induced hyperglycemia. Functional outcomes were evaluated up to 28 days after stroke onset in mice of both sexes using a transient (30 minutes) middle cerebral artery ischemia. Infarct volume (magnetic resonance imaging) and postreperfusion thrombo-inflammation (thrombi, fibrin, neutrophil, phospho-nuclear factor kappa B [p-NFκB], TNF [tumor necrosis factor]-α, and IL [interleukin]-1β levels, markers of neutrophil extracellular traps) were measured post 6 or 48 hours of reperfusion. In addition, functional outcomes (modified Neurological Severity Score, rota-rod, corner, and wire-hanging test) were measured for up to 4 weeks. Stroke upregulated neutrophil α9 expression more in obese mice (P<0.05 versus lean mice). Irrespective of sex, deletion of neutrophil α9 improved functional outcomes up to 4 weeks, concomitant with reduced infarct, improved cerebral blood flow, decreased postreperfusion thrombo-inflammation, and neutrophil extracellular traps formation (NETosis) (P<0.05 versus α9WT obese mice). Obese α9Neu-KO mice were less susceptible to thrombosis in FeCl3 injury-induced carotid thrombosis model. Mechanistically, we found that α9/cellular fibronectin axis contributes to NETosis via ERK (extracellular signal-regulated kinase) and PAD4 (peptidyl arginine deiminase 4), and neutrophil α9 worsens stroke outcomes via cellular fibronectin-EDA but not tenascin C. Obese wild-type mice infused with anti-integrin α9 exhibited improved functional outcomes up to 4 weeks (P<0.05 versus vehicle). Genetic ablation of neutrophil-specific α9 or pharmacological inhibition improves long-term functional outcomes after stroke in mice with obesity-induced hyperglycemia, most likely by limiting thrombo-inflammation.

Obesity-induced hyperglycemia impairs oral tolerance induction and aggravates food allergy

Obesity and type 2 diabetes (T2D) have been found to be associated with abnormalities in several organs, including the intestine. These conditions can lead to changes in gut homeostasis, compromising tolerance to luminal antigens and increasing susceptibility to food allergies. The underlying mechanisms for this phenomenon are not yet fully understood. In this study, we investigated changes in the intestinal mucosa of diet-induced obese mice and found that they exhibited increased gut permeability and reduced Treg cells frequency. Upon oral treatment with ovalbumin (OVA), obese mice failed to develop oral tolerance. However, hyperglycemia treatment improved intestinal permeability and oral tolerance induction in mice. Furthermore, we observed that obese mice exhibited a more severe food allergy to OVA, and this allergy was alleviated after treatment with a hypoglycemic drug. Importantly, our findings were translated to obese humans. Individuals with T2D had higher serum IgE levels and downregulated genes related to gut homeostasis. Taken together, our results suggest that obesity-induced hyperglycemia can lead to a failure in oral tolerance and to exacerbation of food allergy. These findings shed light on the mechanisms underlying the relationship among obesity, T2D, and gut mucosal immunity, which could inform the development of new therapeutic approaches.

Abstract 39: Targeting Neutrophil-specific Integrin Alpha9 In Obesity-induced Hyperglycemia Mice Improves Stroke Outcome

Background: Obesity-induced hyperglycemia is one of the significant risk factors for stroke. Integrin α9β1 is highly expressed on activated neutrophils and stabilizes adhesion to the endothelium via ligands, including tenascin C. While myeloid deletion of α9 reduces susceptibility to ischemic stroke, it is unclear whether this is mediated by neutrophil-derived α9. Purpose: To determine the role of neutrophil-specific α9 in stroke outcome in mice with obesity-induced hyperglycemia. Methods: α9 Neu-KO (α9 fl/fl MRP8Cre + ) and littermate control α9 WT (α9 fl/fl MRP8 Cre - ) mice were fed a 60% high fat diet for 20 weeks. Functional outcomes were evaluated up to 28 days after stroke in mice of both sexes using a transient (30 min) middle cerebral artery ischemia. Infarct volume (MRI) and post-reperfusion thrombo-inflammation (thrombi, fibrin, neutrophil, p-NFκB, NETosis, TNFα, and IL1β levels) were measured post 6 or 48 h of reperfusion. Functional outcomes (mNSS, rotarod, corner, and wire-hanging test) were measured at week 1, 2, 3, and 4. Results: Stroke upregulated neutrophil α9 expression in obese mice (P&lt;.05 vs. lean mice). Genetic ablation of neutrophil-specific α9 improved functional outcomes up to 4 weeks that was concomitant with reduced infarct size, improved CBF, decreased post-reperfusion thrombo-inflammation, and reduced NETosis (P&lt;.05 vs. α9 WT obese mice) irrespective of sex. Intravital microscopy revealed that obese α9 Neu-KO mice were less susceptible to experimental carotid thrombosis (P&lt;.05 vs. α9 WT obese mice). Infusion of tenascin C increased stroke severity in both α9 Neu-KO and α9 WT compared to vehicle, suggesting that neutrophil-specific α9 does not exacerbate stroke via tenascin C. Obese WT mice infused with a blocking anti-integrin α9 IgG exhibited improved functional outcomes up to 4 weeks (P&lt;.05 vs. control IgG). Functional outcomes after stroke were comparable in α9 Neu-KO mice infused with anti-integrin α9 IgG or control IgG, suggesting no off-target effects of the antibody. Conclusion: Both genetic ablation of neutrophil-specific α9 and pharmacological inhibition improve long-term functional outcomes after stroke in mice with obesity-induced hyperglycemia, most likely by limiting thrombo-inflammation and NETosis.

The Antipsychotic Dopamine 2 Receptor Antagonist Diphenylbutylpiperidines Improve Glycemia in Experimental Obesity by Inhibiting Succinyl-CoA:3-Ketoacid CoA Transferase.

Despite significant progress in understanding the pathogenesis of type 2 diabetes (T2D), the condition remains difficult to manage. Hence, new therapeutic options targeting unique mechanisms of action are required. We have previously observed that elevated skeletal muscle succinyl CoA:3-ketoacid CoA transferase (SCOT) activity, the rate-limiting enzyme of ketone oxidation, contributes to the hyperglycemia characterizing obesity and T2D. Moreover, we identified that the typical antipsychotic agent pimozide is a SCOT inhibitor that can alleviate obesity-induced hyperglycemia. We now extend those observations here, using computer-assisted in silico modeling and invivo pharmacology studies that highlight SCOT as a noncanonical target shared among the diphenylbutylpiperidine (DPBP) drug class, which includes penfluridol and fluspirilene. All three DPBPs tested (pimozide, penfluridol, and fluspirilene) improved glycemia in obese mice. While the canonical target of the DPBPs is the dopamine 2 receptor, studies in obese mice demonstrated that acute or chronic treatment with a structurally unrelated antipsychotic dopamine 2 receptor antagonist, lurasidone, was devoid of glucose-lowering actions. We further observed that the DPBPs improved glycemia in a SCOT-dependent manner in skeletal muscle, suggesting that this older class of antipsychotic agents may have utility in being repurposed for the treatment of T2D.

Structurally-engineered fatty acid 1024 (SEFA-1024) improves diet-induced obesity, insulin resistance, and fatty liver disease.

Obesity is a global epidemic that drives morbidity and mortality through cardiovascular disease, diabetes, and non-alcoholic fatty liver disease (NAFLD). No definitive therapy has been approved to improve glycemic control and treat NAFLD in obese patients. Here, we investigated a semi-synthetic, long chain, structurally-engineered fatty acid-1024 (SEFA-1024), as a treatment for obesity-induced hyperglycemia, insulin-resistance, and fatty liver disease in rodent models. A single dose of SEFA-1024 was administered to evaluate glucose tolerance and active glucagon-like peptide 1 (GLP-1) in lean rats in the presence and absence of a DPP-4 inhibitor. The effects of SEFA-1024 on weight loss and glycemic control were assessed in genetic (ob/ob) and environmental (high-fat diet) murine models of obesity. Liver histology, serum liver enzymes, liver lipidomics, and hepatic gene expression were also assessed in the high-fat diet murine model. SEFA-1024 reversed obesity-associated insulin resistance and improved glycemic control. SEFA-1024 increased active GLP-1. In a long-term model of diet-induced obesity, SEFA-1024 reversed excessive weight gain, hepatic steatosis, elevated liver enzymes, hepatic lipotoxicity, and promoted fatty acid metabolism. SEFA-1024 is an enterohepatic-targeted, eicosapentaenoic acid derivative that reverses obesity-induced dysregulated glucose metabolism and hepatic lipotoxicity in genetic and dietary rodent models of obesity. The mechanism by which SEFA-1024 works may include increasing aGLP-1, promoting fatty acid oxidation, and inhibiting hepatic triglyceride formation. SEFA-1024 may serve as a potential treatment for obesity-related diabetes and NAFLD.

233-LB: Ranolazine Fails to Improve Glycemia in Obese Liver-Specific Pyruvate Dehydrogenase–Deficient Mice

Background: Nonalcoholic fatty liver disease (NAFLD) increases risk for obesity-related insulin resistance and type 2 diabetes. Recent studies have demonstrated that stimulating pyruvate dehydrogenase (PDH) , the rate-limiting enzyme in glucose oxidation, can reverse obesity-induced NAFLD. Moreover, our lab has observed that treatment with the antianginal drug, ranolazine, augments hepatic PDH activity, leading to a reversal of obesity-induced glucose intolerance and NAFLD in mice. Our aim herein was to determine whether ranolazine's ability to mitigate obesity-induced NAFLD and hyperglycemia requires increases in hepatic PDH activity. Methods: We generated liver-specific PDH deficient (PDHLiver-/-) mice by crossing floxed Pdha1 mice with albumin-Cre (Alb-Cre) mice. PDHLiver-/- and Alb-Cre mice were placed on a high-fat diet for 12-weeks to induce obesity, whereas their lean controls were fed a low-fat diet. Mice were randomized to treatment with either vehicle control or ranolazine (50 mg/kg) once daily via oral gavage for 5-weeks, following which we assessed glucose homeostasis and hepatic steatosis. Results: Lean PDHLiver-/- mice exhibited no overt phenotypic differences (e.g. adiposity, glucose tolerance) from their Alb-Cre littermates, though a mild but nonsignificant worsening of pyruvate tolerance was observed. Similar findings were observed in obese PDHLiver-/- mice compared to their Alb-Cre littermates. Of interest, ranolazine treatment produced mild improvements in glucose tolerance in obese Alb-Cre mice, but not in obese PDHLiver-/- mice. However, this improvement in ranolazine treated Alb-Cre mice appears to be independent of decreases in hepatic triacylglycerol content. Conclusions: Although hepatic PDH activity appears to contribute to the glucose-lowering actions of ranolazine, this appears to be dissociated from its actions on hepatic steatosis, and impaired hepatic PDH activity per se is not sufficient to produce an NAFLD phenotype. Disclosure C. T. Saed: None. S. Tabatabaei dakhili: None. A. A. Greenwell: None. J. S. F. Chan: None. K. Yang: None. K. Gopal: None. F. Eaton: None. J. R. Ussher: None.

118-LB: The Antipsychotic D2 Receptor Antagonist Diphenylbutylpiperidines Improve Glycemia in Experimental Obesity by Inhibiting Succinyl-CoA—3-Ketoacid CoA transferase

Purpose: Despite significant progress in understanding the pathogenesis of type 2 diabetes (T2D) , it remains difficult to manage, hence, new therapeutic options are required. We previously observed that elevated skeletal muscle succinyl CoA:3-ketoacid CoA transferase (SCOT) activity, the rate-limiting enzyme of ketone (KB) oxidation, contributes to obesity-induced hyperglycemia. Moreover, we identified that the antipsychotic agent, pimozide, is a SCOT inhibitor with glucose-lowering actions. In silico molecular modeling determined that a wide range of DPBPs can theoretically inhibit SCOT activity, therefore, we determined whether the DPBP drug class could be repurposed for the treatment of T2D. Methods: 8-week-old male wild-type and muscle-specific/brain-specific SCOT knockout (SCOTMuscleKO, SCOTBrainKO) mice were subjected to experimental obesity via consumption of a high fat, high sugar diet for 12-weeks. Lean control mice received a low fat, low sugar diet. At 8-weeks, lean and obese mice were treated with DPBPs (penfluridol, fluspirilene, pimozide (10mg/kg)) once every 2 days via oral gavage for 14-days, following which circulating KB levels and glucose homeostasis were assessed. To rule out a contribution of the canonical actions of DPBPs as dopamine 2 (D2) receptor antagonists to DPBP-mediated glucose-lowering, obese mice were treated with the structurally unrelated D2 receptor antagonist, lurasidone (10 mg/kg) . Results: All tested DPBPs improved glucose homeostasis in obese mice through a mechanism dependent on the inhibition of both brain and muscle SCOT activity. Treatment with lurasidone failed to improve glycemia in obese mice, thus consistent with a SCOT-dependent mechanism of action. Conclusions: Our findings suggest all DPBPs have glucose-lowering actions and therefore may have clinical utility in being repurposed for the treatment of T2D. Disclosure S. Tabatabaei dakhili: None. C. A. Velazquez: None. P. A. Crawford: Advisory Panel; Abbott Diabetes, Johnson &amp; Johnson Global Services. M. Glover: None. R. Al batran: None. J. R. Ussher: None. R. Abou farraj: None. A. A. Greenwell: None. C. T. Saed: None. K. Yang: None. K. Gopal: None. J. S. F. Chan: None. C. Lee: None. F. Eaton: None. Funding Canadian Institutes of HealthResearch

Evaluation of Hypoglycemic and Antioxidant Activities of Soybean Meal Products Fermented by Lactobacillus plantarum FPS 2520 and Bacillus subtilis N1 in Rats Fed with High-Fat Diet.

The hypoglycemic and antioxidant activities of Lactobacillus plantarum FPS 2520 and/or Bacillus subtilis N1 fermented soybean meal (SBM) in rats fed a high-fat diet (HFD) were investigated by assessing plasma glucose levels, insulin resistance, and oxidative stress-induced organ damage. Supplementation with FPS 2520- and/or N1-fermented SBM (500 and 1000 mg/kg of body weight per day) to HFD-induced obese rats for 6 weeks significantly down-regulated the concentration of plasma glucose during the oral glucose tolerance test (OGTT), as well as the concentration of fasting plasma glucose, insulin, and the value of the homeostasis model assessment of insulin resistance (HOMA-IR). In addition, plasma and hepatic levels of malondialdehyde (MDA) were alleviated in rats fed fermented SBM, especially SBM fermented by mixed strains. Moreover, fermented SBM treatment reduced HFD-exacerbated increases in plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine, and uric acid levels. Based on these results, we clearly demonstrate the effect of fermented SBM on improving insulin resistance and oxidation-induced organ damage. Therefore, it is suggested that fermented SBM has the potential to be developed as functional foods for the management of obesity-induced hyperglycemia and organ damage.

High fat diet induced abnormalities in metabolism, growth, behavior, and circadian clock in Drosophila melanogaster

AimsThe current lifestyle trend has made people vulnerable to diabetes and related diseases. Years of scientific research have not been able to yield a cure to the disease completely. The current study aims to investigate a link between high-fat diet mediated diabesity and circadian rhythm in the Drosophila model and inferences that might help in establishing a cure to the dreaded disease. Main methodsSeveral experimental methods including phenotypical, histological, biochemical, molecular, and behavioral assays were used in the study to detect obesity, diabetes, and changes in the circadian clock in the fly model. Key findingsThe larva and adults of Drosophila melanogaster exposed to high-fat diet (HFD) displayed excess deposition of fat as lipid droplets and micronuclei formation in the gut, fat body, and crop. Larva and adults of HFD showed behavioral defects. The higher amount of triglyceride, glucose, trehalose in the whole body of larva and adult fly confirmed obesity-induced hyperglycemia. The overexpression of insulin gene (Dilp2) and tribble (trbl) gene expression confirmed insulin resistance in HFD adults. We also observed elevated ROS level, developmental delay, altered metal level, growth defects, locomotory rhythms, sleep fragmentation, and expression of circadian genes (per, tim, and clock) in HFD larva and adults. Thus, HFD impairs the metabolism to produce obesity, insulin resistance, disruption of clock, and circadian clock related co-mordities in D. melanogaster. SignificanceThe circadian gene expression provides an innovative perspective to understand and find a new treatment for type-II diabetes and circadian anomalies.

Benzyl Isothiocyanate Ameliorates High-Fat Diet-Induced Hyperglycemia by Enhancing Nrf2-Dependent Antioxidant Defense-Mediated IRS-1/AKT/TBC1D1 Signaling and GLUT4 Expression in Skeletal Muscle.

Obesity caused lipotoxicity, which results in insulin resistance. We studied whether benzyl isothiocyanate (BITC) improved insulin resistance in muscle. BITC was studied in vivo in mice fed a high-fat diet (HFD) and in vitro in C2C12 myotubes treated with palmitic acid (PA). In C2C12 cells, BITC mitigated PA inhibition of glucose uptake and phosphorylation of IRS-1, AKT, and TBC1D1 in response to insulin. BITC upregulated the expression of HO-1, GSTP, and GCLM mRNA and protein as well as GSH contents, which suppressed oxidative damage. Knockdown of Nrf2 abrogated BITC enhancement of antioxidant defense and subsequently reversed BITC protection against PA-induced insulin resistance. Moreover, BITC upregulated the expression of GLUT4, PPARγ, and C/EBPα. In HFD-fed mice, plasma total cholesterol, nonesterified fatty acid, and glucose levels and HOMA-IR were dose-dependently decreased with 0.05 or 0.1% BITC administration. In gastrocnemius muscle, compared with the HFD group, BITC increased the phosphorylation of AKT and TBC1D1, GSH contents, and the expression of antioxidant enzymes as well as GLUT4. These results indicate that BITC ameliorates obesity-induced hyperglycemia by enhancing insulin sensitivity in muscle. This is partly attributed to its inhibition of lipotoxicity-induced oxidative insult and upregulation of GLUT4 expression.

Strength exercise reduces hepatic pyruvate carboxylase and gluconeogenesis in DIO mice.

Obesity is linked to a reduction in the control of hepatic glucose production, which is the primary mechanism related to fasting hyperglycemia and the development of type 2 diabetes mellitus (T2DM). The main system involved in hepatic gluconeogenesis synthesis is controlled by pyruvate carboxylase (PC), which increases in obesity conditions. Recently, we showed that short-term strength training is an important tool against obesity-induced hyperglycemia. As aerobic exercise can reduce the hepatic PC content of obese animals, we hypothesized that strength exercise can also decrease this gluconeogenic enzyme. Therefore, this study investigated whether the metabolic benefits promoted by short-term strength training are related to changes in hepatic PC content. Swiss mice were divided into three groups: lean control (Ctl), obese sedentary (ObS), and obese short-term strength training (STST). The STST protocol was performed through one session/day for 15 days. The obese exercised animals had reduced hyperglycemia and insulin resistance. These results were related to better control of hepatic glucose production and hepatic insulin sensitivity. Our bioinformatics analysis showed that hepatic PC mRNA levels have positive correlations with glucose levels and adiposity, and negative correlations with locomotor activity and muscle mass. We also found that hepatic mRNA levels are related to lipogenic markers in the liver. Finally, we observed that the obese animals had an increased hepatic PC level; however, STST was efficient in reducing its amount. In conclusion, we provide insights into new biomolecular mechanisms by showing how STST is an efficient tool against obesity-related hyperglycemia and T2DM, even without body weight changes.

Obesity-induced excess of 17-hydroxyprogesterone promotes hyperglycemia through activation of glucocorticoid receptor.

Type 2 diabetes mellitus (T2DM) has become an expanding global public health problem. Although the glucocorticoid receptor (GR) is an important regulator of glucose metabolism, the relationship between circulating glucocorticoids (GCs) and the features of T2DM remains controversial. Here, we show that 17-hydroxyprogesterone (17-OHP), an intermediate steroid in the biosynthetic pathway that converts cholesterol to cortisol, binds to and stimulates the transcriptional activity of GR. Hepatic 17-OHP concentrations are increased in diabetic mice and patients due to aberrantly increased expression of Cyp17A1. Systemic administration of 17-OHP or overexpression of Cyp17A1 in the livers of lean mice promoted the pathogenesis of hyperglycemia and insulin resistance, whereas knockdown of Cyp17A1 abrogated metabolic disorders in obese mice. Therefore, our results identify a Cyp17A1/17-OHP/GR-dependent pathway in the liver that mediates obesity-induced hyperglycemia, suggesting that selectively targeting hepatic Cyp17A1 may provide a therapeutic avenue for treating T2DM.

Pimozide Alleviates Hyperglycemia in Diet-Induced Obesity by Inhibiting Skeletal Muscle Ketone Oxidation

Perturbations in carbohydrate, lipid, and protein metabolism contribute to obesity-induced type 2 diabetes (T2D), though whether alterations in ketone body metabolism influence T2D pathology is unknown. We report here that activity of the rate-limiting enzyme for ketone body oxidation, succinyl-CoA:3-ketoacid-CoA transferase (SCOT/Oxct1), is increased in muscles of obese mice. We also found that the diphenylbutylpiperidine pimozide, which is approved to suppress tics in individuals with Tourette syndrome, is a SCOT antagonist. Pimozide treatment reversed obesity-induced hyperglycemia in mice, which was phenocopied in mice with muscle-specific Oxct1/SCOT deficiency. These actions were dependent on pyruvate dehydrogenase (PDH/Pdha1) activity, the rate-limiting enzyme of glucose oxidation, as pimozide failed to alleviate hyperglycemia in obese mice with a muscle-specific Pdha1/PDH deficiency. This work defines a fundamental contribution of enhanced ketone body oxidation to the pathology of obesity-induced T2D, while suggesting pharmacological SCOT inhibition as a new class of anti-diabetes therapy.

The Molecular Mechanisms of Excessive Hippocampal Endoplasmic Reticulum Stress Depressing Cognition-related Proteins Expression and the Regulatory Effects of Nrf2

Studies have shown that obesity-induced hyperglycemia and hyperlipidemia could cause increased hippocampal endoplasmic reticulum (ER) stress and impaired cognition-related proteins expression, resulting in learning and memory impairment. Meanwhile, aerobic exercise could activate hippocampal nuclear factor erythroid 2-related factor 2 (Nrf2) reducing ER stress. This study investigated the underlying molecular mechanisms of this effect. In order to clarify the relationship among ER stress, Nrf2 signaling and cognition-related proteins expression in vitro, we respectively treated hippocampal cells with high glucose and palmitic acid (PA), ER stress inhibitor 4-phenylbutyrate (4-PBA), and Nrf2 activator Tert-Butylhydroquinone (TBHQ). Results showed that the expression levels of glucose transporter 3 (GLUT3), fatty acid transport protein 1 (FATP1), ER stress biomarkers (GRP78, p-PERK, p-IRE1α and p-eIF2α), ER stress-mediated apoptosis biomarkers (caspase-12, CHOP and Bax/Bcl-2), and the activity of NLRP3-IL-1β inflammatory pathway were significantly increased under high glucose and PA conditions, accompanied with depressed p38/ERK-CREB pathway and decreased levels of brain derived neurotrophic factor (BDNF) and synaptophysin (SYN). On the other hand, both 4-PBA and TBHQ reduced ER stress and reversed the expression of the above-mentioned proteins. Our findings suggest that high glucose and PA could induce excessive ER stress and apoptosis via promoting the overexpression of GLUT3 and FATP1, and ER stress could suppress BDNF and SYN expression through negatively regulating p38/ERK-CREB pathway and positively regulating NLRP3-IL-1β pathway, which could be reversed by activated Nrf2-HO-1 pathway.

Effect of Dietary Silk Peptide on Obesity, Hyperglycemia, and Skeletal Muscle Regeneration in High-Fat Diet-Fed Mice.

Obesity is associated with excess body fat accumulation that can cause hyperglycemia and reduce skeletal muscle function and strength, which characterize the development of sarcopenic obesity. In this study, we aimed to determine the mechanism whereby acid-hydrolyzed silk peptide (SP) prevents high-fat diet (HFD)-induced obesity and whether it regulates glucose uptake and muscle differentiation using in vivo and in vitro approaches. Our findings demonstrate that SP inhibits body mass gain and the expression of adipogenic transcription factors in visceral adipose tissue (VAT). SP also had an anti-diabetic effect in VAT and skeletal muscle because it upregulated glucose transporter type 4 (GLUT4) and uncoupling protein 3 (UCP3) expression. Furthermore, SP reduced ubiquitin proteasome and promoted myoblast determination protein 1 (MyoD)/myogenic factor 4 (myogenin) expression, implying that it may have potential for the treatment of obesity-induced hyperglycemia and obesity-associated sarcopenia.