Severe Maternal Hyperglycemia Exacerbates the Development of Insulin Resistance and Fatty Liver in the Offspring on High Fat Diet

Background. Adverse maternal environments may predispose the offspring to metabolic syndrome in adulthoods, but the underlying mechanism has not been fully understood. Methods. Maternal hyperglycemia was induced by streptozotocin (STZ) injection while control (CON) rats received citrate buffer. Litters were adjusted to eight pups per dam and then weaned to standard diet. Since 13 weeks old, a subset of offspring from STZ and CON dams were switched to high fat diet (HFD) for another 13 weeks. Glucose and insulin tolerance tests (GTT and ITT) and insulin secretion assay were performed; serum levels of lipids and leptin were measured. Hepatic fat accumulation and islet area were evaluated through haematoxylin and eosin staining. Results. STZ offspring exhibited lower survival rate, lower birth weights, and growth inhibition which persisted throughout the study. STZ offspring on HFD showed more severe impairment in GTT and ITT, and more profound hepatic steatosis and more severe hyperlipidemia compared with CON-HFD rats. Conclusions. Offspring from diabetic dams would be prone to exhibit low birth weight and postnatal growth inhibition, but could maintain normal glucose tolerance and insulin sensitivity. HFD accelerates development of insulin resistance in the offspring of diabetic dams mainly via a compensatory response of islets

Fosinopril improves liver fibrosis by upregulating ACE2/Angiotensin-(1-7) axis activation in rats with nonalcoholic steatohepatitis

The aim of this research was to evaluate the effect of the angiotensin converting enzyme (ACE) inhibitor fosinopril on liver fibrosis in rats with high fat diet (HFD) induced nonalcoholic steatohepatitis (NASH). We found that treatment with fosinopril improved liver fibrosis. Moreover, treatment with fosinopril decreased serum Angiotensin (Ang) II, leptin, transforming growth factor β1 and hyaluronic acid concentrations, increased serum ACE2, Ang-(1-7), and adiponectin concentrations in rats fed with HFD. In the liver, fosinopril led to decreased leptin, α-smooth muscle actin, and collagen I expression, increased ACE2 and adiponectin expression. In conclusion, Fosinopril improves liver fibrosis by upregulating ACE2/Ang-(1-7) axis activation in rats with HFD-induced NASH. Furthermore, fosinopril might regulate the progression of liver fibrosis through the downregulation of leptin and the upregulation of adiponectin.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Glucose and Palmitate Differentially Regulate PFKFB3/iPFK2 and Inflammatory Responses in Mouse Intestinal Epithelial Cells

The gene PFKFB3 encodes for inducible 6-phosphofructo-2-kinase, a glycolysis-regulatory enzyme that protects against diet-induced intestine inflammation. However, it is unclear how nutrient overload regulates PFKFB3 expression and inflammatory responses in intestinal epithelial cells (IECs). In the present study, primary IECs were isolated from small intestine of C57BL/6J mice fed a low-fat diet (LFD) or high-fat diet (HFD) for 12 weeks. Additionally, CMT-93 cells, a cell line for IECs, were cultured in low glucose (LG, 5.5 mmol/L) or high glucose (HG, 27.5 mmol/L) medium and treated with palmitate (50 mu mol/L) or bovine serum albumin (BSA) for 24 hr. These cells were analyzed for PFKFB3 and inflammatory markers. Compared with LFD, HFD feeding decreased IEC PFKFB3 expression and increased IEC proinflammatory responses. In CMT-93 cells, HG significantly increased PFKFB3 expression and proinflammatory responses compared with LG. Interestingly, palmitate decreased PFKFB3 expression and increased proinflammatory responses compared with BSA, regardless of glucose concentrations. Furthermore, HG significantly increased PFKFB3 promoter transcription activity compared with LG. Upon PFKFB3 overexpression, proinflammatory responses in CMT-93 cells were decreased. Taken together, these results indicate that in IECs glucose stimulates PFKFB3 expression and palmitate contributes to increased proinflammatory responses. Therefore, PFKFB3 regulates IEC inflammatory status in response to macronutrients.National Institutes of Health [HL108922, HL095556, R01DK095828, R01DK095862]; National Natural Science Foundation of China [81100562/H0711]; Hatch Program of National Institutes of Food and Agriculture (NIFA)SCI(E)[email protected]; [email protected]

Neuronal ablation of GHSR mitigates diet-induced depression and memory impairment via AMPK-autophagy signaling-mediated inflammation

Obesity is associated with chronic inflammation in the central nervous system (CNS), and neuroinflammation has been shown to have detrimental effects on mood and cognition. The growth hormone secretagogue receptor (GHSR), the biologically relevant receptor of the orexigenic hormone ghrelin, is primarily expressed in the brain. Our previous study showed that neuronal GHSR deletion prevents high-fat diet-induced obesity (DIO). Here, we investigated the effect of neuronal GHSR deletion on emotional and cognitive functions in DIO. The neuron-specific GHSR-deficient mice exhibited reduced depression and improved spatial memory compared to littermate controls under DIO. We further examined the cortex and hippocampus, the major regions regulating cognitive and emotional behaviors, and found that the neuronal deletion of GHSR reduced DIO-induced neuroinflammation by suppressing proinflammatory chemokines/cytokines and decreasing microglial activation. Furthermore, our data showed that neuronal GHSR deletion suppresses neuroinflammation by downregulating AMPK-autophagy signaling in neurons. In conclusion, our data reveal that neuronal GHSR inhibition protects against DIO-induced depressive-like behavior and spatial cognitive dysfunction, at least in part, through AMPK-autophagy signaling-mediated neuroinflammation

Berberine Ameliorates Hepatic Steatosis and Suppresses Liver and Adipose Tissue Inflammation in Mice with Diet-induced Obesity

Increasing evidence demonstrates that berberine (BBR) is beneficial for obesity-associated nonalcoholic fatty liver disease (NAFLD). However, it remains to be elucidated how BBR improves aspects of NAFLD. Here we revealed an AMP-activated protein kinase (AMPK)-independent mechanism for BBR to suppress obesity-associated inflammation and improve hepatic steatosis. In C57BL/6J mice fed a high-fat diet (HFD), treatment with BBR decreased inflammation in both the liver and adipose tissue as indicated by reduction of the phosphorylation state of JNK1 and the mRNA levels of proinflammatory cytokines. BBR treatment also decreased hepatic steatosis, as well as the expression of acetyl-CoA carboxylase and fatty acid synthase. Interestingly, treatment with BBR did not significantly alter the phosphorylation state of AMPK in both the liver and adipose tissue of HFD-fed mice. Consistently, BBR treatment significantly decreased the phosphorylation state of JNK1 in both hepatoma H4IIE cells and mouse primary hepatocytes in both dose-dependent and time-dependent manners, which was independent of AMPK phosphorylation. BBR treatment also caused a decrease in palmitate-induced fat deposition in primary mouse hepatocytes. Taken together, these results suggest that BBR actions on improving aspects of NAFLD are largely attributable to BBR suppression of inflammation, which is independent of AMPK.National Institutes of Health [HL108922, HL095556, R01DK095828, R01DK095862]; National Natural Science Foundation of China [81100562/H0711]; Hatch Program of the National Institutes of Food and Agriculture (NIFA)SCI(E)[email protected]; [email protected]

Indole Alleviates Diet-induced Hepatic Steatosis and Inflammation in a Manner Involving Myeloid Cell PFKFB3

Background and aims: Indole is a microbiota metabolite that exerts anti-inflammatory responses. However, the relevance of indole to human non-alcoholic fatty liver disease (NAFLD) is not clear. It also remains largely unknown whether and how indole acts to protect against NAFLD. The present study sought to examine the association between the circulating levels of indole and liver fat content in human subjects and explore the mechanisms underlying indole actions in mice with diet-induced NAFLD. Approach and results: In a cohort of 137 subjects, the circulating levels of indole were reversely correlated with body mass index. In addition, the circulating levels of indole in obese subjects were significantly lower than those in lean subjects and were accompanied with increased liver fat content. At the whole-animal level, treatment of high-fat diet (HFD)-fed C57BL/6J mice with indole caused significant decreases in the severity of hepatic steatosis and inflammation. In cultured cells, indole treatment stimulated the expression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a master regulatory gene of glycolysis, and suppressed macrophage proinflammatory activation in a PFKFB3-dependent manner. Moreover, myeloid cell-specific PFKFB3 disruption exacerbated the severity of HFD-induced hepatic steatosis and inflammation and blunted the effect of indole on alleviating diet-induced NAFLD phenotype. Conclusions: Taken together, our results demonstrate that indole is relevant to human NAFLD and capable of alleviating diet-induced NAFLD phenotypes in mice in a myeloid cell PFKFB3-dependent manner. Therefore, indole mimetic and/or macrophage-specific PFKFB3 activation may be the viable preventive and/or therapeutic approaches for inflammation-associated diseases including NAFLD

Metformin Ameliorates Hepatic Steatosis and Inflammation without Altering Adipose Phenotype in Diet-Induced Obesity

Non-alcoholic fatty liver disease (NAFLD) is closely associated with obesity and insulin resistance. To better understand the pathophysiology of obesity-associated NAFLD, the present study examined the involvement of liver and adipose tissues in metformin actions on reducing hepatic steatosis and inflammation during obesity. C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity-associated NAFLD and treated with metformin (150 mg/kg/d) orally for the last four weeks of HFD feeding. Compared with HFD-fed control mice, metformin-treated mice showed improvement in both glucose tolerance and insulin sensitivity. Also, metformin treatment caused a significant decrease in liver weight, but not adiposity. As indicated by histological changes, metformin treatment decreased hepatic steatosis, but not the size of adipocytes. In addition, metformin treatment caused an increase in the phosphorylation of liver AMP-activated protein kinase (AMPK), which was accompanied by an increase in the phosphorylation of liver acetyl-CoA carboxylase and decreases in the phosphorylation of liver c-Jun N-terminal kinase 1 (JNK1) and in the mRNA levels of lipogenic enzymes and proinflammatory cytokines. However, metformin treatment did not significantly alter adipose tissue AMPK phosphorylation and inflammatory responses. In cultured hepatocytes, metformin treatment increased AMPK phosphorylation and decreased fat deposition and inflammatory responses. Additionally, in bone marrow-derived macrophages, metformin treatment partially blunted the effects of lipopolysaccharide on inducing the phosphorylation of JNK1 and nuclear factor kappa B (NF-κB) p65 and on increasing the mRNA levels of proinflammatory cytokines. Taken together, these results suggest that metformin protects against obesity-associated NAFLD largely through direct effects on decreasing hepatocyte fat deposition and on inhibiting inflammatory responses in both hepatocytes and macrophages

Exosome-Like Vesicles as New Mediators and Therapeutic Targets for Treating Insulin Resistance and β-Cell Mass Failure in Type 2 Diabetes Mellitus

Exosome-like vesicles (ELVs), the smallest class of extracellular vesicles released from cells, function in cellular crosstalk and therefore profoundly affect physiologic responses and pathologic progression. A growing body of evidence supports a novel role for ELVs as important mediators and therapeutic targets due to their effects on regulation of both insulin signaling and β-cell mass. Pathologic conditions associated with type 2 diabetes (such as high blood glucose, inflammation, hypoxia, and fatty acids) can alter the quantity and components of ELVs secreted from the pancreas or peripheral insulin-targeting tissues. These released ELVs can either enter the blood circulation or be taken up by neighboring cells or macrophages, which can lead to insulin resistance or β-cell apoptosis. This review focuses on the roles of ELVs in insulin resistance and β-cell failure and also highlights the potential use of ELVs and exosome-based delivery systems in therapeutic interventions aimed at treating type 2 diabetes mellitus as well as the challenges associated with exosome-targeting therapeutics