Tianshu Zeng

The protective effect of resveratrol on islet insulin secretion and morphology in mice on a high-fat diet

The aim of this study was to investigate the effect of resveratrol on beta cells in male C57BL/6J mice fed a high-fat diet and the possible mechanisms. Male C57BL/6J mice were randomly divided into three groups: normal control (NC) group, high-fat diet (HF) group and high-fat diet and resveratrol treatment (HFR) group (15 in each group). HFR group was fed with high fat diet for 8 weeks and then orally administered resveratrol at 400mg/kg daily. Twenty-four weeks later, the function of insulin secretion in vivo and in vitro was improved robustly in HFR group compared with HF group. The levels of glucose and lipid metabolism, beta cell mass, lipid content, and oxidative stress were lower in HFR group than in HF group. Simultaneously, resveratrol administration promoted the expression of SIRT1 in islets, while the expression of uncoupling protein 2 (UCP2) was restrained. Resveratrol, as well, also had a beneficial effect on the ratios of expressions of Bcl-2/Bax and levels of malondialdehyde/glutathione peroxidase. Resveratrol can protect islets from abnormal insulin secretion and morphological changes induced by a high-fat diet. The effect might be partly related to activated SIRT1 signal pathway, improved oxidative stress induced damage and incidence of apoptosis.

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 non-alcoholic 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.

Lipid overaccumulation and drastic insulin resistance in adult catch-up growth rats induced by nutrition promotion after undernutrition

This study was designed to explore the metabolic changes resulting from catch-up growth in adult (CUGA) induced by varying degrees of nutrition promotion after undernutrition and to confirm whether these changes are transient or not. The CUGA models were developed on rats refed on intakes of normal chow or high-fat diet after a period of caloric restriction. The growth of the rats measured by body weight and length stagnated during caloric restriction and then rapidly accelerated following refeeding. Catch-up growth in adult resulted in an increase in intramuscular and intrahepatic lipid content, visceral fat deposition, and insulin resistance, which is consistent with a transient rise in food efficiency during the early stage of refeeding. In addition, ectopic lipid deposition, visceral fat accumulation, and insulin resistance were more severe in rats refed the high-fat diet than rats refed the normal chow. These findings suggest that CUGA induced by rapid nutrition promotion could result in persistent lipid overaccumulation (increased visceral fat and ectopic lipid deposition) and drastic systemic insulin resistance. The effects of CUGA on metabolic characteristics are dependent on the type of diet that is used for refeeding, especially on the amount of fat intake.

Insulin improves β-cell function in glucose-intolerant rat models induced by feeding a high-fat diet.

Insulin therapy has been shown to contribute to extended glycemia remission in newly diagnosed patients with type 2 diabetes mellitus. This study investigated the effects of insulin treatment on pancreatic lipid content, and β-cell apoptosis and proliferation in glucose-intolerant rats to explore the protective role of insulin on β-cell function. A rat glucose-intolerant model was induced by streptozotocin and a high-fat diet. Plasma and pancreatic triglycerides, free fatty acids, and insulin were measured; and pancreatic β-cell cell apoptosis and proliferation were detected by a propidium iodide cell death assay and immunofluorescence for proliferating cell nuclear antigen. Relative β-cell area was determined by immunohistochemistry for insulin, whereas insulin production in pancreas was assessed by reverse transcriptase polymerase chain reaction. Islet β-cell secreting function was assessed by the index ΔI30/ΔG30. Glucose-intolerant rats had higher pancreatic lipid content, more islet β-cell apoptosis, lower β-cell proliferation, and reduced β-cell area in pancreas when compared with controls. Insulin therapy reduced blood glucose, inhibited pancreatic lipid accumulation and islet β-cell apoptosis, and increased β-cell proliferation and β-cell area in glucose-intolerant rats. Furthermore, impaired insulin secretion and insulin production in glucose-intolerant rats were improved by insulin therapy. Insulin can preserve β-cell function by protecting islets from glucotoxicity and lipotoxicity. It can also ameliorate β-cell area by enhancing β-cell proliferation and reducing β-cell apoptosis.

Increases in energy intake, insulin resistance and stress in rats before Wenchuan earthquake far from the epicenter.

The study of pre-earthquake (PE) behavior in animals has always been shrouded by controversy. There is very little scientific evidence showing that animals can sense the coming of an earthquake and that their organisms undergo physiological changes during the PE period. On the day of the Wenchuan earthquake, prior to the time of its actual occurrence, we were coincidentally able to measure the insulin sensitivity and stress level in rats that were originally part of another study. We detected defects in insulin signaling and a decrease in glucose uptake in skeletal muscle (SkM) and adipose tissue (AT), indicating impaired insulin sensitivity. These changes were associated with significantly increased plasma corticosterone concentration and elevated HSD11B1 mRNA expression in SkM and AT. The increase in insulin resistance (IR) could be attributed to elevated local (SkM and AT) and systemic stress. Interestingly, we also noticed that the food intake in rats showed a sudden increase two days before the earthquake and reached a peak on the day of the earthquake itself. Our observations suggest the possibility that the rats underwent PE physiological changes consisting of an increase in the stress level and consequently leading to an increase in food intake and IR.

Depletion of Kupffer cells attenuates systemic insulin resistance, inflammation and improves liver autophagy in high-fat diet fed mice

The objective of this study was to reveal the exact role of Kupffer cells in the diet-induced insulin resistance, inflammation and liver autophagy. C57BL/6j male mice were fed with either chow diet or high-fat diet (HFD) for 12 weeks. Meanwhile, HFD feeding mice received an intraperitoneal injection of either 0.2% GdCl3 solution (20mg/kg) twice a week to deplete Kupffer cells or natural saline (5mL/kg) as control. The mRNA expressions of Kupffer cells markers (CD68 and F4/80), insulin sensitivity, TNF-α concentration and NF-κB activation and parameters of autophagy were assessed. Results demonstrated that CD68 and F4/80 mRNA expressions in the liver were up-regulated in HFD fed animals, while significantly reduced after GdCl3 administration. HFD feeding led to insulin resistance and TNF-α level and activation of NF-κB in insulin-sensitive tissues (liver, adipose tissue and skeletal muscle) were significantly elevated. Interestingly, alterations above were reversed by varying degrees but significantly after Kupffer cells depletion. Furthermore, western blot showed hepatic LC3-II as well as phosphorylation of AMPK in liver and skeletal muscle were significantly lower in mice fed HFD, and these changes dramatically ameliorated by GdCl3 treating. In conclusion, selective depletion of Kupffer cells significantly attenuated diet-induced insulin resistance, inflammation and promoted liver autophagy. Strategies targeting Kupffer cells function or autophagic processes could be a promising approach to counteract diet induced obesity and related metabolic disorders.

Resveratrol supplementation restores high-fat diet-induced insulin secretion dysfunction by increasing mitochondrial function in islet.

Resveratrol (RSV), a natural compound, is known for its effects on energy homeostasis. Here we investigated the effects of RSV and possible mechanism in insulin secretion of high-fat diet rats. Rats were randomly divided into three groups as follows: NC group (animals were fed ad libitum with normal chow for 8 weeks), HF group (animals were fed ad libitum with high-fat diet for 8 weeks), and HFR group (animals were treated with high-fat diet and administered with RSV for 8 weeks). Insulin secretion ability of rats was assessed by hyperglycemic clamp. Mitochondrial biogenesis genes, mitochondrial respiratory chain activities, reactive oxidative species (ROS), and several mitochondrial antioxidant enzyme activities were evaluated in islet. We found that HF group rats clearly showed low insulin secretion and mitochondrial complex dysfunction. Expression of silent mating type information regulation 2 homolog- 1 (SIRT1) and related mitochondrial biogenesis were significantly decreased. However, RSV administration group (HFR) showed a marked potentiation of glucose-stimulated insulin secretion. This effect was associated with elevated SIRT1 protein expression and antioxidant enzyme activities, resulting in increased mitochondrial respiratory chain activities and decreased ROS level. This study suggests that RSV may increase islet mitochondrial complex activities and antioxidant function to restore insulin secretion dysfunction induced by high-fat diet.

Blocking Nuclear Factor-Kappa B Protects against Diet-Induced Hepatic Steatosis and Insulin Resistance in Mice

Inflammation critically contributes to the development of various metabolic diseases. However, the effects of inhibiting inflammatory signaling on hepatic steatosis and insulin resistance, as well as the underlying mechanisms remain obscure. In the current study, male C57BL/6J mice were fed a chow diet or high-fat diet (HFD) for 8 weeks. HFD-fed mice were respectively treated with p65 siRNA, non-silence control siRNA or vehicle every 4th day for the last 4 weeks. Vehicle-treated (HF) and non-silence siRNA-treated (HFNS) mice displayed overt inflammation, hepatic steatosis and insulin resistance compared with chow-diet-fed (NC) mice. Upon treatment with NF-κB p65 siRNA, HFD-fed (HFPS) mice were protected from hepatic steatosis and insulin resistance. Furthermore, Atg7 and Beclin1 expressions and p-AMPK were increased while p-mTOR was decreased in livers of HFPS mice in relative to HF and HFNS mice. These results suggest a crosslink between NF-κB signaling pathway and liver AMPK/mTOR/autophagy axis in the context of hepatic steatosis and insulin resistance.

Impact of Treatment with Metformin on Adipocytokines in Patients with Polycystic Ovary Syndrome: A Meta-Analysis

Background Metformin is effective for the treatment of polycystic ovary syndrome, but conflicting results regarding its effect on adipocytokine levels (adiponectin, resistin, visfatin, and leptin) in patients with polycystic ovary syndrome receiving metformin treatment have been reported. To provide high-quality evidence about the effect of metformin treatment on adipocytokines in patients with polycystic ovary syndrome, relevant studies that assessed the levels of adipocytokines (adiponectin, resistin, visfatin, and leptin) in patients with polycystic ovary syndrome receiving treatment with metformin administration were reviewed and analyzed. Methods A literature search was conducted in the SCI, PUBMED, EMBASE, and Elsevier databases, and personal contact was made with the authors. Standard mean differences and 95% confidence intervals were calculated and combined appropriately. To ensure synthesis of the best available evidence, sensitivity analyses were performed. Results A total of 34 data sets were included in 4 different outcomes, involving 744 women with polycystic ovary syndrome and adipocytokine levels measured both before and after metformin administration. Metformin treatment was associated with significantly elevated serum adiponectin concentrations (standard mean differences [95% confidence interval], −0.43 [−0.75 to −0.11]) and decreased serum leptin concentrations (0.65 [0.26 to 1.04]), whereas no significant difference in resistin level (−0.01 [−0.49 to 0.45]) or visfatin level (−0.04 [−1.55 to 1.46]) was found. Conclusions Metformin administration was associated with increased serum adiponectin concentrations and decreased serum leptin levels. Further study is needed to elucidate whether this apparent effect decreases the incidence of type 2 diabetes and other metabolic diseases in patients with polycystic ovary syndrome later in life.

Increases in systemic and local stress: a probable mechanism of visceral fat accumulation and insulin resistance in adult catch-up growth rats?

Catch-up growth in adult (CUGA) is increasingly proposed as an important causative factor for the widespread insulin resistance (IR)-related diseases especially in developing countries/territories. We aimed to investigate the effects of CUGA to insulin sensitivity, lipid profile and stress in rats, as well as the probable relationship among them. Male Sprague-Dawley rats were randomly divided into six groups for two sampling points: caloric restriction group (R4) and normal chow controls for four weeks (NC4); CUGA re-fed with normal chow (RN4), CUGA re-fed with high-fat diet (RH4), normal chow controls (NC8) and high-fat diet controls (HF8) for eight weeks. Visceral fat accumulation (visceral adipose tissue [VAT] percentage), systemic (plasma corticosterone) and local (HSD11B1 mRNA expression in skeletal muscle [SkM] and VAT) stress, whole-body and peripheral insulin sensitivity were determined in this study. After four weeks of caloric restriction, R4 rats showed increases in systemic and local stress, decreases in visceral fat accumulation and no IR (whole-body or peripheral). Yet, after re-feeding, sustained systemic and local stress, remarkable visceral fat accumulation and IR (whole-body and peripheral) were found in RN4 compared with NC8, in RH4 compared with NC8 and HF8. Our findings demonstrated that CUGA rats were characterized by significant IR, visceral fat accumulation and stress. These changes were more severe in CUGA re-fed with high-fat diet. The interaction of sustained caloric restriction-induced stress and re-feeding might be of utmost importance in the etiology of visceral fat accumulation and IR in CUGA.