Aims/hypothesis Glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors attenuate postprandial lipaemia through mechanisms that remain unclear. As dyslipidaemia is a contributing risk factor for cardiovascular disease in type 2 diabetes, we examined the mechanisms linking pharmacological and physiological regulation of GLP-1 action to control of postprandial lipid metabolism.Methods Postprandial lipid synthesis and secretion were assessed in normal and fructose-fed hamsters and in wildtype mice that were treated with or without sitagliptin. Apolipoprotein B-48 (ApoB-48) synthesis and secretion were also examined in primary enterocyte cultures. The importance of exogenous vs endogenous GLP-1R signalling for regulation of intestinal lipoprotein synthesis and secretion was assessed in mice and hamsters treated with the GLP-1R agonist exendin-4, the GLP-1R antagonist exendin(9-39) and in Glp1r Electronic supplementary material The online version of this article

No abstract

Metabolic syndrome is associated with insulin resistance, elevated glucose and lipids, inflammation, decreased antioxidant activity, increased weight gain, and increased glycation of proteins. Cinnamon has been shown to improve all of these variables in in vitro, animal, and/or human studies. In addition, cinnamon has been shown to alleviate factors associated with Alzheimer's disease by blocking and reversing tau formation in vitro and in ischemic stroke by blocking cell swelling. In vitro studies also show that components of cinnamon control angiogenesis associated with the proliferation of cancer cells. Human studies involving control subjects and subjects with metabolic syndrome, type 2 diabetes mellitus, and polycystic ovary syndrome all show beneficial effects of whole cinnamon and/or aqueous extracts of cinnamon on glucose, insulin, insulin sensitivity, lipids, antioxidant status, blood pressure, lean body mass, and gastric emptying. However, not all studies have shown positive effects of cinnamon, and type and amount of cinnamon, as well as the type of subjects and drugs subjects are taking, are likely to affect the response to cinnamon. In summary, components of cinnamon may be important in the alleviation and prevention of the signs and symptoms of metabolic syndrome, type 2 diabetes, and cardiovascular and related diseases.

Obesity is associated with a chronic low-grade inflammation characterized by increased levels of proinflammatory cytokines that are implicated in disrupted metabolic homeostasis. Parasitic nematode infection induces a polarized Th2 cytokine response and has been explored to treat autoimmune diseases. We investigated the effects of nematode infection against obesity and the associated metabolic dysfunction. Infection of RIP2-Opa1KO mice or C57BL/6 mice fed a high-fat diet (HFD) with Nippostrongylus brasiliensis decreased weight gain and was associated with improved glucose metabolism. Infection of obese mice fed the HFD reduced body weight and adipose tissue mass, ameliorated hepatic steatosis associated with a decreased expression of key lipogenic enzymes/mediators, and improved glucose metabolism, accompanied by changes in the profile of metabolic hormones. The infection resulted in a phenotypic change in adipose tissue macrophages that was characterized by upregulation of alternative activation markers. Interleukin-13 (IL-13) activation of the STAT6 signaling pathway was required for the infection-induced attenuation of steatosis but not for improved glucose metabolism, whereas weight loss was attributed to both IL-13/STAT6-dependent and -independent mechanisms. Parasitic nematode infection has both preventive and therapeutic effects against the development of obesity and associated features of metabolic dysfunction in mice.

Chokeberries are a rich source of anthocyanins, which may contribute to the prevention of obesity and the metabolic syndrome. The aim of the present study was to determine if an extract from chokeberries would reduce weight gain in rats fed a fructose-rich diet (FRD) and to explore the potential mechanisms related to insulin signalling, adipogenesis and inflammatory-related pathways. Wistar rats were fed a FRD for 6 weeks to induce insulin resistance, with or without chokeberry extract (CBE) added to the drinking-water (100 and 200 mg/kg body weight, daily: CBE100 and CBE200). Both doses of CBE consumption lowered epididymal fat, blood glucose, TAG, cholesterol and LDL-cholesterol. CBE consumption also elevated plasma adiponectin levels and inhibited plasma TNF-a and IL6, compared with the control group. There were increases in the mRNA expression for Irs1, Irs2, Pi3k, Glut1, Glut4 and Gys1, and decreases in mRNA levels of Gsk3b. The protein and gene expression of adiponectin and Pparg mRNA levels were up-regulated and Fabp4, Fas and Lpl mRNA levels were inhibited. The levels of gene expression of inflammatory cytokines, such as Il1b, Il6 and Tnfa were lowered, and protein and gene expression of ZFP36 (zinc finger protein) were enhanced in the epididymal adipose tissue of the rats that consumed the CBE200 extract. In summary, these results suggest that the CBE decreased risk factors related to insulin resistance by modulating multiple pathways associated with insulin signalling, adipogenesis and inflammation.

There is growing evidence suggesting intestinal insulin resistance and overproduction of apolipoprotein (apo) B48 -containing chylomicrons in insulin-resistant states. In the current study, we investigated the potential role of the inflammatory cytokine tumor necrosis factor-␣ (TNF-␣) in the development of insulin resistance and aberrant lipoprotein metabolism in the small intestine in a Syrian golden hamster model. TNF-␣ infusion decreased whole-body insulin sensitivity, based on in vivo euglycemic clamp studies in chow-fed hamsters. Analysis of intestinal tissue in TNF-␣-treated hamsters indicated impaired phosphorylation of insulin receptor-␤, insulin receptor substrate-1, Akt, and Shc and increased phosphorylation of p38, extracellular signal-related kinase-1/2, and Jun NH 2 -terminal kinase. TNF-␣ infusion also increased intestinal production of total apoB48, triglyceride-rich lipoprotein apoB48, and serum triglyceride levels in both fasting and postprandial (fat load) states. The effects of TNF-␣ on plasma apoB48 levels could be blocked by the p38 inhibitor SB203580. Ex vivo experiments using freshly isolated enterocytes also showed TNF-␣-induced p38 phosphorylation and intestinal apoB48 overproduction, effects that could be blocked by SB203580. Interestingly, TNF-␣ increased the mRNA and protein mass of intestinal microsomal triglyceride transfer protein without altering apoB mRNA levels. Enterocytes were found to have detectable levels of both TNF-␣ receptor types (p55 and p75), and antibodies against either of the two TNF-␣ receptors partially blocked the stimulatory effect of TNF-␣ on apoB48 production and p38 phosphorylation. In summary, these data suggest that intestinal insulin resistance can be induced in hamsters by TNF-␣ infusion, and it is accompanied by intestinal overproduction of apoB48-containing lipoproteins. TNF-␣-induced stimulation of intestinal lipoprotein production appears to be mediated via TNF-␣ receptors and the p38 mitogen-activated protein kinase pathway. Diabetes 56: 450 -461, 2007

Epidemiological studies indicate that the consumption of green tea polyphenols (GTP) may reduce the risk of coronary artery disease. To explore the underlying mechanisms of action at the molecular level, we examined the effects of GTP on the cardiac mRNA and protein levels of genes involved in insulin and lipid metabolism and inflammation. In rats fed a high-fructose diet, supplementation with GTP (200 mg/kg BW daily dissolved in distilled water) for 6 wk, reduced systemic blood glucose, plasma insulin, retinol-binding protein 4, soluble CD36, cholesterol, triglycerides, free fatty acids and LDL-C levels, as well as the pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and IL-6. GTP did not affect food intake, bodyweight and heart weight. In the myocardium, GTP also increased the insulin receptor (Ir), insulin receptor substrate 1 and 2 (Irs1 and Irs2), phosphoinositide-3-kinase (Pi3k), v-akt murine thymoma viral oncogene homolog 1 (Akt1), glucose transporter 1 and 4 (Glut1 and Glut4) and glycogen synthase 1 (Gys1) expression but inhibited phosphatase and tensin homolog deleted on chromosome ten (Pten) expression and decreased glycogen synthase kinase 3beta (Gsk3beta) mRNA expression. The sterol regulatory element-binding protein-1c (Srebp1c) mRNA, microsomal triglyceride transfer protein (Mttp) mRNA and protein, Cd36 mRNA and cluster of differentiation 36 protein levels were decreased and peroxisome proliferator-activated receptor (Ppar)gamma mRNA levels were increased. GTP also decreased the inflammatory factors: Tnf, Il1b and Il6 mRNA levels, and enhanced the anti-inflammatory protein, zinc-finger protein, protein and mRNA expression. In summary, consumption of GTP ameliorated the detrimental effects of high-fructose diet on insulin signaling, lipid metabolism and inflammation in the cardiac muscle of rats.

Insulin-resistant states are commonly associated with both increased circulating levels of tumor necrosis factor (TNF)-α and hepatic overproduction of very low density lipoproteins (VLDL). Here, we provide evidence that increased TNF-α can directly stimulate the hepatic assembly and secretion of apolipoprotein B (apoB) 100-containing VLDL1, using the Syrian golden hamster, an animal model that closely resembles humans in hepatic VLDL-apoB100 metabolism. In vivo TNF-α infusion for 4 h in chow-fed hamsters induced whole-body insulin resistance on the basis of euglycemic hyperinsulinemic clamp studies. Immunoprecipitation and immunoblotting analysis of livers from TNF-α-treated hamsters indicated decreased tyrosine phosphorylation of insulin receptor (IR)-β, IR substrate-1 (Tyr), Akt (Ser473), p38, ERK1/2, and JNK but increased serine phosphorylation of IRS-1 (Ser307) and Shc. TNF-α infusion also significantly increased hepatic production of total circulating apoB100 and VLDL-apoB100 in both fasting and postprandial (fat load) states. Ex vivo experiments, using cultured primary hepatocytes from hamsters, also showed TNF-α-induced VLDL-apoB100 oversecretion, an effect that was blocked by TNF receptor 2 antibody. Unexpectedly, TNF-α decreased the sterol regulatory element-binding protein-1c mass and mRNA levels but significantly increased microsomal triglyceride transfer protein mass and mRNA levels in primary hepatocytes. In summary, these data provide direct evidence that TNF-α induces whole-body insulin resistance and impairs hepatic insulin signaling accompanied by overproduction of apoB100-containing VLDL particles, an effect likely mediated via TNF receptor 2.