A role of peroxisome proliferator‐activated receptor γ in non‐alcoholic fatty liver disease

Non‐alcoholic fatty liver disease is becoming a major health burden, as prevalence increases and there are no approved treatment options. Thiazolidinediones target the nuclear receptor peroxisome proliferator‐activated receptor γ (PPARγ) and have been investigated in several clinical trials for their potential in treating non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH). PPARγ has specialized roles in distinct tissues and cell types, and although the primary function of PPARγ is in adipose tissue, where the highest expression levels are observed, hepatic expression levels of PPARγ are significantly increased in patients with NAFLD. Thus, NAFLD patients receiving treatment with PPARγ agonists might have a liver response apart from the one in adipose tissue. Owing to the different roles of PPARγ, new treatment strategies include development of compounds harnessing the beneficial effects of PPARγ while restricting PPARγ unwanted effects such as adipogenesis resulting in weight gain. Furthermore, dual or pan agonists targeting two or more of the PPARs have shown promising results in pre‐clinical research and some are currently proceeding to clinical trials. This MiniReview explores adipose‐ and liver‐specific actions of PPARγ, and how this knowledge may contribute in the search for new treatment modalities in NAFLD/NASH.     

Role of AMPK in pancreatic beta cell function

Pharmacological activation of AMP activated kinase (AMPK) by metformin has proven to be a beneficial therapeutic approach for the treatment of type II diabetes. Despite improved glucose regulation achieved by administration of small molecule activators of AMPK, the potential negative impact of enhanced AMPK activity on insulin secretion by the pancreatic beta cell is an important consideration. In this review, we discuss our current understanding of the role of AMPK in central functions of the pancreatic beta cell, including glucose-stimulated insulin secretion (GSIS), proliferation, and survival. In addition we discuss the controversy surrounding the role of AMPK in insulin secretion, underscoring the merits and caveats of methods used to date.     

Anti-diabetic action of Punica granatum flower extract: activation of PPAR-gamma and identification of an active component

Peroxisome proliferator-activated receptor (PPAR)-gamma activators are widely used in the treatment of type 2 diabetes because they improve the sensitivity of insulin receptors. Punica granatum flower (PGF) has been used as an anti-diabetic medicine in Unani medicinal literature. The mechanism of actions is, however, unknown. In the current study, we demonstrated that 6-week oral administration of methanol extract from PGF (500 mg/kg, daily) inhibited glucose loading-induced increase of plasma glucose levels in Zucker diabetic fatty rats (ZDF), a genetic animal model for type 2 diabetes, whereas it did not inhibit the increase in Zucker lean rats (ZL). The treatment did not lower the plasma glucose levels in fasted ZDF and ZL rats. Furthermore, RT-PCR results demonstrated that the PGF extract treatment in ZDF rats enhanced cardiac PPAR-gamma mRNA expression and restored the down-regulated cardiac glucose transporter (GLUT)-4 (the insulin-dependent isoform of GLUTs) mRNA. These results suggest that the anti-diabetic activity of PGF extract may result from improved sensitivity of the insulin receptor. From the in vitro studies, we demonstrated that the PGF extract enhanced PPAR-gamma mRNA and protein expression and increased PPAR-gamma-dependent mRNA expression and activity of lipoprotein lipase in human THP-1-differentiated macrophage cells. Phytochemical investigation demonstrated that gallic acid in PGF extract is mostly responsible for this activity. Thus, our findings indicate that PPAR-gamma is a molecular target for PGF extract and its prominent component gallic acid, and provide a better understanding of the potential mechanism of the anti-diabetic action of PGF.     

(−)-Catechin promotes adipocyte differentiation in human bone marrow mesenchymal stem cells through PPARγ transactivation

Green tea intake has been shown to confer various health benefits to patients suffering from metabolic disorders. Here, we studied the effect of several major green tea polyphenols on adipocyte differentiation in human bone marrow mesenchymal stem cells (hBM-MSCs) and compared it to the effect of representative antidiabetic drugs. (−)-Catechin was the most potent of the eight green tea polyphenols evaluated in promoting adipocyte differentiation in hBM-MSCs, and this effect was dose-dependent. (−)-Catechin increased the mRNA levels of various adipogenic markers, such as adiponectin, peroxisome proliferator-activated receptor gamma (PPARγ), FABP4, and LPL, as measured during adipocyte differentiation in hBM-MSCs. In addition, (−)-catechin upregulated the secretion of adiponectin in hBM-MSC culture. Using a reporter gene assay and a competitive ligand binding study, (−)-catechin also significantly activated PPARγ in a dose-dependent fashion; however, (+)-catechin, the enantiomer of (−)-catechin, was not effective as a PPARγ agonist, which seems to imply that the effect of (−)-catechin on PPARγ is stereospecific. In conclusion, our data suggest that (−)-catechin promotes adipocyte differentiation and increased sensitivity to insulin in part by direct activation of PPARγ, which could be at the basis of the observed pharmacological benefits of green tea intake in reducing the risk of type 2 diabetes.     

针刺减少噻唑烷二酮类降糖药所致体质量增加的中枢摄食相关机制探讨

噻唑烷二酮类降糖药(TZDs)导致2型糖尿病患者体质量增加甚至肥胖的不良反应限制了其临床应用和推广。针刺已经成为一种较为有效的治疗肥胖的手段,本文从中枢神经系统摄食相关靶基点出发,认为针刺可能通过改变血脑屏障的通透性从而影响TZDs的入脑量或影响下丘脑摄食相关的过氧化物酶体增殖物激活受体γ、瘦素及神经肽Y的活性及表达,抑制摄食,进而减少TZDs所致体质量增加。     

AMPK regulation of fatty acid metabolism and mitochondrial biogenesis: Implications for obesity

Skeletal muscle plays an important role in regulating whole-body energy expenditure given it is a major site for glucose and lipid oxidation. Obesity and type 2 diabetes are causally linked through their association with skeletal muscle insulin resistance, while conversely exercise is known to improve whole body glucose homeostasis simultaneously with muscle insulin sensitivity. Exercise activates skeletal muscle AMP-activated protein kinase (AMPK). AMPK plays a role in regulating exercise capacity, skeletal muscle mitochondrial content and contraction-stimulated glucose uptake. Skeletal muscle AMPK is also thought to be important for regulating fatty acid metabolism; however, direct genetic evidence in this area is currently lacking. This review will discuss the current paradigms regarding the influence of AMPK in regulating skeletal muscle fatty acid metabolism and mitochondrial biogenesis at rest and during exercise, and highlight the potential implications in the development of insulin resistance.     

Comparison of the antidiabetic effects of brain-derived neurotrophic factor and thiazolidinediones in obese diabetic mice

AIMS: Brain-derived neurotrophic factor (BDNF) ameliorates glucose metabolism in obese diabetic db/db mice. The antidiabetic effect of BDNF is dependent on plasma insulin levels, and BDNF enhances insulin action by modulating insulin signalling in peripheral tissues. The aim of the study was to compare the antidiabetic effects of BDNF with those of thiazolidinediones (TZDs), which are insulin-sensitizing agents, through evaluation of the effects of BDNF and TZDs on glucose metabolism, energy expenditure, pancreatic function and hepatic steatosis in db/db mice. METHODS: The effects of BDNF, pioglitazone and rosiglitazone on blood glucose concentration, body weight and pancreatic insulin and glucagon contents and the effects of BDNF and troglitazone treatment for 3 weeks on blood glucose concentration, body and liver weights and histological liver images were examined in db/db mice. Furthermore, since BDNF reduces food intake in obese hyperphagic diabetic mice, the effects of BDNF treatment for 3 weeks on blood glucose concentration, body weight, fat pad and liver weights and rectal temparature in db/db mice were compared with those of troglitazone under pair-fed conditions. RESULTS: BDNF, pioglitazone and rosiglitazone all ameliorated hyperglycaemia in db/db mice, but BDNF increased the pancreatic insulin content more effectively than pioglitazone and rosiglitazone. The pancreatic glucagon content decreased with BDNF, but increased with pioglitazone and rosiglitazone compared with vehicle, and body weight and liver weight increased with troglitazone, but decreased with BDNF compared with vehicle. Histological analysis of the liver showed that BDNF treatment reduced the massive vacuolization observed with vehicle, whereas troglitazone worsened the vacuolization. Body weight, fat pad and liver weights in BDNF-treated mice were significantly lower than those in pair-fed troglitazone-treated db/db mice, and rectal temperature in BDNF-treated mice was significantly higher than that in pair-fed troglitazone-treated mice, suggesting that BDNF enhances energy expenditure. CONCLUSIONS: These data suggest that compared with TZDs, BDNF potently ameliorates pancreatic dysfunction, fatty liver and energy expenditure, thereby exerting favourable antidiabetic effects in type 2 diabetic mice.