ABSTRACT
Perivascular adipose tissue (PVAT) is implicated in the development of vascular diseases; however, the roles of PVAT on OPN expression in diabetic vasculature remain to be determined. This study investigated the role of adipokines derived from diabetic PVAT in regulating the vascular expression of OPN and explored the mechanisms involved. Aortic sections of ob/ob and high-fat diet (HFD)-induced obese (DIO) mice showed an increased expression of OPN, which was paralleled by increased amounts of PVAT characterized by enlargement of adipocytes. In the earlier phase of HFD feeding, macrophage infiltration was mainly localized to the area of PVAT at which adipocytes were enlarged, suggesting a potential link of activated adipocytes to macrophage infiltration. PVAT sections of ob/ob and DIO mice revealed a significantly greater number of macrophages with increased expression of adipokines, including resistin and visfatin. The distribution of resistin in PVAT mostly co-localized with macrophages, while visfatin was expressed in macrophages and other cells. In in vitro studies, OPN expression in vascular smooth muscle cells (VSMCs) co-cultured with PVAT of DIO mice was significantly increased, which was attenuated by a resistin-neutralizing antibody. Likewise, resistin up-regulated expression of OPN mRNA and protein in cultured VSMCs and the pivotal role of AP-1 in resistin-induced OPN transcription was demonstrated. Resistin produced by PVAT plays a pivotal role in the up-regulated expression of OPN in the diabetic vasculature via a signalling pathway that involves activation of AP-1.
Subject(s)
Adipose Tissue/metabolism , Diabetes Mellitus, Experimental/metabolism , Gene Expression Regulation , Osteopontin/metabolism , Resistin/metabolism , Transcription Factor AP-1/metabolism , Animals , Aorta , Base Sequence , Body Weight , Cytokines/genetics , Cytokines/metabolism , Diabetes Mellitus, Experimental/genetics , Diet, High-Fat/adverse effects , Disease Models, Animal , Macrophages/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Obese , Molecular Sequence Data , Myocytes, Smooth Muscle/metabolism , Nicotinamide Phosphoribosyltransferase/genetics , Nicotinamide Phosphoribosyltransferase/metabolism , Obesity , Osteopontin/genetics , Rats , Resistin/genetics , Signal Transduction , Transcription Factor AP-1/genetics , Up-RegulationABSTRACT
Chronic ethanol consumption is well established as a major risk factor for type-2 diabetes (T2D), which is evidenced by impaired glucose metabolism and insulin resistance. However, the relationships between alcohol consumption and the development of T2D remain controversial. In particular, the direct effects of ethanol consumption on proliferation of pancreatic ß-cell and the exact mechanisms associated with ethanol-mediated ß-cell dysfunction and apoptosis remain elusive. Although alcoholism and alcohol consumption are prevalent and represent crucial public health problems worldwide, many people believe that low-to-moderate ethanol consumption may protect against T2D and cardiovascular diseases. However, the J- or U-shaped curves obtained from cross-sectional and large prospective studies have not fully explained the relationship between alcohol consumption and T2D. This review provides evidence for the harmful effects of chronic ethanol consumption on the progressive development of T2D, particularly with respect to pancreatic ß-cell mass and function in association with insulin synthesis and secretion. This review also discusses a conceptual framework for how ethanol-produced peroxynitrite contributes to pancreatic ß-cell dysfunction and metabolic syndrome.