Comparison of the enteroinsular axis in two strains of obese rat, the fatty Zucker and the JCR:LA-corpulent

The 'fatty' Zucker and more recently the JCR:LA-cp 'corpulent' have been studied extensively as genetic models of the hyperinsulinemia, insulin resistance and abnormal fat metabolism of obesity. It has been hypothesized that an abnormal enteroinsular axis leading to hypersecretion of the insulin releasing hormone gastric inhibitory polypeptide (GIP) could contribute to the hyperinsulinemia of obesity, although this has been controversial. The present study was undertaken to compare the enteroinsular axis in fatty Zucker and JCR:LA-cp rats. The in vivo GIP and insulin responses to an oral glucose challenge, as well as glucose tolerance, were compared in lean and obese phenotypes of both strains as well as the sensitivity of the perfused pancreas to the secretagogues glucose, arginine and GIP. In addition, the effect of perfusate glucose concentration on the beta cell response to GIP was assessed in both strains. Tissue samples from the pancreas were taken for immunocytochemical analysis of comparative size and composition of pancreatic islets. Our results indicate that corpulent rats are hyperGIPemic when compared to fatty Zuckers and that hyperinsulinemia (both in vivo and in vitro) is more severe in the JCR:LA-cp than in the fatty Zucker, as is the degree of insulin resistance (as evidenced by glucose intolerance). Islets of corpulent rats were found to be larger than those of fa/fa rats as well as having a larger area occupied by beta cells. It was concluded that GIP may contribute to fasting hyperinsulinemia in the Zucker rat (as a result of a defective glucose threshold for the insulinotropic action of GIP), whereas the hyperGIPemia of the JCR:LA-cp rat may contribute to the massive nutrient-stimulated hyperinsulinemia observed in the male phenotype of this strain.     

Leptin decreases lipogenic enzyme gene expression through modification of SREBP-1c gene expression in white adipose tissue of aging rats

Aging is associated with a significant reduction of lipogenic enzyme gene expression and lipogenesis in white adipose tissue (WAT). The age-related increase of lep gene expression could be, in part, responsible for these changes. Considering that sterol regulatory element binding protein 1c (SREBP-1c) plays an important role in regulation of lipogenic enzyme gene expression, it is likely that the age-related decrease of WAT lipogenic potential could be a consequence of the inhibition of SREBP-1c gene expression by leptin. We determined whether the increase of lep gene expression would account for the age-related decrease in SREBP-1c and its direct target, main lipogenic enzymes acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), by assaying the messenger RNA (mRNA) levels of SREBP-1c, FAS, ACC, and leptin in WAT of 2-month-old (young) and 20-month-old (old) rats. Leptin mRNA level was much higher in the old animals, whereas in contrast, old rats displayed much lower mRNA levels of SREBP-1c and lipogenic enzymes. Moreover, experimentally increased plasma leptin concentration in young rats to the value observed in old rats resulted in the decrease of SREBP-1c, FAS, and ACC mRNA levels in WAT. Thus, the increase of lep gene expression could, in part, account for the reduced SREBP-1c gene expression and, consequently, the diminished lipogenic activity in WAT of old animals.     

固醇调节元件结合蛋白-1c与肝脂肪变性

固醇调节元件结合蛋白-1c是一种核转录因子,可参与脂质生成相关基因表达的调控,增加肝脏脂质合成,与肝脂肪变性关系密切,并参与各种原因引起的脂肪肝的发生.一些药物可以通过抑制固醇调节元件结合蛋白-1c的表达而预防或改善肝脂肪变性,为脂肪肝的治疗提供了新的方向.     

The retardation of vasculopathy induced by attenuation of insulin resistance in the corpulent JCR:LA-cp rat is reflected by decreased vascular smooth muscle cell proliferation in vivo

Proliferation in vivo of vascular smooth muscle cells occurs early in the course of atherosclerosis. Cultured smooth muscle cells (SMCs) explanted from aortas of JCR:LA-cp corpulent rats known to exhibit metabolic derangements and insulin resistance typical of type II diabetes early in life and to develop atherosclerosis later in life exhibit increased proliferation compared with SMCs from lean, normal rats. Vascular smooth muscle proliferation in vitro was found to be positively and significantly correlated with plasma insulin levels in vivo. Proliferation of aortic SMCs from JCR:LA-cp cp/cp corpulent rats cultured in vitro exhibited increased proliferation in the presence of exogenous insulin. Exercise and diet, selected as interventions designed to ameliorate the insulin resistance and hyperinsulinemia in the JCR:LA-cp cp/cp rat, effectively lowered blood insulin levels and decreased subsequent proliferation in vitro of aortic SMCs explanted from these animals. The results indicate that assessment of proliferation of vascular smooth muscle cells ex vivo may provide insight into the presence and severity of atherogenicity in association with insulin resistance in diverse species under diverse circumstances. Accordingly, with appropriate controls, it may be possible to use SMC proliferation ex vivo as a marker of the extent to which an intervention such as administration of insulin sensitizers to experimental animals and human subjects results in a change in behavior of vessel wall elements potentially indicative of amelioration of atherogenicity and detectable as judged from reduced proliferative rates of the cells ex vivo when they have been harvested from vessels exposed to a milieu in which insulin resistance has been attenuated.     

Polyunsaturated fatty acids ameliorate hepatic steatosis in obese mice by SREBP-1 suppression

Leptin-deficient ob/ob mice show many characteristics of obesity, including excess peripheral adiposity as well as severe hepatic steatosis, at least in part, due to increased hepatic lipogenesis. Polyunsaturated fatty acids (PUFAs) are not only ligands for peroxisome proliferator-activated receptor (PPAR) alpha but are also negative regulators of hepatic lipogenesis, which is thought to be mediated by the repression of sterol regulatory element-binding protein (SREBP)-1. We have previously shown that the disruption of SREBP-1 in ob/ob mice decreased their liver triglyceride storage. To examine whether PUFAs could reduce hepatic triglyceride deposition, we challenged ob/ob mice with dietary PUFA. It is demonstrated that PUFA markedly decreased the mature form of SREBP-1 protein and thereby reduced the expression of lipogenic genes such as fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1) in the livers of ob/ob mice. Consequently, the liver triglyceride content and plasma alanine aminotransferase (ALT) levels were decreased. Furthermore, both hyperglycemia and hyperinsulinemia in ob/ob mice were improved by PUFA administration, similar to the effect of PPARalpha activators. In conclusion, PUFAs ameliorate obesity-associated symptoms, such as hepatic steatosis and insulin resistance, presumably through both down-regulation of SREBP-1 and activation of PPARalpha.     

Glucose-induced lipogenesis in pancreatic beta-cells is dependent on SREBP-1

High concentrations of glucose induce de novo fatty acid synthesis in pancreatic β-cells and chronic exposure of elevated glucose and fatty acids synergize to induce accumulation of triglycerides, a phenomenon termed glucolipotoxicity.

Here we investigate the role of sterol-regulatory element binding proteins in glucose-induced lipogenesis in the pancreatic β-cell line INS-1E. We show that glucose induces SREBP-1c expression and SREBP-1 activity independent of insulin secretion and signaling. Using adenoviral expression of SREBP-1c and a SREBP-mutant we show that lipogenic gene expression, de novo fatty acid synthesis and lipid accumulation are induced primarily through sterol-regulatory elements (SREs) and not E-Boxes. Adenoviral expression of a dominant negative SREBP compromises glucose induction of some lipogenic genes and significantly reduces glucose-induction of de novo fatty acid synthesis. Thus, we demonstrate for the first time that SREBP activity is necessary for full glucose induction of de novo fatty acid synthesis in pancreatic β-cells.     

Fibrinolysis and atherogenesis in the JCR:LA-cp rat in relation to insulin and triglyceride concentrations in blood

Summary Increased concentrations of plasminogen activator inhibitor type-1 (PAI-1) in blood and attenuated fibrinolytic activity, hypertriglyceridaemia, and insulin resistance are common in subjects with obesity and non-insulin-dependent diabetes mellitus who are at markedly increased risk for coronary artery disease. To clarify potentially causal relationships between these phenomena, we studied JCR:LA-cp rats, animals that are insulin resistant and prone to vasculopathy. Blood and aortas were obtained from lean and corpulent animals at 1, 2, 4, 6, and 9 months of age. The homozygous corpulent rats were hyperinsulinaemic and hypertriglyceridaemic at all ages tested. Increased activity of PAI-1 was present in blood from corpulent animals at 1, 6, and 9 months of age. Positive correlations were observed between blood PAI-1 and both insulin and triglycerides. As judged from results with aortic rings in in vitro culture, the increased PAI-1 in blood was anteceded by increased expression of PAI-1 in arterial walls. Thus, changes indicative of inhibition of the fibrinolytic system capacity precede gross atherosclerosis. [Diabetologia (1998) 41: 141–147] Received: 8 July 1997 and in revised form: 23 September 1997