Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats

Abstract

Aim/hypothesis. By acting in the brain, insulin suppresses food intake. However, little is known with regard to insulin signalling in the hypothalamus in insulin-resistant states. Methods. Western blotting, immunohistochemistry and polymerase chain reaction assays were combined to compare in vivo hypothalamic insulin signalling through the PI3-kinase and MAP kinase pathways between lean and obese Zucker rats. Results. Intracerebroventricular insulin infusion reduced food intake in lean rats to a greater extent than that observed in obese rats, and pre-treatment with PI3-kinase inhibitors prevented insulin-induced anorexia. The relative abundance of IRS-2 was considerably higher than that of IRS-1 in hypothalamus of both lean and obese rats. Insulin-stimulated phosphorylation of IR, IRS-1/2, the associations of PI 3-kinase to IRS-1/2 and phosphorylation of Akt in hypothalamus were decreased in obese rats compared to lean rats. These effects seem to be mediated by increased phosphoserine content of IR, IRS-1/2 and decreased protein levels of IRS-1/2 in obese rats. In contrast, insulin stimulated the phosphorylation of MAP kinase equally in lean and obese rats. Conclusion/interpretation. This study provides direct measurements of insulin signalling in hypothalamus, and documents selective resistance to insulin signalling in hypothalamus of Zucker rats. These findings provide support for the hypothesis that insulin could have anti-obesity actions mediated by the PI3-kinase pathway, and that impaired insulin signalling in hypothalamus could play a role in the development of obesity in this animal model of insulin-resistance. [Diabetologia (2003[Diabetologia ( ) 46:1629[Diabetologia ( -1640 Keywords Obesity, insulin resistance, hypothalamus, anorexia, signal transduction, phosphatidylinositol 3-kinase/antagonists & inhibitors/*metabolism, mitogen-activated protein kinase. Abbreviations: ERK, extracellular signal-regulated kinase; Grb2, growth factor receptor binding protein 2; IR, insulin receptor; IRS, insulin receptor substrate; MAPK, mitogen-activated protein kinase; PI 3-kinase, phosphatidylinositol 3-kinase; PKC, Protein kinase C; Shc, Src-homology and collagen homology; SHP2, Src-homology phosphatase 2; TNF-α, Tumor-necrosis factor-α.

Circulating ghrelin concentrations are lowered by intracerebroventricular insulin

“…We have demonstrated that insulin acts mainly in the arcuate nucleus to reduce food intake [3]. Together, these data and the results presented here suggest that the reduction in circulating ghrelin, observed after i.c.v.…”

“…Recently it has been reported that different insulin responses are mediated by the effects of insulin on the central nervous system (CNS), including the control of food intake, thermogenesis and, at least in part, hepatic glucose output [3,4]. Thus, we hypothesised that the ability of insulin to suppress ghrelin may be mediated centrally.…”

“…Insulin receptors (IR) are expressed in most tissues of the body, including liver, muscle, fat and neurons of the CNS [3,5]. The IR is a protein tyrosine kinase, which, when activated by insulin binding, phosphorylates intracellular protein substrates, including IRS and Src homology collagen [4].…”

Leptinomimetic effects of the AMP kinase activator AICAR in leptin-resistant rats: prevention of diabetes and ectopic lipid deposition

“…Thus, it has been reported that corticosterone levels are elevated and that adrenalectomy diminishes both the hyperglycaemia and hyperinsulinemia in the fa/fa rat [54]. Likewise hypothalamic signalling in response to insulin [55] is impaired in this rodent. Whether effects on the adrenal or hypothalamus contributed to the AICAR (AMPK)-induced changes observed in the ZDF rat study remains to be determined.…”

PTEN targeting: the search for novel insulin sensitisers provides new insight into obesity research

“…These PIP 3 -dependent events induce important metabolic responses, including glucose transport, lipid and glycogen synthesis, modulation of gene expression, cell proliferation and inhibition of apoptosis. The PI3K pathway mediates the effects of insulin [9] and leptin [10] on satiety. As these mechanisms are relevant to cell metabolism, it was postulated that PIP 3 breakdown may also affect the physiology of insulin action, leading to greater focus on the function of PTEN in insulin signalling.…”