Role of resistin in the central nervous system regulation of glucose and energy homeostasis

Resistin is an adipocyte hormone in rodents that is released into circulation in proportion to fat stores. Resistin induces insulin resistance, although the target tissues mediating this effect remain to be determined. The central nervous system (CNS) is a critical mediator of the actions of peripheral humoral signals on the regulation of glucose and energy balance, including leptin and adiponectin. Resistin is present in the cerebrospinal fluid of rodents and humans, however, its role in regulating neural circuits involved in the regulation of peripheral insulin sensitivity and body weight is unknown. The goal of the present work was to further characterize the role of resistin on glucose and energy homeostasis as well as define the neural mediators functionally linked to its actions. The genetic absence of resistin improves insulin sensitivity in diet-induced and leptin deficient models of obesity, in spite of an exacerbation of obesity in retn-/- -Lep ob/ob mice. It was found that resistin deficiency is associated with altered regulation of hypothalamic neuropeptides. Intracerebroventricular (i.c.v.) resistin increased endogenous glucose production during hyperinsulinemic clamp, consistent with induction of hepatic insulin resistance. Resistin administered i.c.v. was associated with neuronal activation and enhanced expression of neuropeptide Y (NPY) in the arcuate nucleus and dorsomedial nucleus of the hypothalamus. The effects of i.c.v. resistin on hepatic insulin resistance were abrogated in mice lacking NPY as well as in mice treated with NPY Y1-receptor antagonists. Furthermore, in Lepob/ob, i.c.v. resistin enhanced thermogenesis and suppressed food intake. The thermogenic actions of resistin were prevented by pharmacological blockade of melanocortin signaling. Taken together, these data provide support for the role of resistin in regulating hepatic insulin sensitivity and energy expenditure by targeting the hypothalamus.