CILIARY NEUROTROPHIC FACTOR CORRECTS OBESITY AND DIABETES-ASSOCIATED WITH LEPTIN DEFICIENCY AND RESISTANCE

Receptor subunits fur the neurocytokine ciliary neurotrophic factor (C NTF) share sequence similarity with the receptor for leptin, an adipoc yte-derived cytokine involved in body weight homeostasis, We report he re that CNTF and leptin activate a similar pattern of STAT factors in neuronal cells, and that mRNAs for CNTF receptor subunits, similarly t o the mRNA of leptin receptor, are localized in mouse hypothalamic nuc lei involved in the regulation of energy balance, Systemic administrat ion of CNTF or leptin led to rapid induction of the tis-11 primary res ponse gene in the arcuate nucleus, suggesting that both cytokines can signal to hypothalamic satiety centers. Consistent with this idea, CNT F treatment of ob/ob mice, which lack functional leptin, was found to reduce the adiposity, hyperphagia, and hyperinsulinemia associated wit h leptin deficiency. Unlike leptin, CNTF also reduced obesity-related phenotypes in db/db mice, which lack functional leptin receptor, and i n mice with diet-induced obesity, which are partially resistant to the actions of leptin. The identification of a cytokine-mediated anti-obe sity mechanism that acts independently of the leptin system may help t o develop strategies for the treatment of obesity associated with lept in resistance.