SEVERE LEPTIN RESISTANCE IN BROWN FAT-DEFICIENT UNCOUPLING PROTEIN PROMOTER-DRIVEN DIPHTHERIA-TOXIN-A MICE DESPITE SUPPRESSION OF HYPOTHALAMIC NEUROPEPTIDE-Y AND CIRCULATING CORTICOSTERONE CONCENTRATIONS

Brown adipose tissue (EAT) has the capacity for uncoupled mitochondria l respiration and is proposed to be a key site for regulating energy e xpenditure in rodents, To better define the role of BAT in energy home ostasis, we previously created a line of transgenic mice with deficien cy of BAT (UCP promoter-driven diphtheria toxin A transgenic: mice [UC P-DTA]) mice. These mice develop obesity that initially is due to decr eased energy expenditure and later accompanied by hyperphagia despite increased levels of circulating leptin, In addition, the obesity of th ese mice is accompanied by severe insulin-resistant diabetes and hyper lipidemia. To better define the basis for leptin resistance in this mo del, we treated UCP-DTA mice with leptin (300 mu g i.p., b.i.d.) and c ompared their response with that of leptin-treated ob/ob and FVB contr ol mice (30 mu g i.p., b.i.d.). Leptin treatment of FVB and ob/ob mice decreased their body weight; and food intake and improved their gluco se homeostasis, In contrast, tenfold higher dosages of leptin had no e ffect on body weight, food intake, or circulating insulin or glucose c oncentrations of UCP-DTA mice. Hypothalamic neuropeptide Y (NPY) mRNA expression was lower in UCP-DTA mice than in littermate control FVB mi ce in the fed state, and increased progressively in response to food r estriction as leptin levels fell, In parallel to the levels of hypotha lamic NPY; corticosterone levels were initially suppressed and rose wi th food restriction, Thus food intake, body weight, and insulin and gl ucose homeostasis of UCP-DTA mice are all extraordinarily resistant to leptin, whereas hypothalamic NPY and the hypothalamopituitary adrenal (HPA) axis may remain underleptin control, Further elucidation of the mechanisms underlying leptin resistance in UCS-DTA mice may provide v aluable insights into the basis for leptin resistance in human obesity .