CHARACTERIZATION OF EXPRESSION OF HYPOTHALAMIC APPETITE-REGULATING PEPTIDES IN OBESE HYPERLEPTINEMIC BROWN ADIPOSE TISSUE-DEFICIENT (UNCOUPLING PROTEIN-PROMOTER-DRIVEN DIPHTHERIA-TOXIN-A) MICE

Brown adipose tissue-deficient [uncoupling protein (UCP)-promoter-driv en diphtheria toxin A (DTA)I mice develop obesity as a result of both decreased energy expenditure and hyperphagia. The hyperphagia occurs d espite high serum leptin levels. Hence, this is a model of leptin-resi stant obesity in which the mechanism driving hyperphagia is unknown. L eptin is a regulator of a number of hypothalamic neuropeptides involve d in energy homeostasis. In ob/ob mice, leptin deficiency results in i ncreased expression of neuropeptide Y (NPY), agouti-related protein (A GRP), and melanin-concentrating hormone (MCH), and decreased expressio n of POMC. We have previously shown that NPY is reduced in the UCP-DTA mouse, suggesting a normal NPY response to leptin. To define other po tential sites of leptin resistance, we used in situ hybridization to e valuate the expression of messenger RNAs (mRNAs) encoding a number of peptides, including NPY, AGRP, MCH, and POMC. We confirmed that, the d ecrease in NPY expression previously detected by Northern blots reflec ts a decrease in NPY expression in the arcuate nucleus. AGRP mRNA was also decreased, whereas POMC mRNA levels in the arcuate nucleus were t he same as control. MCH mRNA levels in the lateral hypothalamic area w ere also decreased. In contrast, there was induction of NPY expression in the dorsomedial hypothalamic nucleus in the UCP-DTA animals but no t in the controls. The results indicate that these neuropeptides gener ally respond to leptin and that the hyperphagia seen in the UCP-DTA mi ce is likely the result of dysregulated expression of other, as yet un examined, hypothalamic peptides, or lies at sites distal to the hypoth alamus.