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Endocrinology Vol. 139, No. 11 4634-4641
Copyright © 1998 by The Endocrine Society

ARTICLES

Characterization of Expression of Hypothalamic Appetite-Regulating Peptides in Obese Hyperleptinemic Brown Adipose Tissue-Deficient (Uncoupling Protein-Promoter-Driven Diphtheria Toxin A) Mice1

Nicholas A. Tritos, Joel K. Elmquist, Jason W. Mastaitis, Jeffrey S. Flier and Eleftheria Maratos-Flier

Elliot P. Joslin Laboratory (N.A.T., J.W.M., E.M.-F.), Joslin Diabetes Center, Division of Endocrinology (J.K.E., J.S.F.) and Department of Neurology (J.K.E.), Beth Israel Deaconess Medical Center, Program in Neuroscience (J.K.E.), Harvard Medical School, Boston, Massachusetts 02215

Address all correspondence and requests for reprints to: Eleftheria Maratos-Flier, M.D., Joslin Diabetes Center, Room 620, One Joslin Place, Boston, Massachusetts 02215. E-mail: emarat{at}joslab.harvard.edu

Brown adipose tissue-deficient [uncoupling protein (UCP)-promoter-driven diphtheria toxin A (DTA)] mice develop obesity as a result of both decreased energy expenditure and hyperphagia. The hyperphagia occurs despite high serum leptin levels. Hence, this is a model of leptin-resistant obesity in which the mechanism driving hyperphagia is unknown. Leptin is a regulator of a number of hypothalamic neuropeptides involved in energy homeostasis. In ob/ob mice, leptin deficiency results in increased expression of neuropeptide Y (NPY), agouti-related protein (AGRP), and melanin-concentrating hormone (MCH), and decreased expression 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 potential sites of leptin resistance, we used in situ hybridization to evaluate the expression of messenger RNAs (mRNAs) encoding a number of peptides, including NPY, AGRP, MCH, and POMC. We confirmed that the decrease in NPY expression previously detected by Northern blots reflects a decrease in NPY expression in the arcuate nucleus. AGRP mRNA was also decreased, whereas POMC mRNA levels in the arcuate nucleus were the same as control. MCH mRNA levels in the lateral hypothalamic area were also decreased. In contrast, there was induction of NPY expression in the dorsomedial hypothalamic nucleus in the UCP-DTA animals but not in the controls. The results indicate that these neuropeptides generally respond to leptin and that the hyperphagia seen in the UCP-DTA mice is likely the result of dysregulated expression of other, as yet unexamined, hypothalamic peptides, or lies at sites distal to the hypothalamus.




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