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Hyperphagia and Obesity in Female Mice Lacking Tissue Inhibitor of Metalloproteinase-1

Departments of Molecular and Integrative Physiology (I.G., G.W.L., M.G.M., O.A.M.) and Internal Medicine (G.W.L., M.G.M., O.A.M.) and Cell and Molecular Biology Program (T.C.P.), University of Michigan Medical School, Ann Arbor, Michigan 48109-0622; and Departments of Obstetrics and Gynecology (X.Z., W.B.N.) and Molecular and Integrative Physiology (T.R.K., W.B.N.), University of Kansas School of Medicine, Kansas City, Kansas 66160

Address all correspondence and requests for reprints to: Ormond A. MacDougald, Department of Molecular and Integrative Physiology, 7620 Medical Sciences II, 1301 East Catherine Drive, Ann Arbor, Michigan 48109-0622. E-mail: macdouga{at}umich.edu; or Warren B. Nothnick, Department of Obstetrics and Gynecology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160. E-mail: wnothnic{at}kumc.edu.

Certain matrix metalloproteinases and their regulators, the tissue inhibitors of metalloproteinases (TIMPs), are involved in development and remodeling of adipose tissue. In studying Timp1^<tm1Pds> mice, which have a null mutation in Timp1 (Timp1^–/–), we observed that females exhibit increased body weight by 3 months of age due to increased total body lipid and adipose tissue. Whereas Timp1^–/– mice have increased size and number of adipocytes, they also display increased food intake despite hyperleptinemia, suggesting that alterations in hypothalamic leptin action or responsiveness may underlie their weight gain. Indeed, leptin promotes the expression of Timp1 mRNA in the hypothalamus, and leptin signaling via signal transducer and activator of transcription-3 mediates the expression of hypothalamic Timp1. Furthermore, Timp1^–/– mice demonstrate increased food intake and altered expression of certain hypothalamic neuropeptide genes prior to elevated weight gain. Thus, whereas previous data suggested roles for matrix metalloproteinases and TIMPs in the regulation of adipose tissue, these data reveal that Timp1 mRNA is induced by leptin in the hypothalamus and that expression and action of Timp1 contributes to the regulation of feeding and energy balance.