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

• Published in: Endocrinology (Philadelphia) Vol. 150; no. 4; pp. 1697 - 1704
• Main Authors: Gerin, Isabelle, Louis, Gwendolyn W, Zhang, Xuan, Prestwich, Tyler C, Kumar, T. Rajendra, Myers, Martin G, MacDougald, Ormond A, Nothnick, Warren B
• Format: Journal Article
• Language: English
• Published: Chevy Chase, MD Endocrine Society 01-04-2009; Oxford University Press; The Endocrine Society
• Subjects: Absorptiometry, Photon; Adipocytes; Adipocytes - cytology; Adipocytes - metabolism; Adipose tissue; Aging - physiology; Animals; Biological and medical sciences; Body fat; Body size; Body weight; Body Weight - drug effects; Body weight gain; Eating - drug effects; Eating - genetics; Energy balance; Energy Metabolism - drug effects; Energy Metabolism - genetics; Female; Females; Food intake; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression - drug effects; Gene regulation; Glucose Tolerance Test; Hyperphagia; Hyperphagia - genetics; Hypothalamus; Leptin; Leptin - blood; Leptin - pharmacology; Lipids; Male; Matrix metalloproteinase; Matrix metalloproteinases; Medical sciences; Metabolic diseases; Metalloproteinase; Mice; Mice, Mutant Strains; Obesity; Obesity - genetics; Polymerase Chain Reaction; Tissue inhibitor of metalloproteinase 1; Tissue Inhibitor of Metalloproteinase-1 - deficiency; Tissue Inhibitor of Metalloproteinase-1 - genetics; Tissue Inhibitor of Metalloproteinase-1 - physiology; Vertebrates: endocrinology; Obesity; Feeding behavior; Enzyme; Rodentia; Nutrition disorder; Metalloendopeptidases; Peptidases; Vertebrata; Mammalia; Mouse; Animal; Hydrolases; Female; Nutritional status; Hyperphagia
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2008-1409

Certain matrix metalloproteinases and their regulators, the tissue inhibitors of metalloproteinases (TIMPs), are involved in development and remodeling of adipose tissue. In studying Timp1 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.
Timp1-dependent regulation of hypothalamic physiology represents an important determinant of energy balance that directly influences adiposity.