Hyperphagia and obesity in female mice lacking tissue inhibitor of metalloproteinase-1.
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.
Gerin
Isabelle
I
Department of Molecular and Integrative Physiology, Ann Arbor, Michigan 48109-0622, USA.
Louis
Gwendolyn W
GW
Zhang
Xuan
X
Prestwich
Tyler C
TC
Kumar
T Rajendra
TR
Myers
Martin G
MG
Macdougald
Ormond A
OA
Nothnick
Warren B
WB
D015502:Absorptiometry, Photon; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000375:Aging / Q000502:physiology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004435:Eating / Q000187:drug effects / Q000235:genetics; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005951:Glucose Tolerance Test; D006963:Hyperphagia / Q000235:genetics*; D020738:Leptin / Q000097:blood / Q000494:pharmacology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009765:Obesity / Q000235:genetics*; D016133:Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology
D020738:Leptin; D019715:Tissue Inhibitor of Metalloproteinase-1