title: Hyperphagia and leptin resistance in tissue inhibitor of metalloproteinase-2 deficient mice.
abstract: Obesity is a complex genetic and behavioural disorder arising from the improper integration of peripheral signals at central autonomic centres. For the hypothalamus to respond to dynamic physiological alterations, it must retain a degree of plasticity throughout life. Evidence is mounting that an intricate balance between matrix metalloproteinase (MMP)-mediated extracellular matrix proteolysis and tissue inhibitor of metalloproteinase (TIMP)-mediated proteolysis inhibition contributes to tissue remodelling. However, few studies have examined the role of MMPs/TIMPs in hypothalamic remodelling and energy homeostasis. To determine the contribution of TIMP-2 to the hypothalamic regulation of feeding, body mass and food consumption were monitored in TIMP-2 knockout (KO) mice fed a standard chow or high-fat diet (HFD). TIMP-2 KO mice of both sexes gained more weight than wild-type (WT) mice, even when fed the chow diet. Before the onset of obesity, TIMP-2 KO mice were hyperphagic, without increased orexigenic or decreased anorexigenic neuropeptide expression, but leptin resistant (i.e. reduced leptin-induced anorexigenic response and signal transducer and activator of transcription 3 activation). HFD exacerbated weight gain and hyperleptinaemia. In addition, proteolysis was increased in the arcuate nucleus of TIMP-2 KO mice. These data suggest a role for TIMP-2 in hypothalamic control of feeding and energy homeostasis.
authors.affiliation: Department of Anatomy and Neurobiology, University of Vermont College of Medicine, Burlington, VT 05405, USA.
authors.forename: H M
authors.initials: HM
authors.lastname: Stradecki
authors.forename: D M
authors.initials: DM
authors.lastname: Jaworski
mesh_terms: D000818:Animals; D001069:Appetite Regulation / Q000235:genetics; D004032:Diet / Q000009:adverse effects; D004351:Drug Resistance / Q000235:genetics*; D004435:Eating / Q000235:genetics / Q000502:physiology; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006963:Hyperphagia / Q000150:complications / Q000235:genetics*; D020738:Leptin / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011499:Protein Processing, Post-Translational / Q000235:genetics; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics* / Q000378:metabolism; D015430:Weight Gain / Q000235:genetics / Q000502:physiology
chemical_list: D020738:Leptin; D019716:Tissue Inhibitor of Metalloproteinase-2