title: Effect of selective expression of dominant-negative PPARγ in pro-opiomelanocortin neurons on the control of energy balance.
abstract: Peroxisome proliferator-activated receptor-γ (PPARγ), a master regulator of adipogenesis, was recently shown to affect energy homeostasis through its actions in the brain. Deletion of PPARγ in mouse brain, and specifically in the pro-opiomelanocortin (POMC) neurons, results in resistance to diet-induced obesity. To study the mechanisms by which PPARγ in POMC neurons controls energy balance, we constructed a Cre-recombinase-dependent conditionally activatable transgene expressing either wild-type (WT) or dominant-negative (P467L) PPARγ and the tdTomato reporter. Inducible expression of both forms of PPARγ was validated in cells in culture, in liver of mice infected with an adenovirus expressing Cre-recombinase (AdCre), and in the brain of mice expressing Cre-recombinase either in all neurons (NES(Cre)/PPARγ-P467L) or selectively in POMC neurons (POMC(Cre)/PPARγ-P467L). Whereas POMC(Cre)/PPARγ-P467L mice exhibited a normal pattern of weight gain when fed 60% high-fat diet, they exhibited increased weight gain and fat mass accumulation in response to a 10% fat isocaloric-matched control diet. POMC(Cre)/PPARγ-P467L mice were leptin sensitive on control diet but became leptin resistant when fed 60% high-fat diet. There was no difference in body weight between POMC(Cre)/PPARγ-WT mice and controls in response to 60% high-fat diet. However, POMC(Cre)/PPARγ-WT, but not POMC(Cre)/PPARγ-P467L, mice increased body weight in response to rosiglitazone, a PPARγ agonist. These observations support the concept that alterations in PPARγ-driven mechanisms in POMC neurons can play a role in the regulation of metabolic homeostasis under certain dietary conditions.
authors.affiliation: Medical Scientist Training Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; and.
authors.forename: Madeliene
authors.initials: M
authors.lastname: Stump
authors.affiliation: Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; and.
authors.forename: Deng-Fu
authors.initials: DF
authors.lastname: Guo
authors.affiliation: Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; and.
authors.forename: Ko-Ting
authors.initials: KT
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; and.
authors.forename: Masashi
authors.initials: M
authors.lastname: Mukohda
authors.affiliation: Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; and.
authors.forename: Xuebo
authors.initials: X
authors.lastname: Liu
authors.affiliation: Medical Scientist Training Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; and UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Kamal
authors.initials: K
authors.lastname: Rahmouni
authors.affiliation: Medical Scientist Training Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; and UIHC Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa curt-sigmund@uiowa.edu.
authors.forename: Curt D
authors.identifier: 0000-0002-1453-0921
authors.initials: CD
authors.lastname: Sigmund
mesh_terms: D016475:3T3 Cells; D050156:Adipogenesis / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D002460:Cell Line; D059305:Diet, High-Fat / Q000379:methods; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D005260:Female; D057809:HEK293 Cells; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D020738:Leptin / Q000378:metabolism; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D015430:Weight Gain / Q000187:drug effects / Q000502:physiology
chemical_list: D020738:Leptin; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D011333:Pro-Opiomelanocortin
keywords: POMC; PPARγ; neuron; rosiglitazone