title: A role for central nervous system PPAR-γ in the regulation of energy balance.
abstract: The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a nuclear receptor that is activated by lipids to induce the expression of genes involved in lipid and glucose metabolism, thereby converting nutritional signals into metabolic consequences. PPAR-γ is the target of the thiazolidinedione (TZD) class of insulin-sensitizing drugs, which have been widely prescribed to treat type 2 diabetes mellitus. A common side effect of treatment with TZDs is weight gain. Here we report a previously unknown role for central nervous system (CNS) PPAR-γ in the regulation of energy balance. We found that both acute and chronic activation of CNS PPAR-γ, by either TZDs or hypothalamic overexpression of a fusion protein consisting of PPAR-γ and the viral transcriptional activator VP16 (VP16-PPAR-γ), led to positive energy balance in rats. Blocking the endogenous activation of CNS PPAR-γ with pharmacological antagonists or reducing its expression with shRNA led to negative energy balance, restored leptin sensitivity in high-fat-diet (HFD)-fed rats and blocked the hyperphagic response to oral TZD treatment. These findings have implications for the widespread clinical use of TZD drugs and for understanding the etiology of diet-induced obesity.
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Karen K
authors.initials: KK
authors.lastname: Ryan
authors.forename: Bailing
authors.initials: B
authors.lastname: Li
authors.forename: Bernadette E
authors.initials: BE
authors.lastname: Grayson
authors.forename: Emily K
authors.initials: EK
authors.lastname: Matter
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Woods
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Seeley
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D002490:Central Nervous System / Q000187:drug effects / Q000502:physiology*; D004734:Energy Metabolism / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000494:pharmacology; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology; D008297:Male; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D020318:Rats, Long-Evans; D011993:Recombinant Fusion Proteins / Q000235:genetics; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000009:adverse effects / Q000494:pharmacology; D015430:Weight Gain / Q000187:drug effects / Q000502:physiology
chemical_list: D007004:Hypoglycemic Agents; D047495:PPAR gamma; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D045162:Thiazolidinediones; D000077154:Rosiglitazone