title: Brain PPAR-γ promotes obesity and is required for the insulin-sensitizing effect of thiazolidinediones.
abstract: In adipose tissue, muscle, liver and macrophages, signaling by the nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR-γ) is a determinant of insulin sensitivity and this receptor mediates the insulin-sensitizing effects of thiazolidinediones (TZDs). As PPAR-γ is also expressed in neurons, we generated mice with neuron-specific Pparg knockout (Pparg brain knockout (BKO)) to determine whether neuronal PPAR-γ signaling contributes to either weight gain or insulin sensitivity. During high-fat diet (HFD) feeding, food intake was reduced and energy expenditure increased in Pparg-BKO mice compared to Pparg(f/f) mice, resulting in reduced weight gain. Pparg-BKO mice also responded better to leptin administration than Pparg(f/f) mice. When treated with the TZD rosiglitazone, Pparg-BKO mice were resistant to rosiglitazone-induced hyperphagia and weight gain and, relative to rosiglitazone-treated Pparg(f/f) mice, experienced only a marginal improvement in glucose metabolism. Hyperinsulinemic euglycemic clamp studies showed that the increase in hepatic insulin sensitivity induced by rosiglitazone treatment during HFD feeding was completely abolished in Pparg-BKO mice, an effect associated with the failure of rosiglitazone to improve liver insulin receptor signal transduction. We conclude that excess weight gain induced by HFD feeding depends in part on the effect of neuronal PPAR-γ signaling to limit thermogenesis and increase food intake. Neuronal PPAR-γ signaling is also required for the hepatic insulin sensitizing effects of TZDs.
authors.affiliation: Department of Medicine, University of California-San Diego (UCSD), San Diego, California, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.forename: David A
authors.initials: DA
authors.lastname: Sarruf
authors.forename: Saswata
authors.initials: S
authors.lastname: Talukdar
authors.forename: Shweta
authors.initials: S
authors.lastname: Sharma
authors.forename: Pingping
authors.initials: P
authors.lastname: Li
authors.forename: Gautam
authors.initials: G
authors.lastname: Bandyopadhyay
authors.forename: Sarah
authors.initials: S
authors.lastname: Nalbandian
authors.forename: WuQiang
authors.initials: W
authors.lastname: Fan
authors.forename: Jiaur R
authors.initials: JR
authors.lastname: Gayen
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Mahata
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Webster
authors.forename: Michael W
authors.initials: MW
authors.lastname: Schwartz
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Olefsky
mesh_terms: D000368:Aged; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000503:physiopathology; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009765:Obesity / Q000209:etiology* / Q000503:physiopathology; D047495:PPAR gamma / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000077154:Rosiglitazone; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology*; D015430:Weight Gain / Q000187:drug effects / Q000502:physiology
chemical_list: D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone