Brain PPAR-γ promotes obesity and is required for the insulin-sensitizing effect of thiazolidinediones - PubMed (original) (raw)

doi: 10.1038/nm.2332. Epub 2011 May 1.

David A Sarruf, Saswata Talukdar, Shweta Sharma, Pingping Li, Gautam Bandyopadhyay, Sarah Nalbandian, WuQiang Fan, Jiaur R Gayen, Sushil K Mahata, Nicholas J Webster, Michael W Schwartz, Jerrold M Olefsky

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Brain PPAR-γ promotes obesity and is required for the insulin-sensitizing effect of thiazolidinediones

Min Lu et al. Nat Med. 2011 May.

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.

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Figures

Fig. 1

Fig. 1. Neuronal deletion of Pparγ in brain knockout mice

(a) Quantification of wild type Pparγ mRNA in various brain regions of Pparγ f/f mice and BKO mice. Data shown are the fold induction of gene expression normalized with housekeeping gene and expressed as mean ± SEM. (b) RT–PCR showing wild type and mutant (KO) Pparγ mRNA in various tissues in control and BKO mice. (c) Quantification of tissue Pparγ mRNA expression. Data shown are the fold induction of gene expression normalized with housekeeping gene and expressed as mean ± SEM. Asterisks indicate statistical significance (p < 0.05) between conditions connected by bars.

Fig. 2

Fig. 2. Energy balance parameters in Pparγ brain KO mice

(a) Body weight of _Pparγ_–f/f and BKO mice on either standard chow or HFD. Dagger indicates statistical significance (p < 0.01) between genotypes. (b) Body composition analysis of control (n = 8) and Pparγ BKO (n = 6) mice at wk 5 on HFD. (c) Ambulatory activity of control (n = 7) and BKO (n = 6) mice at wk 6 on HFD. (d) Average 24–h energy expenditure in control (n = 8) and BKO (n = 6) mice after adjustment for body size differences and 24–h average activity. (e) Weekly caloric intake of control (n = 12) and BKO (n = 11) mice at weeks 1 and 12 on HFD. (f) Serum leptin concentration in control and BKO mice fed either standard chow or HFD (n = 5–9 per group). (g) Western blot showing acute leptin–stimulated phosphorylation of STAT3 (Y705) in hypothalamus. Data shown are quantified ratio of p–STAT3/total STAT3 normalized to vehicle group. All data are mean ± SEM. Statistical significance between control and Pparγ BKO mice, or between conditions connected by bars, is indicated by asterisks (p < 0.05), daggers (p < 0.01), double daggers (p < 0.001), or NS (not significant).

Fig. 3

Fig. 3. Effect of rosiglitazone on weight gain and food intake in control and Pparγ BKO mice

(a) Rosiglitazone–induced weight gain in _Pparγ_f/f (n = 14), Syn–Cre (n = 6), and Pparγ BKO (n = 11) mice. Age of mice, start time of HFD, and HFD + rosiglitazone (rosi) are indicated. (b) Body weight gain of control and Pparγ BKO mice that were fed HFD for 16 wk followed by HFD with or without rosiglitazone treatment. Data are shown for weeks 28–34 (n = 6–14 per group). (c) Weekly caloric intake before and after rosiglitazone treatment in HFD-fed mice showing the effect of rosiglitazone on food intake in control (n = 14) and Pparγ BKO (n = 11) mice. (d) Measurement of Ucp1 mRNA in epididymal white adipose tissue from control and Pparγ BKO mice. (e) BAT Ucp1 mRNA expression in control and Pparγ BKO mice after rosiglitazone treatment. (f) Histochemical image of BAT from control and Pparγ BKO mice after rosiglitazone treatment stained with H&E. (g) Muscle Ucp3 mRNA expression in control and Pparγ BKO mice on HFD with or without rosiglitazone treatment (n = 5–10 per group). (h) Liver Ucp3 mRNA expression in control and Pparγ BKO mice on HFD or after rosiglitazone treatment (n = 5–10 per group). (a)–(c), data are shown as mean ± SEM. (d)–(h), all qPCR data shown are the fold induction of gene expression normalized with housekeeping gene and expressed as mean ± SEM. Statistical significance between control and Pparγ BKO mice, or between conditions connected by bars, is indicated by asterisks (p < 0.05), daggers (p < 0.01), or NS (not significant).

Fig. 4

Fig. 4. Neuronal PPARγ is required for the full insulin–sensitizing effect of TZD treatment

(a) Intraperitoneal glucose tolerance tests (IPGTTs) on _Pparγ_f/f and BKO mice on HFD with or without rosiglitazone treatment for 7 wk (n = 6–12 per group). Statistical significance between values from rosiglitazone–treated control and Pparγ BKO mice indicated by asterisks (p < 0.05) and dagger (p < 0.01). (b)–(f), Hyperinsulinemic euglycemic clamp study on control and Pparγ BKO mice fed a HFD with or without rosiglitazone treatment for 8 wk (n = 7–12 per group). Glucose infusion rate (GIR) (b), insulin–stimulated glucose disposal rate (IS–GDR) (c), basal hepatic glucose production rate (basal HGP) (d), insulin–stimulated rate of HGP (e), and percent suppression of HGP by insulin (f) are shown. (g) Immunoblotting analysis of insulin-stimulated protein phosphorylation in liver extracts from control and BKO mice fed a HFD in the presence or absence of rosiglitazone treatment. (h) Quantification of relative phospho–protein levels normalized to respective total kinase protein content or β–tubulin. Data are shown as mean ± SEM. (i) Liver Pck1 (Pepck) mRNA expression in control and BKO mice fed a HFD or after rosiglitazone treatment (n = 5–10 per group). (j) Liver weight of control and Pparγ BKO mice (n = 10–14 per group) on HFD with or without rosiglitazone treatment. All data shown are as mean ± SEM. Statistical significance between conditions connected by bars is indicated by asterisks (p < 0.05), daggers (p < 0.01), or NS (no significance).

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