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. 2015 Aug;29(8):3182-92.
doi: 10.1096/fj.14-268300. Epub 2015 Apr 17.

Transient Receptor Potential Vanilloid type-1 Channel Regulates Diet-Induced Obesity, Insulin Resistance, and Leptin Resistance

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Free PMC article

Transient Receptor Potential Vanilloid type-1 Channel Regulates Diet-Induced Obesity, Insulin Resistance, and Leptin Resistance

Eunjung Lee et al. FASEB J. .
Free PMC article

Abstract

Insulin resistance is a major characteristic of obesity and type 2 diabetes, but the underlying mechanism is unclear. Recent studies have shown a metabolic role of capsaicin that may be mediated via the transient receptor potential vanilloid type-1 (TRPV1) channel. In this study, TRPV1 knockout (KO) and wild-type (WT) mice (as controls) were fed a high-fat diet (HFD), and metabolic studies were performed to measure insulin and leptin action. The TRPV1 KO mice became more obese than the WT mice after HFD, partly attributed to altered energy balance and leptin resistance in the KO mice. The hyperinsulinemic-euglycemic clamp experiment showed that the TRPV1 KO mice were more insulin resistant after HFD because of the ∼40% reduction in glucose metabolism in the white and brown adipose tissue, compared with that in the WT mice. Leptin treatment failed to suppress food intake, and leptin-mediated hypothalamic signal transducer and activator of transcription (STAT)-3 activity was blunted in the TRPV1 KO mice. We also found that the TRPV1 KO mice were more obese and insulin resistant than the WT mice at 9 mo of age. Taken together, these results indicate that lacking TRPV1 exacerbates the obesity and insulin resistance associated with an HFD and aging, and our findings further suggest that TRPV1 has a major role in regulating glucose metabolism and hypothalamic leptin's effects in obesity.

Keywords: aging; capsaicin; glucose metabolism; hyperinsulinemic-euglycemic clamp.

Figures

Figure 1.
Figure 1.
TRPV1 deletion accelerates diet-induced obesity in mice. TRPV1 KO and WT mice (12 wk old) were fed an HFD (n = 10–12) or chow diet (n = 6) for 5 wk. A) Body weight was measured during 5 wk of HFD or chow. B, C) Whole-body fat (B) and lean mass (C) were measured weekly by 1H MRS. *P < 0.05 vs. HFD-fed WT mice.
Figure 2.
Figure 2.
Altered energy balance in TRPV1-deficient mice. Indirect calorimetry was performed in metabolic cages for 3 consecutive days in age-matched WT and TRPV1 KO mice (n = 6 for each group). A) Food intake was measured on days 1, 2, and 3 by the metabolic cages. A 24 h timeline is shown of the Vo2 consumption (B) and Vco2 production (C) rates. D) A 24 h timeline of physical activity in HFD-fed mice. E) Averaged physical activity during the night cycle in WT and TRPV1 KO mice before (baseline) and after 5 wk of high-fat feeding. *P < 0.05 vs. WT mice or baseline.
Figure 3.
Figure 3.
Increased insulin resistance in HFD-fed TRPV1 KO mice. All mice were 12 wk of age at the beginning of the experiment and were fed an HFD (n = 10–12) or chow diet (n = 6 for each group) for 5 wk. A) Plasma insulin levels were measured with ELISA. Samples were taken from the mice at the beginning and end of hyperinsulinemic-euglycemic clamp experiments. B) Steady-state glucose infusion rate during the experiments in awake mice. C) Insulin-stimulated whole-body glucose turnover was calculated by infusion of [3H]glucose during the tests. D) Insulin-stimulated whole-body glycolysis rates. *P < 0.05 vs. WT mice or chow-fed mice.
Figure 4.
Figure 4.
Reduced glucose metabolism in adipose tissue and heart of HFD-fed TRPV1 KO mice. Insulin-stimulated glucose uptake in individual organs was calculated by injecting 2-[14C]DG during hyperinsulinemic-euglycemic clamp experiments. A–D) Insulin-stimulated glucose uptake in white and brown adipose tissue, heart, and skeletal muscle from WT and TRPV1 KO mice fed chow (n = 6 for each group) or an HFD (n = 10–12). E) Basal and clamp HGP rates and hepatic insulin action were calculated as percentage of insulin-mediated suppression of HGP. *P < 0.05 vs. WT mice or chow-fed mice.
Figure 5.
Figure 5.
Leptin resistance in TRPV1 KO mice. A) Plasma leptin levels were measured by ELISA in WT (n = 12) and TRPV1 KO (n = 10) mice, before and after 5 wk on an HFD. B) Plasma leptin levels were normalized to whole-body fat mass, measured with 1H MRS. CE) Leptin (20 μg/d) was infused continuously for 6 d with implantable osmotic pumps in 12-wk-old WT (n = 5) and TRPV1 KO (n = 5) mice. Daily food intake was measured with metabolic cages; basal levels in each mouse were obtained by measuring average food intake for 3 d. Plasma leptin levels (C), daily food intake (D), and percentage change in food intake at baseline and after leptin treatment (E) are shown. *P < 0.05, baseline vs. leptin infused mice. WT vs. KO mice, chow diet vs. high-fat diet.
Figure 6.
Figure 6.
Impaired leptin signaling in TRPV1-deficient cells. A) p-STAT3 at Tyr705, with or without leptin (100 ng/ml) for 10 minutes, as determined by Western blot analysis in MEFs with siRNA-mediated knockdown of TRPV1. The numbers above the Western blot lanes denote the relative normalized phosphorylation levels compared to the control at each time point. B) p-STAT at Tyr705 was examined by Western blot in the hypothalamus of the WT and TRPV1 KO mice after intraperitoneal injection of leptin (2 mg/kg body weight). Quantitative data are shown as means ± se (n = 3 mice/group). Quantitative analyses of p-STAT3 and STAT3 were performed with ImageJ software in 3 independent experiments. C, D) SOCS3 mRNA and protein levels in primary cultured MEFs from WT and TRPV1 KO mice. E) White adipose tissue expression of SOCS3 in the WT and TRPV1 KO mice, without or with leptin stimulation.
Figure 7.
Figure 7.
Increased obesity, insulin resistance, and leptin resistance in aging TRPV1 KO mice. A) Body weights were measured at 3 and 9 mo of age in WT (n = 4) and TRPV1 KO (n = 4) mice fed a chow diet. B, C) Whole-body fat and lean mass were measured by 1H MRS at 3 and 9 mo of age. D) Steady-state glucose infusion rates during hyperinsulinemic-euglycemic clamp tests were measured in awake mice to assess insulin sensitivity at 9 mo of age (n = 4 for each group). E) Plasma leptin levels were measured with ELISA in 9-mo-old WT (n = 4) and TRPV1 KO (n = 4) mice. F) Daily food intake was measured in vehicle- and leptin-injected mice before and 24 h after leptin injection. G) Percentage change in food intake before and after leptin injection. *P < 0.05 vs. WT mice or 3-mo-old mice.

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