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, 302 (7), E807-16

TRPM2 Ca2+ Channel Regulates Energy Balance and Glucose Metabolism

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TRPM2 Ca2+ Channel Regulates Energy Balance and Glucose Metabolism

Zhiyou Zhang et al. Am J Physiol Endocrinol Metab.

Abstract

TRPM2 Ca(2+)-permeable cation channel is widely expressed and activated by markers of cellular stress. Since inflammation and stress play a major role in insulin resistance, we examined the role of TRPM2 Ca(2+) channel in glucose metabolism. A 2-h hyperinsulinemic euglycemic clamp was performed in TRPM2-deficient (KO) and wild-type mice to assess insulin sensitivity. To examine the effects of diet-induced obesity, mice were fed a high-fat diet for 4-10 mo, and metabolic cage and clamp studies were conducted in conscious mice. TRPM2-KO mice were more insulin sensitive partly because of increased glucose metabolism in peripheral organs. After 4 mo of high-fat feeding, TRPM2-KO mice were resistant to diet-induced obesity, and this was associated with increased energy expenditure and elevated expressions of PGC-1α, PGC-1β, PPARα, ERRα, TFAM, and MCAD in white adipose tissue. Hyperinsulinemic euglycemic clamps showed that TRPM2-KO mice were more insulin sensitive, with increased Akt and GSK-3β phosphorylation in heart. Obesity-mediated inflammation in adipose tissue and liver was attenuated in TRPM2-KO mice. Overall, TRPM2 deletion protected mice from developing diet-induced obesity and insulin resistance. Our findings identify a novel role of TRPM2 Ca(2+) channel in the regulation of energy expenditure, inflammation, and insulin resistance.

Figures

Fig. 1.
Fig. 1.
Transient receptor potential melastatin 2 (TRPM2)-deficient mice are more insulin sensitive. Male TRPM2-deficient (KO) mice (n = 11) and wild-type (WT) littermates (n = 11) were studied at 3–4 mo of age. A: whole body fat and lean mass were noninvasively measured using 1H-MRS. B: plasma glucose levels during intraperitoneal glucose tolerance test in mice (n = 7 for each group). C and D: plasma glucose and insulin levels at basal state (overnight-fasted) and during hyperinsulinemic euglycemic clamps in mice. E: steady-state glucose infusion rates during euglycemic clamps in conscious mice. *P < 0.02 vs. WT mice. F: insulin-stimulated whole body glucose turnover was estimated using [3H]glucose infusion during clamps. *P < 0.02 vs. WT mice. G: insulin-stimulated whole body glycogen synthesis was calculated during clamps. *P < 0.03 vs. WT mice. H and I: insulin-stimulated glucose uptake in heart and white adipose tissue (WAT; epidydimal) was measured using 2-[14C]deoxyglucose injection during clamps. *P < 0.02 vs. WT mice.
Fig. 2.
Fig. 2.
Increased insulin signaling in TRPM2-deficient heart. A: heart samples were obtained at the end of insulin clamps, and insulin signaling was measured as insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation normalized to total IRS-1 protein levels. B: calmodulin protein levels were determined from heart samples using Western blot. *P < 0.05 vs. WT mice.
Fig. 3.
Fig. 3.
TRPM2-deficient mice are resistant to diet-induced obesity. A: body weight was measured during 4 mo of high-fat diet (HFD; n = 7–10, *P < 0.05 vs. 0 mo). B and C: whole body fat and lean mass were measured using 1H-MRS before HFD (0 mo) and at 2, 3, and 4 mo of HFD (n = 7–10, *P < 0.05 vs. 0 mo). D: another group of mice were fed a HFD for 10 mo, and body weights were measured at the end (n = 8; *P < 0.05 vs. WT-HFD). ♢ and ☐, WT; ■, TRPM2-KO.
Fig. 4.
Fig. 4.
Increased energy expenditure in TRPM2-deficient mice. Indirect calorimetry was performed using metabolic cages in age-matched (∼6 mo of age) male TRPM2-KO and WT littermates fed chow diet (n = 5 for each group) and after ∼4 mo of HFD (n = 4 for each group). All data are expressed per kg of whole body lean mass measured using 1H-MRS. A: 24-h V̇o2 consumption rates in chow-fed mice. B: 24-h V̇co2 production rates in chow-fed mice. C: 24-h average V̇o2 consumption and V̇co2 production rates in chow-fed mice. D: 24-h V̇co2 production rates in HFD-fed mice. E: 24-h average energy expenditure rates in HFD-fed mice. *P < 0.05 vs. WT or HFD-fed WT mice.
Fig. 5.
Fig. 5.
TRPM2-KO mice are more insulin sensitive than WT mice after HFD. Male TRPM2-KO (n = 8) and WT littermates (n = 6) were studied at ∼6 mo of age after 4 mo of HFD. A: intraperitoneal glucose tolerance test was performed in HFD-fed mice (n = 7–10; *P < 0.05 vs. WT-HFD mice). B: plasma insulin levels at basal (overnight-fasted) and during clamps (*P < 0.05 vs. WT-HFD mice). C: steady-state glucose infusion rates during clamps in HFD-fed mice (*P < 0.05 vs. WT-HFD mice). D: insulin-stimulated whole body glucose turnover during clamps in HFD-fed mice (*P < 0.04 vs. WT-HFD mice). E and F: insulin-stimulated glucose uptake in skeletal muscle (gastrocnemius) and heart (*P < 0.02 vs. WT-HFD mice). GI: heart samples were used for Akt and GSK-3β serine phosphorylation, IRS-1 tyrosine phosphorylation, and respective total protein levels using Western blots (n = 4–5; *P < 0.05 vs. WT-HFD mice).
Fig. 6.
Fig. 6.
AC: calmodulin levels and superoxide dismutase (SOD) activity in heart and skeletal muscle (gastrocnemius) in TRPM2-KO and WT mice fed chow diet and after 4 mo of HFD. Data represent means ± SE; n = 5 for each group. *P < 0.05 vs. WT-chow mice. D and E: hyperglycemic clamps were performed to assess in vivo insulin secretion in awake TRPM2-KO and WT mice after 4 mo of high-fat feeding. Data represent means ± SE; n = 6 for each group.
Fig. 7.
Fig. 7.
TRPM2 deficiency upregulates adipose tissue expression of metabolic and mitochondrial genes. A: WAT samples were obtained from TRPM2-KO and WT mice after 4 mo of HFD for quantitative real-time PCR analysis of peroxisome proliferator-activated receptor (PPAR)γ coactivator-1α (PGC-1α), PGC-1β, PPARα, estrogen-related receptor-α (ERRα), medium-chain acyl-CoA dehydrogenase (MCAD), and mitochondrial transcriptional factor A (TFAM). Data represent means ± SE; n = 4. B: PGC-1α protein expression in WAT. C: serum monocyte chemoattractant protein-1 (MCP-1) levels were measured using multiplex Luminex. D and E: Western blots were performed in WAT to measure CD68 and F4/80 expression. Data represent means ± SE; n = 4–6. *P < 0.05 vs. WT or WT-HFD mice.
Fig. 8.
Fig. 8.
TRPM2 deficiency attenuates HFD-induced inflammation in adipose tissue. WAT and liver samples were obtained from TRPM2-KO and WT mice after 4 mo of HFD. AC: adipose tissue levels of IL-1β, IL-6, and keratinocyte-derived chemokine (KC) were measured using multiplex Luminex. D and E: Western blots were performed in liver samples to measure CD68 and TLR4 expression. Relative expression of CD68 and Toll-like receptor 4 (TLR4) was quantified by Western analysis of the same blot, with β-actin serving as a loading control. Data represent means ± SE; n = 4–6. *P < 0.05 vs. WT-HFD mice.

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