BACKGROUND AND PURPOSEThe growing epidemic of obesity and metabolic diseases necessitates the development of novel strategies to prevent and treat such diseases. Current research suggests that browning of white adipose tissue (WAT) promotes energy expenditure to counter obesity. Recent research suggests that activation of the TRPV1 channels counters obesity. However, the mechanism by which activation of TRPV1 channels counters obesity still remains unclear. EXPERIMENTAL APPROACHWe evaluated the effect of dietary capsaicin to induce a browning program in WAT by activating TRPV1 channels to prevent dietinduced obesity using wild-type and TRPV1 À/À mouse models. We performed experiments using preadipocytes and fat pads from these mice. KEY RESULTSCapsaicin stimulated the expression of brown fat-specific thermogenic uncoupling protein-1 and bone morphogenetic protein8b in WAT. Capsaicin triggered browning of WAT by promoting sirtuin-1 expression and activity via TRPV1 channel-dependent elevation of intracellular Ca 2+ and phosphorylation of Ca 2+ /calmodulin-activated protein kinase II and AMP-activated kinase. Capsaicin increased the expression of PPARγ 1 coactivator α and enhanced metabolic and ambulatory activity. Further, capsaicin stimulated sirtuin-1-dependent deacetylation of PPARγ and the transcription factor PRDM-16 and facilitated PPARγ-PRDM-16 interaction to induce browning of WAT. Dietary capsaicin did not protect TRPV1 À/À mice from obesity. CONCLUSIONS AND INTERPRETATIONSOur results show for the first time that activation of TRPV1 channels by dietary capsaicin triggers browning of WAT to counteract obesity. Our results suggest that activation of TRPV1 channels is a promising strategy to counter obesity. IntroductionObesity is the hallmark of metabolic syndrome (Maestu et al., 2010). It foreshadows type II diabetes, dyslipidemia, vascular anomalies and the overall risk of cardiovascular diseases (Arya et al., 2002). Decreased physical activity coupled with increased high-fat diet (HFD) intake prompts obesity (Yagi et al., 2014). Effective clinical management is still lacking to combat obesity. Recent studies indicate that high fructose in a diet is a critical factor leading to obesity as the combination of sugars and refined carbohydrates along with fat lead to metabolic syndrome Lucan and DiNicolantonio, 2015). Recent evidence suggests that browning of white adipose tissue (WAT) might serve as a novel strategy to improve metabolic health (Bartelt and Heeren, 2014). WAT stores energy in the form of fat, while brown adipocytes promote energy expenditure via thermogenesis by burning fat. Browning of WAT favours the energy expenditure by triggering thermogenesis, which suppresses diet-induced weight gain (Cao et al., 2011;Bordicchia et al., 2012;Bi et al., 2014). Further analysis of molecular mechanisms underscoring induction of browning of WAT led to identification of adipogenic factors, their stabilization and interaction with proteins, which serve as catalysts for browning of WAT (Ohno et al., 2012;Qia...

Background: TRPM8 channels are highly expressed in prostate tissues, where the role of this cold receptor is not well understood. Results: Testosterone activates TRPM8 in various cellular systems and in the planar lipid bilayers. Conclusion: TRPM8 is an ionotropic testosterone receptor. Significance: TRPM8 channels may be implicated in various physiological processes regulated by androgens.

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Peripheral coupling between the sarcoplasmic reticulum (SR) and plasma membrane (PM) forms signaling complexes that regulate the membrane potential and contractility of vascular smooth muscle cells (VSMCs). The mechanisms responsible for these membrane interactions are poorly understood. In many cells, STIM1 (stromal-interaction molecule 1), a single transmembrane-domain protein that resides in the endoplasmic reticulum (ER), transiently moves to ER-PM junctions in response to depletion of ER Ca2+ stores and initiates store-operated Ca2+ entry (SOCE). Fully differentiated VSMCs express STIM1 but exhibit only marginal SOCE activity. We hypothesized that STIM1 is constitutively active in contractile VSMCs and maintains peripheral coupling. In support of this concept, we found that the number and size of SR-PM interacting sites were decreased, and SR-dependent Ca2+ signaling processes were disrupted in freshly isolated cerebral artery SMCs from tamoxifen-inducible, SMC-specific STIM1-knockout (Stim1-smKO) mice. VSMCs from Stim1-smKO mice also exhibited a reduction in nanoscale colocalization between Ca2+-release sites on the SR and Ca2+-activated ion channels on the PM, accompanied by diminished channel activity. Stim1-smKO mice were hypotensive, and resistance arteries isolated from them displayed blunted contractility. These data suggest that STIM1 - independent of SR Ca2+ store depletion - is critically important for stable peripheral coupling in contractile VSMCs.

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