TRPV1 activation counters diet-induced obesity through sirtuin-1 activation and PRDM-16 deacetylation in brown adipose tissue

Abstract

Background/Objective An imbalance between energy intake and expenditure leads to obesity. Increasing metabolism and thermogenesis in brown adipose tissue (BAT) can help in overcoming obesity. Here, we investigated the effect of activation of transient receptor potential vanilloid subfamily 1 (TRPV1) in the upregulation of thermogenic proteins in BAT to counter diet-induced obesity. Subjects/Methods We investigated the effect of dietary supplementation of capsaicin (TRPV1 agonist) on the expression of metabolically important thermogenic proteins in BAT of wild type and TRPV1−/− mice that received either a normal chow or high fat (± capsaicin; TRPV1 activator) diet by immunoblotting. We measured the metabolic activity, respiratory quotient and BAT lipolysis. Results CAP antagonized high fat diet (HFD)-induced obesity without decreasing energy intake in mice. HFD suppressed TRPV1 expression and activity in BAT and CAP countered this effect. HFD feeding caused glucose intolerance, hypercholesterolemia and decreased the plasma concentration of glucagon like peptide-1 and CAP countered these effects. HFD suppressed the expression of metabolically important thermogenic genes, ucp-1, bmp8b, sirtuin 1, pgc-1α and prdm-16 in BAT and CAP prevented this effect. CAP increased the phosphorylation of sirtuin 1 and induced an interaction between PPARγ with PRDM-16. Further, CAP treatment, in vitro, decreased the acetylation of PRDM-16, which was antagonized by inhibition of TRPV1 by capsazepine, chelation of intracellular Ca2+ by cell permeable BAPTA-AM or the inhibition of SIRT-1 by EX 527. Further, CAP supplementation, post HFD, promoted weight loss and enhanced the respiratory exchange ratio. CAP did not have any effect in TRPV1−/− mice. Conclusions Our data show that activation of TRPV1 in BAT enhances the expression of SIRT-1, which facilitates the deacetylation and interaction of PPARγ and PRDM-16. These data suggest that TRPV1 activation is a novel strategy to counter diet-induced obesity by enhancing metabolism and energy expenditure.

Oleuropein: A natural antioxidant molecule in the treatment of metabolic syndrome

“…TRP receptors have been implicated in adipogenesis in 3T3-L3 preadipocyte differentiation , and another known TRPA1 ligand, capsaicin, has been shown to prevent diet-induced obesity. The effect was observed in TRPA1 knockout mice (Baskaran et al, 2017). In the study by Y.…”

“…TRP receptors have been implicated in adipogenesis in 3T3‐L3 preadipocyte differentiation (Zhang et al, ), and another known TRPA1 ligand, capsaicin, has been shown to prevent diet‐induced obesity. The effect was observed in TRPA1 knockout mice (Baskaran et al, ). In the study by Y. Oi‐Kano et al (), drawing on a previous studies finding that TRPA1 activation simulated adrenaline secretion (Iwasaki, Tanabe, Kobata, & Watanabe, ), it was found that oleuropein enhanced UCP1 expression in IBAT by stimulating noradrenaline secretion via the β2‐ and β3‐adrenoceptors following TRPA1 and TRPV1 activation (Y. Oi‐Kano et al, ).…”

Brown Adipose Tissue, Diet-Induced Thermogenesis, and Thermogenic Food Ingredients: From Mice to Men

“…Taken together, oral administration of either pungent capsaicin or non-pungent capsinoids increases whole-body EE and prevents obesity through the activation of the TRPV1-SNS-BAT axis in small rodents. It is possible that capsaicin also acts directly on TRPV1 expressed in BAT (109). By contrast, the direct action of capsinoids on TRPV1 in brown adipocytes is unlikely because orally ingested capsinoids are rapidly hydrolyzed in the small intestine and are usually undetectable in general circulation (110).…”

Feeding brown fat: dietary phytochemicals targeting non-shivering thermogenesis to control body weight

“…A role of BAT in capsiate action is further supported by an acute capsiate exposure for 30 min that upregulated UCP1 mRNA levels in the BAT and evolved to higher UCP1 protein abundance in the BAT from male mice after 2 weeks of capsiate supplementation (186) . A detailed study by Baskaran et al (182) substantiates the interplay between CAP, active BAT and TRPV1 in male mice (182) . The addition of CAP to HFD Brown fat in weight management 9 (0⋅01 % w/w) over a 32 week intervention period prevented weight gain by almost 35 % compared to HFD controls and led to a final BW comparable to mice on standard diet.…”

“…Adrenergic input is a potent activator of the thermogenic BAT programme as well as subcutaneous WAT browning and TRPV1 is expressed in both adipose types. Additionally, murine TRPV1 levels are upregulated in both BAT and WAT following a CAP-enriched diet (182)(183)(184) . Therefore, it was soon hypothesised that enforced BAT functionality or a bigger brown/brite adipocyte pool contributes to the physiologic effects of CAP.…”