Activation of TRPV2 negatively regulates the differentiation of mouse brown adipocytes

Abstract

Transient receptor potential vanilloid 2 (TRPV2) acts as a Ca(2+)-permeable non-selective cation channel that has been reported to be sensitive to temperature, mechanical force, and some chemicals. We recently showed that TRPV2 is critical for maintenance of the thermogenic function of brown adipose tissue in mice. However, the involvement of TRPV2 in the differentiation of brown adipocytes remains unexplored. We found that the expression of TRPV2 was dramatically increased during the differentiation of brown adipocytes. Non-selective TRPV2 agonists (2-aminoethoxydiphenyl borate and lysophosphatidylcholine) inhibited the differentiation of brown adipocytes in a dose-dependent manner during the early stage of differentiation of brown adipocytes. The inhibition was rescued by a TRPV2-selective antagonist, SKF96365 (SKF). Mechanical force, which activates TRPV2, also inhibited the differentiation of brown adipocytes in a strength-dependent manner, and the effect was reversed by SKF. In addition, the inhibition of adipocyte differentiation by either TRPV2 ligand or mechanical stimulation was significantly smaller in the cells from TRPV2KO mice. Moreover, calcineurin inhibitors, cyclosporine A and FK506, partially reversed TRPV2 activation-induced inhibition of brown adipocyte differentiation. Thus, we conclude that TRPV2 might be involved in the modulation of brown adipocyte differentiation partially via a calcineurin pathway.

Role of Thermo-Sensitive Transient Receptor Potential Channels in Brown Adipose Tissue

“…56) We previously showed that TRPV2 is more highly expressed in mouse brown adipocytes than TRPV1, TRPV3, TRPV4, and TRPM8. 57,94) Our results demonstrated that primary TRPV2-deficient (TRPV2KO) adipocytes show decreased mRNA levels of multiple genes involved in mitochondrial oxidative metabolism, such as Ucp1 and PPARγ coactivator 1-alpha (Ppargc1α). Moreover, reduced responses to the β-adrenergic receptor agonist isoproterenol were observed in TRPV2KO adipocytes in vitro.…”

“…57) Although expression of TRPV2 was increased during the differentiation of brown adipocytes, TRPV2 is also expressed in pre-adipocytes. 94) In isolated pre-adipocytes from mouse iBAT, activation of TRPV2 by its agonist (2APB or LPC) prevented differentiation of brown adipocytes in a dosedependent manner during the early stages of differentiation. 94) Mechanical force, which can activate TRPV2, also inhibited differentiation of brown adipocytes in a strength-dependent manner, and the effect was reversed by SKF96365.…”

“…94) In isolated pre-adipocytes from mouse iBAT, activation of TRPV2 by its agonist (2APB or LPC) prevented differentiation of brown adipocytes in a dosedependent manner during the early stages of differentiation. 94) Mechanical force, which can activate TRPV2, also inhibited differentiation of brown adipocytes in a strength-dependent manner, and the effect was reversed by SKF96365. TRPV2 agonist-induced prevention of differentiation can be blocked by the calcineurin inhibitors cyclosporine A and FK506, which are reported to recover the [Ca 2+ ] i -induced impairment of differentiation in 3T3-L1 cells.…”

TRPV2 regulates BAT thermogenesis and differentiation

“…Moreover, the expression of TRPV2 was significantly increased in differentiated brown adipocytes compared with preadipocytes at mRNA, protein and functional levels. 7 Therefore, we hypothesized that TRPV2 plays significant roles in BAT thermogenesis and differentiation (Fig. 1).…”

“…Importantly, brown adipocyte differentiation was facilitated in cells from TRPV2KO mice. TRPV2-mediated inhibition of brown adipocyte differentiation was recovered by a calcineurin inhibitor, FK506 or cyclosporine A, 7 suggesting the involvement of a calcineurin-dependent pathway in the process. Interestingly, TRPV2-dependent inhibition of mouse brown adipocyte differentiation occurred only in the early stages of differentiation (differentiation day 0-3) and not in the late stages (differentiation day 4-6).…”