TRPV4 modulation affects mitochondrial parameters in adipocytes and its inhibition upregulates lipid accumulation

Abstract

Enhanced lipid-droplet formation by adipocytes is a complex process and relevant for obesity. Using knock-out animals, involvement of TRPV4, a thermosensitive ion channel in the obesity has been proposed. However, exact role/s of TRPV4 in adipogenesis and obesity remain unclear and contradictory. Here we used in vitro culture of 3T3L-1 preadipocytes and primary murine-mesenchymal stem cells as model systems, and a series of live-cell-imaging to analyse the direct involvement of TRPV4 exclusively at the adipocytes that are free from other complex signalling as expected in in-vivo condition. Functional TRPV4 is endogenously expressed in pre- and in mature-adipocytes. Pharmacological inhibition of TRPV4 enhances differentiation of preadipocytes to mature adipocytes, increases expression of adipogenic and lipogenic genes, enhances cholesterol, promotes bigger lipid-droplet formation and reduces the lipid droplet temperature. TRPV4 regulates mitochondrial-temperature, Ca2+-load, ATP, superoxides, cardiolipin, membrane potential ({Delta}{Psi}m), and lipid-mitochondrial contact sites. TRPV4 also regulates the extent of actin fibres, affecting the cells mechanosensing ability. These findings link TRPV4-mediated mitochondrial changes in the context of lipid-droplet formation involved in adipogenesis and confirms the direct involvement of TRPV4 in adipogenesis. These findings may have broad implication in treating adipogenesis and obesity in future. Summary StatementThermosensitive ion channel TRPV4 regulates adipogenesis and changes mitochondria metabolism to facilitate bigger lipid droplet formation