UCP1-Independent Signaling Involving in Tibetan Pig Inguinal Adipocytes Provide New Insights into Adaptive Thermogenesis.

Tibetan pigs exhibit heritable adaptations to be cold resistant, even in the absence of key thermogenic genes such as UCP1, leaving the mechanism of adaptive thermogenesis remains further research. Here, we reported that Tibetan pigs exist functional beige adipocytes in inguinal adipose tissue, and RNA-seq analysis found that genes involved in UCP1-independent thermogenic pathways were included in these most highly upregulated transcripts. Enhanced calcium cycling by activation of a1-adrenergic receptors stimulates UCP1-independent thermogenesis in beige adipocytes involving RYR3, CASQ1 and ITPR3. Besides, inhibition of RYR3, CASQ1, or ITPR3 expression all affects the calcium ion cycling. However, RYR3-mediated calcium cycling displayed higher requirement in inguinal adipocytes thermogenesis and mitochondrial respiration from Tibetan pigs. Calcium cycling and creatine cycling converge to control UCP1-independent thermogenesis. And there are multiple mechanisms contributing to the thermogenic phenotype in inguinal fat of Tibetan pigs. Our study provides novel insights into the thermogenic pathways implicated in cold adaptation throughout mammalian evolution, particularly noteworthy given the loss of the UCP1 gene in pigs.