Human thermogenic adipocyte regulation by the long noncoding RNA LINC00473

Human thermogenic adipose tissue mitigates metabolic disease, thus raising much interest in understanding its development and function. Here, we show that human thermogenic adipocytes specifically express a primate-specific long noncoding RNA (lncRNA), LINC00473, which is highly correlated with UCP1 expression and is decreased in obesity and type-2 diabetes. LINC00473 is detected in progenitor cells, and increases following differentiation and in response to cyclic AMP (cAMP). In contrast to other known adipocyte long intergenic noncoding RNAs, LINC00473 shuttles out of the nucleus, colocalizes and can be cross-linked to mitochondrial and lipid droplet proteins. Up- or downregulation of LINC00473 results in reciprocal alterations in lipolysis, respiration and transcription of genes associated with mitochondrial oxidative metabolism. Depletion of PLIN1 results in impaired cAMP-responsive LINC00473 expression and lipolysis, indicating bidirectional interactions among PLIN1, LINC00473 and mitochondrial oxidative functions. Thus, we suggest that LINC00473 is a key regulator of human thermogenic adipocyte function and reveal a role for a lncRNA in interorganelle communication and human energy metabolism.