Human thermogenic adipocyte regulation by the long noncoding RNA LINC00473

• DOI: 10.1038/s42255-020-0205-x
• Publication Date: 2020-05-21T16:03:00Z
• Authors: Khanh-Van Tran; Erin L. Brown; Tiffany DeSouza; Naja Zenius Jespe...; Cecilie Nandrup-Bus; Qin Yang; Zinger Yang; Anand Desai; So Yun Min; Raziel Rojas-Rodr...; Morten Lundh; Amir Feizi; Hanni Willenbrock; Therese Juhlin La...; Mai Charlotte Kro...; Kimberly Malka; Anthony M. Mozzicato; Atul S. Deshmukh; Brice Emanuelli; Bente Klarlund Pe...; Timothy Fitzgibbons; Camilla Scheele; Silvia Corvera; Søren Nielsen
• Keywords: Adult; Male; 0301 basic medicine; Perilipin-1; brown; non-coding RNA; lipid droplet; Cell Communication; Fatty Acids, Nonesterified; adipocyte; Article; forskolin; norepinephrine; 03 medical and health sciences; Oxygen Consumption; fat; Adipocytes; Humans; Obesity; UMCCTS funding; Cells, Cultured; Aged; Aged, 80 and over; Cell Nucleus; brite; Lipid Droplets; Middle Aged; mitochondria; Diabetes Mellitus, Type 2; Gene Expression Regulation; lipolysis; beige; Female; RNA, Long Noncoding; Energy Metabolism; PLIN1; respiration

Human thermogenic adipose tissue mitigates metabolic disease, raising much interest in understanding its development and function. Here, we show that human thermogenic adipocytes specifically express a primate-specific long non-coding RNA, LINC00473 which is highly correlated with UCP1 expression and decreased in obesity and type-2 diabetes. LINC00473 is detected in progenitor cells, and increases upon differentiation and in response to cAMP. In contrast to other known adipocyte LincRNAs, LINC00473 shuttles out of the nucleus, colocalizes and can be crosslinked to mitochondrial and lipid droplet proteins. Up- or down- regulation 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 between PLIN1, LINC00473 and mitochondrial oxidative functions. Thus, we suggest that LINC00473 is a key regulator of human thermogenic adipocyte function, and reveals a role for a LincRNA in inter-organelle communication and human energy metabolism.