Project description:Increases in organismal energy expenditure, as during cold exposure or exercise training, can improve metabolic health. This process is dependent also on brown adipose tissue (BAT) thermogenesis in mice and humans. Understanding and harnessing the molecular circuits activating BAT function is thus of great interest to devise novel approaches to counteract obesity and type 2 diabetes (T2D). In contrast to protein-coding genes, the role of long noncoding RNAs (lncRNAs) during BAT differentiation and function remains poorly understood. To address this, we performed RNA-Seq and identified the maternal allele-specific (imprinted) lncRNA H19 increased upon cold-mediated BAT activation and decreased upon chronic diet-induced obesity (DIO) BAT dysfunction. An inverse correlation of H19 expression with body-mass indices (BMI) was observed in a cohort of >160 lean and obese humans. H19 silencing impaired adipogenesis and oxidative metabolism in brown but not white adipocytes, while H19 gain-of-function increased nutrient oxidation and mitochondrial respiration, thus supporting a BAT-regulatory role for H19. In vivo H19 overexpression protected against DIO, improved insulin sensitivity and rescued DIO-mediated defects in energy expenditure in conjunction with improved mitochondrial biogenesis. In contrast, BAT-selective H19 loss decreased energy dissipation and sensitized towards high fat diet-induced body weight gains. When investigating other parent-of-origin specific, monoallelically expressed genes, we strikingly observed that paternally expressed genes (PEGs) were largely absent from BAT and coordinately downregulated during brown adipogenesis, whilst the same gene set was robustly expressed in white fat stores, a phenomenon not observed for maternally expressed genes (MEGs). Using H19 loss- and gain-of-function in primary adipocytes, we demonstrate that H19 acts as ‘PEG gatekeeper’ in brown, not white adipocytes, potentially due to recruitment of PEG-inactivating H19-MBD1 complexes in mature brown adipocytes. The exclusive PEG expression in white adipose tissuer could underly the observed susceptibility of mice exhibiting high PEG abundances towards DIO-evoked weight gain. Collectively, we here define novel roles for the imprinted lncRNA H19 in brown adipocyte differentiation and function in vitro, control of energy expenditure in vivo and repression of paternal allele-specific gene expression in BAT. This has far-reaching implications for our understanding of how monoallelical gene expression affects metabolic eustasis in both rodent models and, potentially, human patients.

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Uncoupling Metabolic Health from Thermogenesis via BCAA Flux in Brown Fat

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