HAND2 is a novel obesity-linked adipogenic transcription factor regulated by glucocorticoid signaling.
Adipocytes are critical cornerstones of energy metabolism. While obesity-induced adipocyte dysfunction is associated with insulin resistance and systemic metabolic disturbances, adipogenesis, the formation of new adipocytes and healthy adipose tissue expansion are associated with metabolic benefits. Understanding the molecular mechanisms governing adipogenesis is of great clinical potential to efficiently restore metabolic health in obesity. Here we show that Heart-and neural crest derivatives-expressed protein 2 (HAND2) is an obesity-linked adipocyte transcription factor regulated by glucocorticoids and required for adipocyte differentiation in vitro. In a large cohort of humans with obesity, white adipose tissue (WAT) HAND2expression was correlated to body-mass-index (BMI). The HAND2gene was enriched in white adipocytes, induced early in differentiation and respondedto dexamethasone, a typical glucocorticoid receptor (GR, encoded by NR3C1) agonist. Silencing of NR3C1in human multipotent adipose-derivedstem cells (hMADS) or deletion of GR in a transgenic conditional mouse model results in diminished HAND2expression, establishing that adipocyte HAND2 is regulated by glucocorticoids via GR in vitroand in vivo. Using a combinatorial RNAseq approach we identified gene clustersregulated by the GR-HAND2 pathway. Interestingly, silencing of HAND2impairedadipocyte differentiation in hMADS and primary mouse adipocytes. However, a conditional adipocyte Hand2deletion mouse model using Cre under control of theAdipoqpromoter did not mirror these effectson adipose tissue differentiation, indicating thatHand2 was required at stagespriortoAdipoq expression.In summary, our study identifies HAND2 as a novel obesity-linked adipocyte transcription factor, highlighting new mechanisms of GR-dependent adipogenesis in human and mice.
Institute of Experimental Genetics (IEG)
Research Unit Analytical Pathology (AAP)
Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)