Oestrogen signalling in white adipose progenitor cells inhibits differentiation into brown adipose and smooth muscle cells

Oestrogen, often via oestrogen receptor alpha (ER alpha) signalling, regulates metabolic physiology, highlighted by post-menopausal temperature dysregulation (hot flashes), glucose intolerance, increased appetite and reduced metabolic rate. Here we show that ERa signalling has a role in adipose lineage specification in mice. ER alpha regulates adipose progenitor identity and potency, promoting white adipogenic lineage commitment. White adipose progenitors lacking ERa reprogramme and enter into smooth muscle and brown adipogenic fates. Mechanistic studies highlight a TGF beta programme involved in progenitor reprogramming downstream of ER alpha signalling. The observed reprogramming has profound metabolic outcomes; both female and male adipose-lineage ER alpha-mutant mice are lean, have improved glucose sensitivity and are resistant to weight gain on a high-fat diet. Further, they are hypermetabolic, hyperphagic and hyperthermic, all consistent with a brown phenotype. Together, these findings indicate that ER alpha cell autonomously regulates adipose lineage commitment, brown fat and smooth muscle cell formation, and systemic metabolism, in a manner relevant to prevalent metabolic diseases.