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

Abstract

Oestrogen, often via oestrogen receptor alpha (ERα) signalling, regulates metabolic physiology, highlighted by post-menopausal temperature dysregulation (hot flashes), glucose intolerance, increased appetite and reduced metabolic rate. Here we show that ERα signalling has a role in adipose lineage specification in mice. ERα regulates adipose progenitor identity and potency, promoting white adipogenic lineage commitment. White adipose progenitors lacking ERα reprogramme and enter into smooth muscle and brown adipogenic fates. Mechanistic studies highlight a TGFβ programme involved in progenitor reprogramming downstream of ERα signalling. The observed reprogramming has profound metabolic outcomes; both female and male adipose-lineage ERα-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 ERα cell autonomously regulates adipose lineage commitment, brown fat and smooth muscle cell formation, and systemic metabolism, in a manner relevant to prevalent metabolic diseases.

Estrogen Receptor α and β in Mouse: Adipose-Derived Stem Cell Proliferation, Migration, and Brown Adipogenesis In Vitro

“…The underlying mechanism is probably based on TGFβ signaling which is involved in progenitor reprogramming downstream of the ERα signal pathway [51]. The authors' conclusion of that study has similarities with ours but differences still remain.…”

Membrane and nuclear estrogen receptor a collaborate to suppress adipogenesis but not triglyceride content

“…At the level of adipocyte development, E2 and genistein act through undetermined ER isoforms to suppress human bone marrow progenitor commitment to the adipocyte lineage that underlies visceral fat development (7). Recent work on adipose niche progenitors suggests that direct ERα action promotes subcutaneous fat development that is considered metabolically advantageous (8). TGF‐β has been implicated in the effects of E2 on both bone marrow and adipocyte niche sources of stem/progenitor cells (7, 8), but additional mechanisms are likely to be important and are poorly understood.…”

“…Recent work on adipose niche progenitors suggests that direct ERα action promotes subcutaneous fat development that is considered metabolically advantageous (8). TGF‐β has been implicated in the effects of E2 on both bone marrow and adipocyte niche sources of stem/progenitor cells (7, 8), but additional mechanisms are likely to be important and are poorly understood. Furthermore, the functions of various ER subcellular pools that may regulate adipose progenitor differentiation are unknown.…”

Adipocyte biology: It is time to upgrade to a new model

“…In contrast, work in an adipose lineage-specific ERα KO mouse model showed that ERα signaling promoted the commitment of progenitor cells to the white adipocyte lineage (Lapid et al, 2014). Other studies have also demonstrated proadipogenic effects for estrogen, although Androgen receptors are expressed at higher levels in visceralderived ASCs than scASCs, in both rats and humans (Dieudonne et al, 1995(Dieudonne et al, , 1998.…”