PRDM16 controls a brown fat/skeletal muscle switch

Abstract

Summary Brown fat can increase energy expenditure and protect against obesity through a specialized program of uncoupled respiration. We show here by in vivo fate mapping that brown but not white fat cells arise from precursors that express myf5, a gene previously thought to be expressed only in the myogenic lineage. Notably, the transcriptional regulator, PRDM16 controls a bidirectional cell fate switch between skeletal myoblasts and brown fat cells. Loss of PRDM16 from brown fat precursors causes a loss of brown fat characteristics and promotes muscle differentiation. Conversely, ectopic expression of PRDM16 in myoblasts induces their differentiation into brown fat cells. PRDM16 stimulates brown adipogenesis by binding to PPARγ and activating its transcriptional function. Finally, PRDM16-deficient brown fat displays an abnormal morphology, reduced thermogenic gene expression and elevated expression of muscle-specific genes. Taken together, these data indicate that PRDM16 specifies the brown fat lineage from a progenitor that expresses myoblast markers and is not involved in white adipogenesis.

Uncoupling protein 1 expression in adipocytes derived from skeletal muscle fibro/adipogenic progenitors is under genetic and hormonal control

“…Previous studies claimed that MPs are able to differentiate into white46, 47, 48 or brown‐like adipocytes26, 27 under certain conditions. However, most of these studies relied on single muscle fibre isolations46, 47, 48 or on pre‐plating of collagenase‐digested tissue47 to obtain the progenitor populations, which could potentially result in the isolation of non‐myogenic, interstitial cells surrounding myofibers.…”

“…Seale et al 26. have shown that primary myoblasts isolated from newborn mice are able to differentiate into brown adipocytes when expression of the transcription factor PRDM16 is induced.…”

Promotion of lipid storage rather than of thermogenic competence by fetal versus newborn calf serum in primary cultures of brown adipocytes

“…Again it should not be surprising that acquirement of thermogenic competence is not paralleled by promotion of adipose conversion, as the brown adipocytes studied here are of a different lineage from those giving rise to white adipocytes and are more related to muscle cells. 19,20,44,45 …”

“…However, in the early phases of differentiation, brown adipocytes express a series of myogenic genes, both transcription factors and structural proteins, 19 and the lineage of classical brown adipocytes is closely related to that of skeletal muscle. 20 Thus, acquisition of an adipocyte phenotype may not indicate progression to fully differentiated brown adipocyte characteristics. As the myogenic gene expression is transient during brown adipocyte development, myogenic genes cannot be chosen as differentiation markers.…”

Foetal bovine intermuscular adipose tissue exhibits histological and metabolic features of brown and white adipocytes during the last third of pregnancy

“…It is not yet clear whether intermuscular AT from appearance onwards expresses the cellular and molecular features of primarily brown AT or of both brown and white AT. This question is reinforced by the recent characterization in mice of two distinct adipose cell precursors: one committed in either brown adipocytes or muscular cells, and the second is committed in either brown or white adipocyte (Seale et al, 2008). These recent findings could prompt the hypothesis that intermuscular AT, due to its muscle-based anatomical location, has a cellular origin similar to that of muscle, consequently leading to different cellular and metabolic features to those reported for perirenal AT during foetal life.…”