Unwiring the transcriptional heat circuit.

Mature adipocytes are postmitotic (1), and therefore development of adipocytes requires the proliferation and differentiation of progenitor cells into mature adipocytes. The identity of adipose precursor cells and the molecular mechanisms that control their proliferation and differentiation are only partially understood. Brown adipose tissue (BAT) is specialized for energy expenditure through a process mediated by uncoupling protein 1 (UCP1) that uncouples respiration from ATP synthesis and generates heat (2). Current knowledge defines two types of thermogenic adipocytes based on their distinct origins, anatomical locations, and differential abilities to respond to stimuli. The classical brown adipocytes mainly develop during embryonic stage, form a discrete depot, and exert a high level of basal thermogenic capacity. The other type of brown fat-like cells, called beige or brite adipocytes, are dispersed in white adipose tissue (WAT) and are recruited and induced in response to certain stimuli. Although beige adipocytes also generate heat by UCP1-mediated proton leak, they arise from a myogenic factor 5-negative (Myf5) developmental lineage distinct from brown adipocytes, which develop from Myf5 progenitors (Fig. 1) (3, 4). Aside from the adrenergic pathways that activate thermogenesis in both brown and beige adipocytes, whether there exists a common factor that marks and specifies the fate of these thermo-competent cells remains unknown. In PNAS, Wang et al. (5) identify early B-cell factor 2 (Ebf2) as a marker that specifies the brown and beige adipocyte lineage from muscle, dermal, and white adipocyte lineages and provide new insight into transcriptional targets of Ebf2 that may play a role in activating the thermogenic gene program. Ebf proteins are members of the helix– loop–helix transcription factors originally identified in mouse B-lymphocytes (6). Although it belongs to the Ebf family of proteins, Ebf2 is not expressed in mature B cells; rather, it is abundantly expressed in adipocytes, neurons, and immature osteoblasts (7–9). Ebf2 has been shown to play a role in establishing the osteoblast niche for hematopoiesis (10), regulating somite development (11), and initiating white adipocyte differentiation (12). Recently, the same group of authors discovered that Ebf2 cooperates with peroxisome proliferator-activated recep=tor-γ (PPARγ) to regulate the expression of brown adipocyte-selective genes in classical brown adipocytes (13). In the current study, Wang et al. (5) use an unbiased approach to search for genes that mark committed brown fat precursors and the results lead them back to Ebf2. Interestingly, Ebf2 not only determines the identity of the classical brown fat cells, but also marks the beige fat progenitors present in WAT. Moreover, Ebf2 serves as a functional determinant for both brown and beige adipocytes and poises the precursor cells to become thermogenically competent (Fig. 1). Taken together, these results allow for the construction of a lineage roadmap that highlights platelet-derived growth factor receptor-α (PDGFrα) expression as key intersection in a common adipogenic differentiation. Furthermore, Ebf2 expression is common to different lineages that share thermogenic capacity. A key technical advancement in the study of Wang et al. (5) is the ability to sort cells with white, brown, and beige adipogenic potential from one another using Myf5-lineage tracing coupled with the Ebf2 GFP reporter. Although brown and beige adipocytes are qualitatively similar in that they both expend energy in the form of heat for thermoregulation, the quantitative functional difference between these cells types can now be assessed. Wang et al. (5) investigated changes in gene transcription in these different cell types to Adipogenic precursor cell (PDGFr +) Dermo1