The Notch-Pdgfrβ axis suppresses brown adipocyte progenitor differentiation in early postnatal mice

Abstract

De novo brown adipogenesis holds potential in combating the epidemics of obesity and diabetes. However, the identity of brown adipocyte progenitor cells (APCs) and their regulation have not been extensively studied. Here through in vivo lineage tracing, we observed that PDGFR beta+ pericytes give rise to developmental brown adipocytes, but not to those in adult homeostasis. In contrast, TBX18+ pericytes contribute to brown adipogenesis throughout both developmental and adult stages, though in a depot-specific manner. Mechanistically, Notch inhibition in PDGFR beta+ pericytes promotes brown adipogenesis through the downregulation of PDGFRβ. Furthermore, inhibition of Notch signaling in PDGFR beta+ pericytes mitigates HFHS (high-fat, high-sucrose) induced glucose and metabolic impairment in both developmental and adult stages. Collectively, these findings show that the Notch/PDGFR beta axis negatively regulates developmental brown adipogenesis, and its repression promotes brown adipose tissue expansion and improves metabolic health.

Pericytes as the Orchestrators of Vasculature and Adipogenesis

“…Moreover, these cells demonstrate the ability to differentiate into beige adipocytes in small clusters under prolonged cold exposure for two weeks; of note, this occurs in multiple waves depending on the extent and time course of cold stress [14]. A recent study focusing on BAT demonstrated that PDGFRβ + PCs gave rise to brown adipocytes at an early stage, but not in adulthood [15].…”

“…Likewise, another study demonstrated that TBX18 plays a minor role in de novo beige adipogenesis [54]. However, in BAT, TBX18 + PCs act as progenitors of brown adipocytes in multiple regions, such as thoracic perivascular and supraclavicular depots, but not in intrascapular and periaortic regions, suggesting that TBX18 + PCs contribute to brown adipocytes in a depot-specific manner [15].…”

“…It has been challenging to define PCs by a particular molecular marker due to the fact that PC subtypes vary across tissues [6][7][8][9], coupled with differences in the characteristics, functions, and locations of this cell population in a tissue-dependent manner [10]. For example, platelet-derived growth factor receptor-beta (PDGFRβ) [11][12][13][14][15], nerve/glial antigen 2 (NG2, also known as chondroitin sulfate proteoglycan 4, CSPG4) [12,16,17], clusters of differentiation 146 (CD146) [12,[18][19][20][21][22], T-box18 (TBX18) [15], α-smooth muscle actin (α-SMA) [10,23], and NESTIN [24,25] are commonly used as PC markers in most of the tissues. However, other tissue-specific markers were also proposed by a single-cell transcriptome analytic study: such as Kcnk3 in the lung, Rgs4 in the heart, myosin heavy chain 11 (Myh11) and Knca5 in the kidney, Pcp4l1 in the bladder, and Higd1b in the lung and the heart [26].…”