BMP7 Drives Human Adipogenic Stem Cells into Metabolically Active Beige Adipocytes

Abstract

Adult humans have a substantial amount of inducible-brown (or beige) fat, which is associated with increased energy expenditure and reduced weight gain via thermogenesis. Despite the identification of key regulators of beige adipogenesis, impacts of dietary factors on adaptive thermogenesis are largely unknown, partly due to a lack of validated human cell models. Bone morphogenetic protein 7 (BMP7) is known to promote brown adipogenesis in rodent and human progenitor cells. However, controversy still surrounds the cellular identity in BMP7-mediated transition of white to brown adipocytes. The aim of this study is to confirm BMP7-derived human adipocytes as a relevant in vitro model of human beige adipocyte by verifying the cellular lineage and metabolic activity. In this study, we hypothesized that pre-exposure of stromal vascular (SV) fraction of primary human adipogenic precursor cells (hASC) to BMP7 would convert metabolically active brown adipocytes. Our results showed that exposure of hASC to human BMP7 was associated with significant escalation of 1) UCP1 gene expression, a signature gene of brown adipocytes, 2) beige specific marker gene expression (i.e., CD137 and TMEM26), 3) glucose and fatty acid uptake, and 4) basal and cAMP-stimulated oxygen consumption rate compared to white adipocyte control. Taken together, we demonstrated that BMP7 mediates conversion of hASC into metabolically active beige adipocytes. By confirming the cellular identity and metabolic activity, this BMP7-induced human beige adipocytes from hASC should aid in the discovery and assessment of bioactive molecules to promote adaptive thermogenesis.

Inhibitory Effects of Toll-Like Receptor 4, NLRP3 Inflammasome, and Interleukin-1β on White Adipocyte Browning

“…All protocols and procedures were approved by the Institutional Review Board at the University of Nebraska-Lincoln and King Saud University. Isolation of human adipose-derived stem cells ( h ASC) and differentiation of adipocytes were conducted as we described previously [18]. For cultures of primary mouse adipocytes, subcutaneous fat-derived stem cells were used and differentiated as we described previously [13].…”

Role of Brown Fat in Lipoprotein Metabolism and Atherosclerosis

“…However, recent studies reported that stem cells from human WAT treated with the peroxisome proliferator-activated receptor-γ agonist rosiglitazone 79 or bone morphogenetic protein 7 80 easily differentiate toward beige adipocytes and markedly enhance oxygen consumption. In addition, bone morphogenetic protein 7-driven browning of adipocytes results in higher glucose and FA uptake than white adipocytes.…”

“…In addition, bone morphogenetic protein 7-driven browning of adipocytes results in higher glucose and FA uptake than white adipocytes. 80 Browning of WAT has therapeutic potential, as humans have large amounts of WAT that may be susceptible to browning. This is nicely illustrated by a markedly increased brown fat mass and energy expenditure in patients who have a pheochromocytoma, a catecholamine-producing neuroendocrine tumor.…”

Modulation of transforming growth factor-β/follistatin signaling and white adipose browning: therapeutic implications for obesity related disorders

“…Furthermore, lipoprotein lipase (LPL) expression in perivascular BAT depots surrounding the aorta is negatively correlated with plasma TG levels [57]. Stem cells derived from human WAT treated with with peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone or bone morphogenic protein 7 (BMP7) easily differentiate into beige adipocytes and have markedly enhanced oxygen consumption [58], [59]. In a recent report, thermogenic adipocytes were reported to promote HDL lipidome remodeling in humans after cold exposure irrespective of total plasma HDL-C concentrations [60].…”