Bone morphogenetic proteins 4 and 7 increase human white and brown adipocyte thermogenic capacity

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Abstract

Adipocytes exist along a functional spectrum: white adipocytes are energy storing, and brown adipocytes have thermogenic capacity such that activation may counteract obesity-related disease. In between are UCP1-expressing beige adipocytes, which can transition between these two energetic states. We previously showed that bone morphogenetic protein 7 (BMP7), a member of the TGF-β superfamily, enables differentiation of brown preadipocytes to mature thermogenic cells. To see whether immortalized, clonal human white and brown preadipocytes (hWAs and hBAs, respectively) would become more thermogenic in response to BMP exposure, we treated them with BMP7 or BMP4 for the first 7 days of a 30-day differentiation protocol. In hBAs, absence of either BMP7 or BMP4 led to lower expression of brown-specific markers and oxygen consumption relative to 7 days with either BMP. hWAs treated for 7 days with either BMP did not increase expression of thermogenic protein UCP1 nor induce a brown-like transcription profile. However, BMP-treated hWAs produced adipocytes that had higher basal and drug-induced maximal oxygen consumption, which was UCP1-independent and due substantially to the futile creatine cycle. Our results demonstrate that energetically quiescent hWAs can be pushed into an energy-expending phenotype without transdifferentiation into beige adipocytes, providing a new approach to treat obesity-related metabolic disease.

Authors

Kelly T. Long, Cheryl Cero, Sahara L. Ali, Nhuquynh Nguyen, Adrienne R. Guarnieri, Ju Hee Kim, Young Jae Bahn, Jurgen Heymann, Jonathan M. Dreyfuss, Sushil G. Rane, Yu-Hua Tseng, Aaron M. Cypess