Human 'brite/beige' adipocytes develop from capillary networks, and their implantation improves metabolic homeostasis in mice


Uncoupling protein 1 (UCP1) is highly expressed in brown adipose tissue, where it generates heat by uncoupling electron transport from ATP production. UCP1 is also found outside classical brown adipose tissue depots1,2,3,4, in adipocytes that are termed 'brite' (brown-in-white) or 'beige'. In humans, the presence of brite or beige (brite/beige) adipocytes is correlated with a lean, metabolically healthy phenotype5,6,7,8, but whether a causal relationship exists is not clear. Here we report that human brite/beige adipocyte progenitors proliferate in response to pro-angiogenic factors, in association with expanding capillary networks. Adipocytes formed from these progenitors transform in response to adenylate cyclase activation from being UCP1 negative to being UCP1 positive, which is a defining feature of the beige/brite phenotype, while displaying uncoupled respiration. When implanted into normal chow-fed, or into high-fat diet (HFD)-fed, glucose-intolerant NOD-scid IL2rgnull (NSG) mice, brite/beige adipocytes activated in vitro enhance systemic glucose tolerance. These adipocytes express neuroendocrine and secreted factors, including the pro-protein convertase PCSK1, which is strongly associated with human obesity. Pro-angiogenic conditions therefore drive the proliferation of human beige/brite adipocyte progenitors, and activated beige/brite adipocytes can affect systemic glucose homeostasis, potentially through a neuroendocrine mechanism.

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Figure 1: The proliferation of human adipogenic precursors requires angiogenesis.
Figure 2: The induction of a human brite/beige phenotype in adipocytes derived from capillary networks.
Figure 3: Characteristics and metabolic effects of human brite/beige adipocytes derived from capillary networks.
Figure 4: Mechanism for metabolic effects of human brite/beige adipocytes.

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This study was funded by US National Institutes of Health grants R01DK089101 (to S.C.), R24OD018259 (to M.A.B.), R01DK089185 (to M.P.C.), R01-DK080756, R01-DK079999, R24-DK090963 and U24-DK093000 (all to J.K.K.), and American Heart Association grant 12FTF11260010 (to T.F.). The authors acknowledge the use of the University of Massachusetts (UMASS) Flow Cytometry Core, the UMASS Genomics Core, the UMASS Mouse Phenotyping Center and the UMASS Morphology Core for conducting these studies.

Author information

S.Y.M., S.C., M.A.B. and M.P.C. designed the experiments; S.Y.M. and R.R.-R. obtained adipose tissue, generated cells and performed experiments on cells; J.K. and S.Y.M. performed experiments on mice; A.B., M.N., T.F. and M.P.C. obtained and analyzed perivascular adipose tissue samples; J.H.K., H.-L.N. and J.K.K. performed and analyzed metabolic phenotyping experiments. S.Y.M. and S.C. wrote the manuscript. All authors contributed to editing the manuscript. S.C. managed the project.

Correspondence to Silvia Corvera.

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Min, S., Kady, J., Nam, M. et al. Human 'brite/beige' adipocytes develop from capillary networks, and their implantation improves metabolic homeostasis in mice. Nat Med 22, 312–318 (2016).

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