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

Nat Med. 2016 Mar;22(3):312-8. doi: 10.1038/nm.4031. Epub 2016 Jan 25.

Abstract

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 depots, 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 phenotype, 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 IL2rg(null) (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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism*
  • Adipocytes / transplantation
  • Adipocytes, Brown / metabolism
  • Adipocytes, Brown / transplantation
  • Adipocytes, White / metabolism
  • Adipocytes, White / transplantation
  • Adult
  • Aged
  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Blood Glucose / metabolism*
  • Capillaries
  • Cell Transplantation
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Diet, High-Fat
  • Enkephalins / genetics
  • Enkephalins / metabolism
  • Female
  • Fluorescent Antibody Technique
  • Glucose Clamp Technique
  • Glucose Intolerance / metabolism*
  • Glucose Tolerance Test
  • Homeostasis
  • Humans
  • Integrin beta1 / genetics
  • Integrin beta1 / metabolism
  • Interleukin-33 / genetics
  • Interleukin-33 / metabolism
  • Iodide Peroxidase / genetics
  • Iodide Peroxidase / metabolism
  • Ion Channels / genetics
  • Ion Channels / metabolism
  • Male
  • Mice
  • Middle Aged
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Neovascularization, Physiologic*
  • Obesity / metabolism
  • Oxygen Consumption*
  • Polymerase Chain Reaction
  • Proprotein Convertase 1 / genetics
  • Proprotein Convertase 1 / metabolism
  • Protein Precursors / genetics
  • Protein Precursors / metabolism
  • Proteins
  • RNA, Messenger / metabolism*
  • Receptor, Platelet-Derived Growth Factor alpha / genetics
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Uncoupling Protein 1

Substances

  • Apoptosis Regulatory Proteins
  • Blood Glucose
  • CIDEA protein, human
  • DNA-Binding Proteins
  • Enkephalins
  • IL33 protein, human
  • Integrin beta1
  • Interleukin-33
  • Ion Channels
  • Mitochondrial Proteins
  • Protein Precursors
  • Proteins
  • RNA, Messenger
  • UCP1 protein, human
  • Ucp1 protein, mouse
  • Uncoupling Protein 1
  • ornithine decarboxylase antizyme
  • proenkephalin
  • iodothyronine deiodinase type II
  • Iodide Peroxidase
  • Receptor, Platelet-Derived Growth Factor alpha
  • PCSK1 protein, human
  • Proprotein Convertase 1