White to brown fat phenotypic switch induced by genetic and environmental activation of a hypothalamic-adipocyte axis

Cell Metab. 2011 Sep 7;14(3):324-38. doi: 10.1016/j.cmet.2011.06.020.

Abstract

Living in an enriched environment with complex physical and social stimulation leads to improved cognitive and metabolic health. In white fat, enrichment induced the upregulation of the brown fat cell fate determining gene Prdm16, brown fat-specific markers, and genes involved in thermogenesis and β-adrenergic signaling. Moreover, pockets of cells with prototypical brown fat morphology and high UCP1 levels were observed in the white fat of enriched mice associated with resistance to diet-induced obesity. Hypothalamic overexpression of BDNF reproduced the enrichment-associated activation of the brown fat gene program and lean phenotype. Inhibition of BDNF signaling by genetic knockout or dominant-negative trkB reversed this phenotype. Our genetic and pharmacologic data suggest a mechanism whereby induction of hypothalamic BDNF expression in response to environmental stimuli leads to selective sympathoneural modulation of white fat to induce "browning" and increased energy dissipation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenoviridae
  • Adipocytes / cytology
  • Adipocytes / metabolism*
  • Adipose Tissue, Brown / cytology
  • Adipose Tissue, Brown / metabolism*
  • Adipose Tissue, White / cytology
  • Adipose Tissue, White / metabolism*
  • Animals
  • Brain-Derived Neurotrophic Factor / antagonists & inhibitors
  • Brain-Derived Neurotrophic Factor / deficiency
  • Brain-Derived Neurotrophic Factor / genetics
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Gene Knockout Techniques
  • Hypothalamus / cytology
  • Hypothalamus / metabolism*
  • Ion Channels / genetics
  • Ion Channels / metabolism
  • Male
  • Maze Learning
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / pharmacology
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Motor Activity / genetics
  • Obesity / genetics
  • Obesity / metabolism
  • Phenotype
  • Receptor, trkB / genetics
  • Receptor, trkB / metabolism
  • Thermogenesis / physiology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Uncoupling Protein 1

Substances

  • Brain-Derived Neurotrophic Factor
  • DNA-Binding Proteins
  • Ion Channels
  • MicroRNAs
  • Mitochondrial Proteins
  • Prdm16 protein, mouse
  • Transcription Factors
  • Ucp1 protein, mouse
  • Uncoupling Protein 1
  • Receptor, trkB