Cell Metabolism
Volume 26, Issue 2, 1 August 2017, Pages 437-446.e5
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Short Article
Long-Term Cold Adaptation Does Not Require FGF21 or UCP1

https://doi.org/10.1016/j.cmet.2017.07.016Get rights and content
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Highlights

  • UCP1 and/or FGF21 are not required for metabolic homeostasis in chronic cold

  • Mitochondrial failure and inflammatory signals in UCP1-ablated BAT

  • FGF21-independent “browning” of white adipose tissue in the cold

  • Bioenergetic evaluation of “putative alternative heating pathways” in beige adipocytes

Summary

Brown adipose tissue (BAT)-dependent thermogenesis and its suggested augmenting hormone, FGF21, are potential therapeutic targets in current obesity and diabetes research. Here, we studied the role of UCP1 and FGF21 for metabolic homeostasis in the cold and dissected underlying molecular mechanisms using UCP1-FGF21 double-knockout mice. We report that neither UCP1 nor FGF21, nor even compensatory increases of FGF21 serum levels in UCP1 knockout mice, are required for defense of body temperature or for maintenance of energy metabolism and body weight. Remarkably, cold-induced browning of inguinal white adipose tissue (iWAT) is FGF21 independent. Global RNA sequencing reveals major changes in response to UCP1- but not FGF21-ablation in BAT, iWAT, and muscle. Markers of mitochondrial failure and inflammation are observed in BAT, but in particular the enhanced metabolic reprogramming in iWAT supports the thermogenic role of UCP1 and excludes an important thermogenic role of endogenous FGF21 in normal cold acclimation.

Keywords

adaptive thermogenesis
beige adipose tissue
browning
uncoupling protein
energy metabolism
endocrine cross talk
Pm20d1
cold exposure
mitochondrial respiration

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