Knockout of the X-linked Fgf13 in the hypothalamic paraventricular nucleus impairs sympathetic output to brown fat and causes obesity

FASEB J. 2019 Oct;33(10):11579-11594. doi: 10.1096/fj.201901178R. Epub 2019 Jul 24.

Abstract

Fibroblast growth factor (FGF)13, a nonsecreted, X-linked, FGF homologous factor, is differentially expressed in adipocytes in response to diet, yet Fgf13's role in metabolism has not been explored. Heterozygous Fgf13 knockouts fed normal chow and housed at 22°C showed hyperactivity accompanying reduced core temperature and obesity when housed at 30°C. Those heterozygous knockouts showed defects in thermogenesis even at 30°C and an inability to protect core temperature. Surprisingly, we detected trivial FGF13 in adipose of wild-type mice fed normal chow and no obesity in adipose-specific heterozygous knockouts housed at 30°C, and we detected an intact brown fat response through exogenous β3 agonist stimulation, suggesting a defect in sympathetic drive to brown adipose tissue. In contrast, hypothalamic-specific ablation of Fgf13 recapitulated weight gain at 30°C. Norepinephrine turnover in brown fat was reduced at both housing temperatures. Thus, our data suggest that impaired CNS regulation of sympathetic activation of brown fat underlies obesity and thermogenesis in Fgf13 heterozygous knockouts fed normal chow.-Sinden, D. S., Holman, C. D., Bare, C. J., Sun, X., Gade, A. R., Cohen, D. E., Pitt, G. S. Knockout of the X-linked Fgf13 in the hypothalamic paraventricular nucleus impairs sympathetic output to brown fat and causes obesity.

Keywords: FHF2; brown adipose tissue; fibroblast; growth factor homologous factor; thermogenesis.

Publication types

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

MeSH terms

  • Adipocytes / metabolism
  • Adipose Tissue, Brown / metabolism*
  • Adipose Tissue, White / metabolism
  • Adiposity / physiology
  • Animals
  • Diet, High-Fat / methods
  • Energy Metabolism / physiology
  • Female
  • Fibroblast Growth Factors / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity / metabolism*
  • Paraventricular Hypothalamic Nucleus / metabolism*
  • Thermogenesis / physiology
  • Weight Gain / physiology

Substances

  • fibroblast growth factor 13
  • Fibroblast Growth Factors