Knockout of the X-linked Fgf13 in the Hypothalamic Paraventricular Nucleus Impairs Sympathetic Output to Brown Fat and Causes Obesity

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 degrees C showed hyperactivity accompanying reduced core temperature and obesity when housed at 30 degrees C. Those heterozygous knockouts showed defects in thermogenesis even at 30 degrees 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 degrees C, and we detected an intact brown fat response through exogenous beta 3 agonist stimulation, suggesting a defect in sympathetic drive to brown adipose tissue. In contrast, hypothalamic-specific ablation of Fgf13 recapitulated weight gain at 30 degrees 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.