(P06-011-24) The Role of FGF21 in High-Fat Diet-Induced Alterations in Brown Adipose Tissue Metabolism

Objectives: Brown adipose tissue (BAT) utilizes fuels like glucose and lipids to influence peripheral metabolism. High-fat diet (HFD) consumption induces insulin resistance and impaired fat oxidation in BAT. Pharmacologic levels of fibroblast growth factor 21 (FGF21) have been shown to activate BAT and increase BAT insulin signaling. We aimed to determine whether endogenous FGF21 protects BAT against HFD-induced impairments in BAT metabolism.

Methods: Five-to-six-week-old male wild-type (WT) and Fgf21 knockout (Fgf21^-/-) mice were fed a normal-fat (19% fat-derived kcal) or high-fat (60% fat-derived kcal) diet for five weeks. Fifteen minutes before sacrifice, vehicle (saline) or insulin (0.6 U/kg body weight) were given via I.P. injection. BAT, retroperitoneal white adipose tissue (rpWAT), epididymal WAT (eWAT), and liver were collected. Markers of insulin signaling, including Akt and GSK3β, and the thermogenic protein, uncoupling protein 1 (UCP1) were measured via Western blot. Insulin signaling data were analyzed by two-way ANOVA, and other measurements were analyzed by unpaired t test.

Results: The HFD increased body weight by 34% in WT mice and 31% in Fgf21^-/- mice. In both WT and Fgf21^-/- mice, the HFD significantly increased adiposity (p=0.0009, p=0.0054 respectively). Fgf21^-/- mice had increased liver to body weight ratio compared to WT mice (p= < 0.0001). HFD reduced UCP1 expression in BAT by 41%, but had no effect on BAT UCP1 expression in Fgf21^-/- mice. HFD impaired insulin signaling in BAT of WT mice. Insulin signaling in Fgf21^-/- mice is currently being measured; however, we hypothesize that Fgf21^-/- mice will have greater HFD-induced impairments in insulin signaling than WT mice.

Conclusions: Short-term HFD consumption impairs BAT metabolism, and preliminary data suggest that these impairments are not seen in mice lacking FGF21. Endogenous FGF21 may play an important role in protecting BAT from HFD- and obesity-induced alterations in BAT metabolism.

Funding Sources: Arnold and Mabel Beckman Foundation and the Center for Neuroinflammation and Cardiometabolic Diseases