Insulin-sensitizing effects of fibroblast growth factor-21 in underfed sheep.

Reversal of insulin resistance by fibroblast growth factor-21(FGF21) in rodent and non-human primate models of obesity and in well-fed (WF) sheep was associated with increased production of the insulin-sensitizing hormone adiponectin. In contrast, FGF21 therapy failed to increase plasma adiponectin and improve insulin action in energy-deficient ruminants facing metabolically demanding states such as early lactation dairy cows. The goal of the study was to test the hypothesis that FGF21 is unable to improve insulin action in energy-deficient ruminants as a consequence of its failure to increase plasma adiponectin. Non-pregnant, non-lactating ewes were treated for 12 d with FGF21 or excipient when WF (2-fold of maintenance energy requirement, n = 4) or underfed (UF; 0.5-fold of maintenance energy requirement, n = 4). Plasma variables were measured as indices of insulin action (glucose, insulin, and adiponectin), lipolysis (fatty acids), and ketogenesis (β-hydroxybutyrate) on days 1, 4, 7, 10, and 12 of treatment. The effect of treatments on insulin action was assessed by measuring glucose disposal during insulin tolerance tests on day 10 and glucose tolerance tests on day 11. Quantitative RT-PCR was used to measure expression of genes mediating FGF21 effects in adipose tissue. Underfed ewes lost weight (energy balance, EB, P < 0.01) and had reduced plasma glucose (EB, P = 0.04) and insulin (EB × Day, P = 0.01), confirming negative EB. In UF ewes, FGF21 retained the ability to reduce plasma glucose (FGF21, P = 0.02) but not plasma insulin. FGF21 improved insulin action in both WF and UF ewes during glucose (insulin response area; FGF21, P = 0.02) and insulin tolerance tests (FGF21, P = 0.04) and did so in the absence of increased plasma adiponectin in UF ewes. Underfeeding reduced adipose tissue expression of the FGF21 co-receptor β-Klotho (EB, P < 0.01) and attenuated FGF21 stimulation of the FGF-responsive genes SPRY4 (EB × FGF21, P = 0.07) and DUSP4 (EB × FGF21, P = 0.02). FGF21 failed to increase adiponectin mRNA expression at both feeding levels. FGF21 had no effect on plasma fatty acids but reduced plasma β-hydroxybutyrate in UF ewes (EB × FGF21, P = 0.02). These data show that energy insufficiency alone does not prevent FGF21 improvement of insulin action in ruminants and that increased adiponectin production is not necessary for FGF21 insulin-sensitizing effects.