123 Fibroblast growth factor 21 (FGF21) improves insulin action in obese sheep.

Abstract Insulin resistance (IR) is a fundamental mechanism regulating nutrient partitioning in ruminants. IR promotes the diversion of maternal nutrients toward fetal growth in late pregnant ewes but can become excessive and increase susceptibility to pregnancy toxemia in obese ewes. The novel hormone fibroblast growth factor 21 (FGF21) has been shown to act as an insulin-sensitizing hormone in rodents and non-human primates, but its effects in ruminants experiencing IR remain unclear. This study aimed to assess whether FGF21 can improve insulin action in ewes experiencing insulin resistance as a consequence of obesity. To create groups differing in fatness, twelve non-pregnant, non-lactating Finn × Dorset ewes were assigned to either a restricted or unrestricted feeding regimen for 48 weeks. Initial body weight (55.0±1.3 kg) and subcutaneous backfat thickness (4.9±0.2 mm) were similar across groups. Over the next 48 weeks, the unrestricted group became obese, gaining significantly more body weight (55 vs. 9 kg; P < 0.01) and subcutaneous backfat thickness (7 vs. 0 mm; P < 0.01) than the lean restricted group. Ewes from each group were then used in a single reversal design with treatment and intervening periods of 7 days each; both groups were fed at 1.1 times their individual maintenance energy requirements during the experimental periods. Treatments were daily subcutaneous injections of excipient or human FGF21 (12.5 mg/kg of metabolic body weight). Obese ewes experienced marked insulin resistance, with 3.3-fold higher plasma insulin and 1.9-fold higher free fatty acids (P < 0.01), along with impaired glucose disposal during glucose and insulin tolerance tests (P ≤ 0.05). FGF21 treatment reduced plasma glucose irrespective of fatness (P = 0.02). FGF21 treatment progressively decreased plasma insulin in obese ewes (FGF21 × Day,P = 0.02) but had no effect in lean ewes. FGF21 reduced the insulin response area in both lean and obese ewes during glucose tolerance tests (P < 0.01) and increased insulin-dependent glucose disposal irrespective of fatness (P = 0.04) during insulin tolerance tests. FGF21 effects were associated with a progressive increase in plasma concentration of the insulin-sensitizing hormone adiponectin in lean ewes but not in obese ewes (FGF21 × Fatness × Day, P = 0.05). These findings confirm the ability of FGF21 to alleviate insulin resistance in ruminants and show that the insulin-sensitizing effects of FGF21 do not require increased plasma adiponectin. Funding Sources: The CNPq award 201955/2017-2 to ACRS and NIFA-USDA award 7005434 to YRB.