Fibroblast growth factor-21 improves insulin action in nonlactating ewes.

During metabolically demanding physiological states, ruminants and other mammals coordinate nutrient use among tissues by varying the set point of insulin action. This set point is regulated in part by metabolic hormones with some antagonizing (e.g., growth hormone and TNFα) and others potentiating (e.g., adiponectin) insulin action. Fibroblast growth factor-21 (FGF21) was recently identified as a sensitizing hormone in rodent and primate models of defective insulin action. FGF21 administration, however, failed to improve insulin action in dairy cows during the naturally occurring insulin resistance of lactation, raising the possibility that ruminants as a class of animals or lactation as a physiological state are unresponsive to FGF21. To start addressing this question, we asked whether FGF21 could improve insulin action in nonlactating ewes. Gene expression studies showed that the ovine FGF21 system resembles that of other species, with liver as the major site of FGF21 expression and adipose tissue as a target tissue based on high expression of the FGF21 receptor complex and activation of p44/42 extracellular signal-regulated kinase (ERK1/2) following exogenous FGF21 administration. FGF21 treatment for 13 days reduced plasma glucose and insulin over the entire treatment period and improved glucose disposal during a glucose tolerance test. FGF21 increased plasma adiponectin by day 3 of treatment but had no effect on the plasma concentrations of total, C16:0-, or C18:0-ceramide. Overall, these data confirm that the insulin-sensitizing effects of FGF21 are conserved in ruminants and raise the possibility that lactation is an FGF21-resistant state.

Effects of birth weight and dietary fat on intake, body composition, and plasma thyroxine in neonatal lambs.

Intrauterine growth restriction (IUGR) is often observed in one of the fetuses carried by well-fed prolific ewes. This condition is the result of an insufficient placental size to cover the nutritional needs of the fetus during the near exponential growth phase of the last trimester. After birth, these IUGR offspring have an elevated appetite and lower maintenance energy requirements, suggesting dysregulation of homeostatic systems governing energy metabolism. It is also unknown whether the consequent increase in fatness occurs similarly in both visceral and carcass fractions. To address these questions, lambs differing in birth size (BS, IUGR vs. Normal, 2.6 ± 0.05 vs. 4.2 ± 0.07 kg, P < 0.001) were offered unlimited amounts of a low fat [LF; 22% of dry matter (DM)] or a high fat (HF; 38% of DM) milk replacer and slaughtered on day 14 of postnatal age (n = 7 to 8 for each BS × Diet); a second group of IUGR lambs (n = 3 for each diet) was slaughtered when they reached 8.5 kg, corresponding to the weight of Normal lambs on day 14. When normalized to body weight (BW), the DM and energy intake of IUGR lambs were higher than those of Normal lambs over the first 14 d of life (BS, P < 0.01), but contrary to expectations, the HF diet did not exacerbate these effects of the IUGR condition. Intrauterine growth restricted lambs had increased viscera fat with both diets (BS and Diet, P < 0.05) but increased carcass fat only with the LF diet (BS × Diet, P = 0.08); the fatness promoting effect of the IUGR condition was increased in both body fractions when lamb groups were compared at the fixed BW of 8.5 kg. A subset of metabolic hormones was analyzed, including the metabolic rate-setting hormone thyroxine (T4) and its possible positive regulator leptin. Plasma T4 was lower in IUGR than in Normal lambs at birth (P < 0.05) but then disappeared by day 7 of postnatal life (BS × Day, P < 0.01). On the other hand, the HF diet had no effect on plasma T4 over the first 3 d but caused an increase, irrespective of BS by day 11 (Diet × Day, P < 0.001). Plasma leptin increased with dietary fat and time (P < 0.06) but bore no relation to the effects of BS or Diet on plasma T4. These data show that IUGR and Normal lambs are similarly unable to adjust caloric intake in early life and that the fatness promoting effects of the IUGR condition are more pronounced in the viscera than in the carcass. These data also reveal dynamic regulation of plasma T4 by BS and Diet in neonatal lambs.

Short- and long-term effects of leucine and branched-chain amino acid supplementation of a protein- and energy-reduced diet on muscle protein metabolism in neonatal pigs.

The objective of this study was to determine if enteral leucine or branched-chain amino acid (BCAA) supplementation increases muscle protein synthesis in neonates who consume less than their protein and energy requirements, and whether this increase is mediated via the upregulation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway or the decrease in muscle protein degradation signaling. Neonatal pigs were fed milk replacement diets containing reduced energy and protein (R), R supplemented with BCAA (RBCAA), R supplemented with leucine (RL), or complete protein and energy (CON) at 4-h intervals for 9 (n = 24) or 21 days (n = 22). On days 9 and 21, post-prandial plasma amino acids and insulin were measured at intervals for 4 h; muscle protein synthesis rate and activation of mTOR-related proteins were determined at 120 min post-feeding in muscle. For all parameters measured, the effects of diet were not different between day 9 or day 21. Compared to CON and R, plasma leucine and BCAA were higher (P ≤ 0.01) in RL- and RBCAA-fed pigs, respectively. Body weight gain, protein synthesis, and activation of S6 kinase (S6K1), 4E-binding protein (4EBP1), and eukaryotic initiation factor 4 complex (eIF4E·eIF4G) were decreased in RBCAA, RL, and R relative to CON (P < 0.01). RBCAA and RL upregulated (P ≤ 0.01) S6K1, 4EBP1, and eIF4E·eIF4G compared to R. In conclusion, when protein and energy are restricted, both leucine and BCAA supplementation increase mTOR activation, but do not enhance skeletal muscle protein synthesis and muscle growth in neonatal pigs.