Ramos Dos Santos Antonio Carlos, McGuckin Molly M, Giesy Sarah L, Boisclair Yves R
Department of Animal Science, College of Agriculture and Life Sciences, Cornell University, Ithaca, NY 14853, USA.
J Anim Sci. 2025 Jan 4;103. doi: 10.1093/jas/skaf217.
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.
在肥胖的啮齿动物和非人类灵长类动物模型以及营养良好（WF）的绵羊中，成纤维细胞生长因子21（FGF21）逆转胰岛素抵抗与胰岛素增敏激素脂联素的产生增加有关。相比之下，在面临代谢需求状态（如泌乳早期奶牛）的能量缺乏反刍动物中，FGF21治疗未能增加血浆脂联素并改善胰岛素作用。本研究的目的是检验以下假设：由于FGF21未能增加血浆脂联素，因此无法改善能量缺乏反刍动物的胰岛素作用。非妊娠、非泌乳母羊在WF（维持能量需求的2倍，n = 4）或进食不足（UF；维持能量需求的0.5倍，n = 4）时，用FGF21或赋形剂治疗12天。在治疗的第1、4、7, 10和12天，测量血浆变量作为胰岛素作用（葡萄糖、胰岛素和脂联素）、脂肪分解（脂肪酸）和生酮作用（β-羟基丁酸）的指标。通过在第10天的胰岛素耐量试验和第11天的葡萄糖耐量试验中测量葡萄糖处置来评估治疗对胰岛素作用的影响。定量RT-PCR用于测量介导FGF21在脂肪组织中作用的基因表达。进食不足的母羊体重减轻（能量平衡，EB，P < 0.01），血浆葡萄糖（EB，P = 0.04）和胰岛素降低（EB×天数，P = 0.01），证实为负EB。在UF母羊中，FGF21保留了降低血浆葡萄糖的能力（FGF21，P = 0.02），但不能降低血浆胰岛素。在葡萄糖（胰岛素反应面积；FGF21，P = 0.02）和胰岛素耐量试验（FGF21，P = 0.04）期间，FGF21改善了WF和UF母羊的胰岛素作用，并且在UF母羊血浆脂联素未增加的情况下也是如此。进食不足降低了FGF21共受体β-klotho在脂肪组织中的表达（EB，P < 0.01），并减弱了FGF21对FGF反应基因SPRY4（EB×FGF21，P = 0.07）和DUSP4（EB×FGF21，P = 0.02）的刺激。在两种喂养水平下，FGF21均未能增加脂联素mRNA表达。FGF21对血浆脂肪酸没有影响，但降低了UF母羊的血浆β-羟基丁酸（EB×FGF21，P = 0.02）。这些数据表明，仅能量不足并不能阻止FGF21改善反刍动物的胰岛素作用，并且脂联素产生增加对于FGF21的胰岛素增敏作用不是必需的。
