Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, 169 Newton Road, 3322 PBDB, Iowa City, IA, 52242, USA.
Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
Sci Rep. 2020 Nov 11;10(1):19521. doi: 10.1038/s41598-020-76593-2.
Alterations in macronutrient intake can have profound effects on energy intake and whole-body metabolism. For example, reducing protein intake increases energy expenditure, increases insulin sensitivity and decreases body weight in rodents. Fibroblast growth factor 21 (FGF21) signaling in the brain is necessary for the metabolic effects of dietary protein restriction and has more recently been proposed to promote protein preference. However, the neuron populations through which FGF21 elicits these effects are unknown. Here, we demonstrate that deletion of β-klotho in glutamatergic, but not GABAergic, neurons abrogated the effects of dietary protein restriction on reducing body weight, but not on improving insulin sensitivity in both diet-induced obese and lean mice. Specifically, FGF21 signaling in glutamatergic neurons is necessary for protection against body weight gain and induction of UCP1 in adipose tissues associated with dietary protein restriction. However, β-klotho expression in glutamatergic neurons was dispensable for the effects of dietary protein restriction to increase insulin sensitivity. In addition, we report that FGF21 administration does not alter protein preference, but instead promotes the foraging of other macronutrients primarily by suppressing simple sugar consumption. This work provides important new insights into the neural substrates and mechanisms behind the endocrine control of metabolism during dietary protein dilution.
宏量营养素摄入的改变会对能量摄入和全身代谢产生深远影响。例如，减少蛋白质摄入会增加能量消耗、提高胰岛素敏感性并降低啮齿动物的体重。脑内成纤维细胞生长因子 21（FGF21）信号对于饮食蛋白限制的代谢作用是必要的，并且最近有人提出它可以促进蛋白质偏好。然而，FGF21 引发这些作用的神经元群体尚不清楚。在这里，我们证明在谷氨酸能神经元而非 GABA 能神经元中删除β-klotho 可消除饮食蛋白限制对降低体重的影响，但不能消除肥胖和瘦小鼠中胰岛素敏感性的改善。具体而言，谷氨酸能神经元中的 FGF21 信号对于防止体重增加和与饮食蛋白限制相关的脂肪组织中 UCP1 的诱导是必需的。然而，谷氨酸能神经元中β-klotho 的表达对于饮食蛋白限制增加胰岛素敏感性的作用是可有可无的。此外，我们报告称，FGF21 的给药不会改变蛋白质偏好，而是通过主要抑制简单糖的消耗来促进其他宏量营养素的觅食。这项工作为饮食蛋白稀释时内分泌对代谢的控制的神经基础和机制提供了重要的新见解。
