The Hypothalamic Glucagon-Like Peptide 1 Receptor Is Sufficient but Not Necessary for the Regulation of Energy Balance and Glucose Homeostasis in Mice.
The Hypothalamic Glucagon-Like Peptide 1 Receptor Is Sufficient but Not Necessary for the Regulation of Energy Balance and Glucose Homeostasis in Mice.
复制标题
下丘脑胰高血糖素样肽1受体足够，但对于调节小鼠的能量平衡和葡萄糖稳态不需要。
作者：
Burmeister MA;Ayala JE;Smouse H;Landivar-Rocha A;Brown JD;Drucker DJ;Stoffers DA;Sandoval DA;Seeley RJ;Ayala JE
下丘脑胰高血糖素样肽1（GLP-1）受体（GLP-1 R）的药理学激活可促进体重减轻并改善葡萄糖耐量。这表明下丘脑GLP-1 R是足够的，但未表明是否需要外源性GLP-1 R激动剂（GLP-1 RA）或内源性GLP-1对这些参数的影响。为了解决这个问题，我们将携带floxed Glp 1 r等位基因的小鼠与表达Nkx2.1-Cre的小鼠杂交，以敲低整个下丘脑的Glp 1 r表达（GLP-1 RKD ΔNkx2.1cre）。我们还产生了专门在两种GLP-1 RA反应性下丘脑进食核/细胞类型（室旁核（GLP-1 RKD Δ Sim 1 cre）和前阿黑皮素神经元（GLP-1 RKD ΔPOMCcre））中缺乏Glp 1 r表达的小鼠。喂食饲料的GLP-1 RKD ΔNkx2.1cre小鼠表现出摄食量和能量消耗增加，对体重无净影响。当喂食高脂肪饮食时，这些小鼠表现出正常的食物摄入量，但能量消耗增加，体重增加减少。在GLP-1 RKD Δ Sim 1cre和GLP-1 RKD ΔPOMCcre小鼠中未观察到这些表型。外周给药GLP-1 RA毒蜥外泌肽-4和利拉鲁肽的急性厌食和葡萄糖耐量效应在所有小鼠品系中均得到保留。长期利拉鲁肽给药降低了喂食普通饲料的GLP-1 RKD ΔNkx2.1cre小鼠的体重，但该效应在喂食高脂饲料后减弱。总之，经典的稳态控制区域对于GLP-1 RA对营养稳态的影响是足够的，但不是单独必需的。
Pharmacological activation of the hypothalamic glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) promotes weight loss and improves glucose tolerance. This demonstrates that the hypothalamic GLP-1R is sufficient but does not show whether it is necessary for the effects of exogenous GLP-1R agonists (GLP-1RA) or endogenous GLP-1 on these parameters. To address this, we crossed mice harboring floxed Glp1r alleles to mice expressing Nkx2.1-Cre to knock down Glp1r expression throughout the hypothalamus (GLP-1RKDΔNkx2.1cre). We also generated mice lacking Glp1r expression specifically in two GLP-1RA–responsive hypothalamic feeding nuclei/cell types, the paraventricular nucleus (GLP-1RKDΔSim1cre) and proopiomelanocortin neurons (GLP-1RKDΔPOMCcre). Chow-fed GLP-1RKDΔNkx2.1cre mice exhibited increased food intake and energy expenditure with no net effect on body weight. When fed a high-fat diet, these mice exhibited normal food intake but elevated energy expenditure, yielding reduced weight gain. None of these phenotypes were observed in GLP-1RKDΔSim1cre and GLP-1RKDΔPOMCcre mice. The acute anorectic and glucose tolerance effects of peripherally dosed GLP-1RA exendin-4 and liraglutide were preserved in all mouse lines. Chronic liraglutide treatment reduced body weight in chow-fed GLP-1RKDΔNkx2.1cre mice, but this effect was attenuated with high-fat diet feeding. In sum, classic homeostatic control regions are sufficient but not individually necessary for the effects of GLP-1RA on nutrient homeostasis.