Carmody Jill S, Muñoz Rodrigo, Yin Huali, Kaplan Lee M
Obesity, Metabolism, and Nutrition Institute and Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; and.
Obesity, Metabolism, and Nutrition Institute and Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; and Departamento de Cirugia Digestiva, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
Am J Physiol Endocrinol Metab. 2016 May 15;310(10):E855-61. doi: 10.1152/ajpendo.00412.2015. Epub 2016 Mar 29.
Roux-en-Y gastric bypass (RYGB) causes profound weight loss and remission of diabetes by influencing metabolic physiology, yet the mechanisms behind these clinical improvements remain undefined. After RYGB, levels of glucagon-like peptide-1 (GLP-1), a hormone that enhances insulin secretion and promotes satiation, are substantially elevated. Because GLP-1 signals in both the periphery and the brain to influence energy balance and glucose regulation, we aimed to determine the relative requirements of these systems to weight loss and improved glucose tolerance following RYGB surgery in mice. By pharmacologically blocking peripheral or central GLP-1R signaling, we examined whether GLP-1 action is necessary for the metabolic improvements observed after RYGB. Diet-induced obese mice underwent RYGB or sham operation and were implanted with osmotic pumps delivering the GLP-1R antagonist exendin-(9-39) (2 pmol·kg(-1)·min(-1) peripherally; 0.5 pmol·kg(-1)·min(-1) centrally) for up to 10 wk. Blockade of peripheral GLP-1R signaling partially reversed the improvement in glucose tolerance after RYGB. In contrast, fasting glucose and insulin sensitivity, as well as body weight, were unaffected by GLP-1R antagonism. Central GLP-1R signaling did not appear to be required for any of the metabolic improvements seen after this operation. Collectively, these results suggest a detectable but only modest role for GLP-1 in mediating the effects of RYGB and that this role is limited to its well-described action on glucose regulation.
Roux-en-Y胃旁路术（RYGB）通过影响代谢生理学导致显著体重减轻和糖尿病缓解，但其临床改善背后的机制仍不明确。RYGB术后，胰高血糖素样肽-1（GLP-1）水平大幅升高，GLP-1是一种可增强胰岛素分泌并促进饱腹感的激素。由于GLP-1在外周和大脑中均有信号传导以影响能量平衡和葡萄糖调节，我们旨在确定这些系统对小鼠RYGB手术后体重减轻和葡萄糖耐量改善的相对需求。通过药理学方法阻断外周或中枢GLP-1R信号传导，我们研究了GLP-1作用对于RYGB术后观察到的代谢改善是否必要。饮食诱导的肥胖小鼠接受RYGB或假手术，并植入渗透泵，持续10周给予GLP-1R拮抗剂艾塞那肽（9-39）（外周2 pmol·kg⁻¹·min⁻¹；中枢0.5 pmol·kg⁻¹·min⁻¹）。阻断外周GLP-1R信号传导部分逆转了RYGB术后葡萄糖耐量的改善。相比之下，空腹血糖、胰岛素敏感性以及体重不受GLP-1R拮抗作用的影响。该手术术后观察到的任何代谢改善似乎均不需要中枢GLP-1R信号传导。总体而言，这些结果表明GLP-1在介导RYGB效应中具有可检测到但仅适度的作用，且该作用仅限于其对葡萄糖调节的已知作用。
