Song Wei, Cheng Daojun, Hong Shangyu, Sappe Benoit, Hu Yanhui, Wei Neil, Zhu Changqi, O'Connor Michael B, Pissios Pavlos, Perrimon Norbert
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400715, China.
Cell Metab. 2017 Feb 7;25(2):386-399. doi: 10.1016/j.cmet.2017.01.002.
While high-caloric diet impairs insulin response to cause hyperglycemia, whether and how counter-regulatory hormones are modulated by high-caloric diet is largely unknown. We find that enhanced response of Drosophila adipokinetic hormone (AKH, the glucagon homolog) in the fat body is essential for hyperglycemia associated with a chronic high-sugar diet. We show that the activin type I receptor Baboon (Babo) autonomously increases AKH signaling without affecting insulin signaling in the fat body via, at least, increase of Akh receptor (AkhR) expression. Further, we demonstrate that Activin-β (Actβ), an activin ligand predominantly produced in the enteroendocrine cells (EEs) of the midgut, is upregulated by chronic high-sugar diet and signals through Babo to promote AKH action in the fat body, leading to hyperglycemia. Importantly, activin signaling in mouse primary hepatocytes also increases glucagon response and glucagon-induced glucose production, indicating a conserved role for activin in enhancing AKH/glucagon signaling and glycemic control.
高热量饮食会损害胰岛素反应，进而导致高血糖，但高热量饮食是否以及如何调节反调节激素，目前仍知之甚少。我们发现，果蝇脂肪体中脂肪动激素（AKH，即胰高血糖素的同源物）反应增强对于慢性高糖饮食所致的高血糖至关重要。我们表明，I型激活素受体狒狒（Babo）可自主增强AKH信号传导，且至少通过增加Akh受体（AkhR）的表达，而不影响脂肪体中的胰岛素信号传导。此外，我们证明，激活素-β（Actβ）是一种主要在中肠肠内分泌细胞（EEs）中产生的激活素配体，在慢性高糖饮食作用下会上调，并通过Babo发出信号，促进脂肪体中的AKH作用，从而导致高血糖。重要的是，激活素信号传导在小鼠原代肝细胞中也会增强胰高血糖素反应以及胰高血糖素诱导的葡萄糖生成，这表明激活素在增强AKH/胰高血糖素信号传导和血糖控制方面具有保守作用。
