Goldstein J L, Zhao T-j, Li R L, Sherbet D P, Liang G, Brown M S
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046, USA.
Cold Spring Harb Symp Quant Biol. 2011;76:121-7. doi: 10.1101/sqb.2011.76.010447. Epub 2011 Jul 22.
After brief starvation, vertebrates maintain blood glucose by releasing fatty acids from adipose tissue. The fatty acids provide energy for gluconeogenesis in liver and are taken up by muscle, sparing glucose. After prolonged starvation, fat stores are depleted, yet blood glucose can be maintained at levels sufficient to preserve life. Using a new mouse model, we demonstrate that survival after prolonged starvation requires ghrelin, an octanoylated peptide hormone that stimulates growth hormone (GH) secretion. We studied wild-type mice and mice lacking ghrelin as a result of knockout of GOAT, the enzyme that attaches octanoate to ghrelin. Mice were fed 40% of their normal intake for 7 d. Fat stores in both lines of mice became depleted after 4 d. On day 7, mice were fasted for 23 h. In wild-type mice, ghrelin and GH rose massively, and blood sugar was maintained at ~60 mg/dL. In Goat(-/-) mice, ghrelin was undetectable and GH failed to rise appropriately. Blood sugar declined to ~20 mg/dL, and the animals were moribund. Infusion of ghrelin or GH prevented hypoglycemia. Our results support the following sequence: (1) Starvation lowers blood glucose; (2) glucose-sensing neurons respond by activating sympathetic neurons; (3) norepinephrine, released in the stomach, stimulates ghrelin secretion; (4) ghrelin releases GH, which maintains blood glucose. Thus, ghrelin lies at the center of a hormonal response that permits mice to survive an acute fast superimposed on chronic starvation.
在短期饥饿后，脊椎动物通过从脂肪组织释放脂肪酸来维持血糖水平。脂肪酸为肝脏中的糖异生提供能量，并被肌肉摄取，从而节省葡萄糖。在长期饥饿后，脂肪储备耗尽，但血糖仍可维持在足以维持生命的水平。我们使用一种新的小鼠模型证明，长期饥饿后的存活需要胃饥饿素，这是一种刺激生长激素（GH）分泌的辛酰化肽激素。我们研究了野生型小鼠和由于敲除将辛酸连接到胃饥饿素的酶GOAT而缺乏胃饥饿素的小鼠。小鼠被喂食正常摄入量的40%，持续7天。4天后，两种品系小鼠的脂肪储备都耗尽了。在第7天，小鼠禁食23小时。在野生型小鼠中，胃饥饿素和生长激素大量升高，血糖维持在60mg/dL。在Goat(-/-)小鼠中，检测不到胃饥饿素，生长激素也未能适当升高。血糖降至20mg/dL，动物濒死。注入胃饥饿素或生长激素可预防低血糖。我们 的结果支持以下顺序：(1)饥饿降低血糖；(2)葡萄糖感应神经元通过激活交感神经元做出反应；(3)胃中释放的去甲肾上腺素刺激胃饥饿素分泌；(4)胃饥饿素释放生长激素，维持血糖。因此，胃饥饿素处于激素反应的中心，使小鼠能够在慢性饥饿的基础上承受急性禁食并存活下来。
