Division of Endocrinology, Beth Israel Deaconess Medical Center, Center for Life Sciences, 7th Fl., 330 Brookline Ave., Boston, MA 02215, USA.
Am J Physiol Endocrinol Metab. 2009 Nov;297(5):E1197-204. doi: 10.1152/ajpendo.00357.2009. Epub 2009 Sep 8.
In mice of normal weight and with diet-induced obesity, a high-fat, low-carbohydrate ketogenic diet (KD) causes weight loss, reduced circulating glucose and lipids, and dramatic changes in hepatic gene expression. Many of the effects of KD are mediated by fibroblast growth factor 21 (FGF21). We tested the effects of KD feeding on ob/ob mice to determine if metabolic effects would occur in obesity secondarily to leptin deficiency. We evaluated the effect of prolonged KD feeding on weight, energy homeostasis, circulating metabolites, glucose homeostasis, and gene expression. Subsequently, we evaluated the effects of leptin and fasting on FGF21 expression in ob/ob mice. KD feeding of ob/ob mice normalized fasting glycemia and substantially reduced insulin and lipid levels in the absence of weight loss. KD feeding was associated with significant increases in lipid oxidative genes and reduced expression of lipid synthetic genes, including stearoyl-coenzyme A desaturase 1, but no change in expression of inflammatory markers. In chow-fed ob/ob mice, FGF21 mRNA was elevated 10-fold compared with wild-type animals, and no increase from this elevated baseline was seen with KD feeding. Administration of leptin to chow-fed ob/ob mice led to a 24-fold induction of FGF21. Fasting also induced hepatic FGF21 in ob/ob mice. Thus, KD feeding improved ob/ob mouse glucose homeostasis without weight loss or altered caloric intake. These data demonstrate that manipulation of dietary macronutrient composition can lead to marked improvements in metabolic profile of leptin-deficient obese mice in the absence of weight loss.
在正常体重的小鼠和饮食诱导肥胖的小鼠中,高脂肪、低碳水化合物的生酮饮食(KD)可导致体重减轻、循环葡萄糖和脂质减少以及肝基因表达的显著变化。KD 的许多作用是通过成纤维细胞生长因子 21(FGF21)介导的。我们测试了 KD 喂养对 ob/ob 小鼠的影响,以确定在瘦素缺乏的情况下,肥胖是否会继发于 KD 的代谢作用。我们评估了长期 KD 喂养对体重、能量平衡、循环代谢物、葡萄糖稳态和基因表达的影响。随后,我们评估了瘦素和禁食对 ob/ob 小鼠 FGF21 表达的影响。KD 喂养可使 ob/ob 小鼠的空腹血糖正常化,并在不减轻体重的情况下显著降低胰岛素和脂质水平。KD 喂养与脂质氧化基因的显著增加和脂质合成基因(包括硬脂酰辅酶 A 去饱和酶 1)的表达减少相关,但炎症标志物的表达没有变化。在 chow 喂养的 ob/ob 小鼠中,FGF21 mRNA 比野生型动物高 10 倍,并且在 KD 喂养时没有从这个升高的基线增加。给予 leptin 可使 chow 喂养的 ob/ob 小鼠的 FGF21 诱导增加 24 倍。禁食也可诱导 ob/ob 小鼠的肝 FGF21。因此,KD 喂养改善了 ob/ob 小鼠的葡萄糖稳态,而没有减轻体重或改变热量摄入。这些数据表明,饮食宏量营养素组成的改变可以导致缺乏瘦素的肥胖小鼠的代谢谱显著改善,而无需减轻体重。