School of Veterinary Medicine, University of California Davis, Davis, CA, USA.
Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia.
Int J Obes (Lond). 2021 Feb;45(2):348-357. doi: 10.1038/s41366-020-00678-1. Epub 2020 Sep 11.
Activation of vagal afferent neurons (VAN) by postprandial gastrointestinal signals terminates feeding and facilitates nutrient digestion and absorption. Leptin modulates responsiveness of VAN to meal-related gastrointestinal signals. Rodents with high-fat diet (HF) feeding develop leptin resistance that impairs responsiveness of VAN. We hypothesized that lack of leptin signaling in VAN reduces responses to meal-related signals, which in turn decreases absorption of nutrients and energy storage from high-fat, calorically dense food.
Mice with conditional deletion of the leptin receptor from VAN (Nav1.8-Cre/LepR; KO) were used in this study. Six-week-old male mice were fed a 45% HF for 4 weeks; metabolic phenotype, food intake, and energy expenditure were measured. Absorption and storage of nutrients were investigated in the refed state.
After 4 weeks of HF feeding, KO mice gained less body weight and fat mass that WT controls, but this was not due to differences in food intake or energy expenditure. KO mice had reduced expression of carbohydrate transporters and absorption of carbohydrate in the jejunum. KO mice had fewer hepatic lipid droplets and decreased expression of de novo lipogenesis-associated enzymes and lipoproteins for endogenous lipoprotein pathway in liver, suggesting decreased long-term storage of carbohydrate in KO mice.
Impairment of leptin signaling in VAN reduces responsiveness to gastrointestinal signals, which reduces intestinal absorption of carbohydrates and de novo lipogenesis resulting in reduced long-term energy storage. This study reveals a novel role of vagal afferents to support digestion and energy storage that may contribute to the effectiveness of vagal blockade to induce weight loss.
通过餐后胃肠信号激活迷走传入神经元（VAN）可终止进食，并促进营养物质的消化和吸收。瘦素调节 VAN 对与进餐相关的胃肠信号的反应性。高脂肪饮食（HF）喂养的啮齿动物会产生瘦素抵抗，从而损害 VAN 的反应性。我们假设 VAN 中缺乏瘦素信号会降低对进餐相关信号的反应，从而减少从高脂肪、高热量食物中吸收营养物质和储存能量。
本研究使用了 VAN 中瘦素受体条件性缺失的小鼠（Nav1.8-Cre/LepR；KO）。6 周龄雄性小鼠被喂食 45%HF 饲料 4 周；测量代谢表型、食物摄入量和能量消耗。在再喂养状态下研究了营养物质的吸收和储存。
HF 喂养 4 周后，KO 小鼠的体重和脂肪量增加少于 WT 对照组，但这并不是由于食物摄入量或能量消耗的差异所致。KO 小鼠的空肠碳水化合物转运体表达减少，碳水化合物吸收减少。KO 小鼠的肝脏脂质滴减少，内源性脂蛋白途径中新生脂肪生成相关酶和脂蛋白的表达减少，表明 KO 小鼠中碳水化合物的长期储存减少。
VAN 中瘦素信号的损害降低了对胃肠信号的反应性，从而减少了碳水化合物的肠道吸收和新生脂肪生成，导致长期能量储存减少。这项研究揭示了迷走传入神经在支持消化和能量储存方面的新作用，这可能有助于迷走神经阻断诱导体重减轻的有效性。
