Kuah Rachel, Wang Melissa T, Yang Zeyu, Back Grace, Li Rosa J W, Bruce Kyla, LoChoy Jessica N, Beaudry Jacqueline L, Barros Daniel R, Zhang Song-Yang, Lam Tony K T
Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.
Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
Diabetes. 2025 Jul 22. doi: 10.2337/db25-0100.
An acute increase of lipids in the upper small intestine (USI) of rodents and humans triggers lipid-sensing pathways to reduce food intake. However, USI lipid sensing does not reduce feeding in high-fat (HF) fed conditions, and the underlying mechanism remains elusive. Here, we report that HF feeding in male rats impaired USI lipid infusion to stimulate glucose-dependent insulinotropic polypeptide (GIP) secretion and decrease refeeding, and the defects of USI lipid sensing were restored by metformin. Next, we found that infusion of GIP receptor (GIPR) agonist in the nucleus of the solitary tract (NTS), but not mediobasal hypothalamus or area postrema, resulted in decreased refeeding in chow-fed rats. The anorectic effect of NTS GIPR agonist remained intact in HF rats and was inhibited by a genetic knockdown of GIPR. Finally, an inhibition of NTS GIPR also negated the ability of USI lipid sensing with metformin to decrease refeeding despite an increase in plasma GIP levels in HF rats. Thus, USI lipid sensing in HF rats is enhanced by metformin to trigger an endocrine GIP to NTS GIPR axis to reduce food intake, thereby unveiling small intestinal lipid-sensing pathways as potential targets to enhance GIP action and reduce weight in obesity.
High-fat (HF) feeding in rats impairs upper small intestine (USI) lipid sensing to increase plasma glucose-dependent insulinotropic polypeptide (GIP) levels and reduce feeding. Metformin enhances USI lipids to increase GIP and reduce feeding in HF-fed rats. GIP activates the GIP receptor (GIPR) in the nucleus of the solitary tract (NTS), which reduces food intake in HF-fed rats. GIPR in the NTS is required for small intestinal lipids with metformin to reduce feeding.
啮齿动物和人类上小肠（USI）中脂质的急性增加会触发脂质感应途径以减少食物摄入量。然而，在高脂（HF）喂养条件下，USI脂质感应并不会减少进食，其潜在机制仍不清楚。在此，我们报告雄性大鼠的HF喂养会损害USI脂质输注，从而刺激葡萄糖依赖性促胰岛素多肽（GIP）分泌并减少再次进食，而二甲双胍可恢复USI脂质感应的缺陷。接下来，我们发现，在孤束核（NTS）而非中基底下丘脑或最后区注入GIP受体（GIPR）激动剂，会导致正常饮食大鼠的再次进食减少。NTS GIPR激动剂的厌食作用在HF大鼠中保持不变，并被GIPR的基因敲低所抑制。最后，尽管HF大鼠血浆GIP水平升高，但抑制NTS GIPR也会消除二甲双胍介导的USI脂质感应减少再次进食的能力。因此，二甲双胍增强了HF大鼠的USI脂质感应，从而触发内分泌GIP至NTS GIPR轴以减少食物摄入量，从而揭示小肠脂质感应途径作为增强GIP作用和减轻肥胖体重的潜在靶点。
大鼠的高脂（HF）喂养会损害上小肠（USI）脂质感应，从而增加血浆葡萄糖依赖性促胰岛素多肽（GIP）水平并减少进食。二甲双胍增强USI脂质，从而增加GIP并减少HF喂养大鼠的进食。GIP激活孤束核（NTS）中的GIP受体（GIPR），从而减少HF喂养大鼠的食物摄入量。NTS中的GIPR是小肠脂质与二甲双胍减少进食所必需的。
