Astudillo-Guerrero Camila, Fernandois Daniela, Caron Emilie, Prevot Vincent, Thaler Joshua P, Dorfman Mauricio D, Cruz Gonzalo
Laboratorio de Alteraciones Reproductivas y Metabólicas, Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.
Programa de Doctorado en Ciencias Mención Neurociencia, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.
Am J Physiol Cell Physiol. 2025 Sep 1;329(3):C834-C847. doi: 10.1152/ajpcell.00357.2025. Epub 2025 Jul 31.
Time-restricted feeding (TRF) has been shown to improve glycemic control, reduce liver fat, and decrease cardiovascular risk in humans and diet-induced obese (DIO) mice. However, the mechanisms associated with this improvement are not completely understood. High-fat diet (HFD)-associated hypothalamic inflammation and glial activation promote obesity and metabolic dysfunction, raising the possibility that TRF mitigates these factors. Specifically, TRF increases circulating levels of β-hydroxybutyrate (BHB), a ketone body that crosses the blood-brain barrier and has anti-inflammatory properties. Here, we evaluated whether the beneficial effects of TRF are associated with changes in hypothalamic inflammation and gliosis. Furthermore, we assessed the ability of peripheral or central administration of BHB to mimic the metabolic phenotype of TRF. Consistent with prior studies in HFD-fed mice, weight loss induced by TRF was modest, due to a transient decrease in food intake offset by a persistent reduction in energy expenditure. Despite the limited effect on body weight and adiposity, TRF markedly improved glucose tolerance in DIO mice, restoring glucose homeostasis to the level of chow-fed controls. Unexpectedly, TRF increased hypothalamic markers of gliosis in DIO mice. Finally, although TRF induced the predicted rise in circulating BHB levels, chronic systemic or ICV administration of BHB had no effect on glucose tolerance and hypothalamic gliosis. Together, these data suggest that increased hypothalamic gliosis may contribute to the improvement of glucose tolerance induced by TRF in DIO mice. This study shows that time-restricted feeding (TRF) improves glucose tolerance in obese mice independently of weight loss. Surprisingly, this benefit is linked to increased hypothalamic gliosis, challenging the view that gliosis is solely detrimental in obesity. Although TRF elevates circulating β-hydroxybutyrate (BHB), peripheral and central BHB delivery fails to mimic TRF's glycemic benefits or affect hypothalamic gliosis. These findings suggest gliosis may play a previously unrecognized role in mediating TRF's metabolic benefits.
限时进食（TRF）已被证明可改善人体和饮食诱导肥胖（DIO）小鼠的血糖控制、减少肝脏脂肪并降低心血管风险。然而，与这种改善相关的机制尚未完全明确。高脂饮食（HFD）相关的下丘脑炎症和神经胶质细胞激活会促进肥胖和代谢功能障碍，这增加了TRF减轻这些因素的可能性。具体而言，TRF会增加β-羟基丁酸（BHB）的循环水平，BHB是一种可穿过血脑屏障且具有抗炎特性的酮体。在此，我们评估了TRF的有益效果是否与下丘脑炎症和神经胶质增生的变化有关。此外，我们评估了外周或中枢给予BHB模拟TRF代谢表型的能力。与先前对高脂饮食喂养小鼠的研究一致，但由于食物摄入量的短暂减少被能量消耗的持续降低所抵消，TRF诱导的体重减轻幅度较小。尽管对体重和肥胖的影响有限，但TRF显著改善了DIO小鼠的葡萄糖耐量，将葡萄糖稳态恢复到正常饮食对照组的水平。出乎意料的是，TRF增加了DIO小鼠下丘脑神经胶质增生的标志物。最后，尽管TRF导致循环BHB水平出现预期的升高，但长期全身性或脑室内给予BHB对葡萄糖耐量和下丘脑神经胶质增生均无影响。综上所述，这些数据表明下丘脑神经胶质增生增加可能有助于改善TRF诱导的DIO小鼠的葡萄糖耐量。这项研究表明，限时进食（TRF）可独立于体重减轻而改善肥胖小鼠的葡萄糖耐量。令人惊讶的是，这种益处与下丘脑神经胶质增生增加有关，这挑战了神经胶质增生在肥胖中仅具有有害作用的观点。尽管TRF会升高循环β-羟基丁酸（BHB）水平，但外周和中枢给予BHB均无法模拟TRF的血糖益处或影响下丘脑神经胶质增生。这些发现表明，神经胶质增生可能在介导TRF的代谢益处方面发挥了先前未被认识到的作用。
