Payant Mikayla A, Sankhe Aditi S, Miller Persephone A, Vieira Sarah S, Dumiaty Yasmina, Phy-Lim Jenny, Levy Zachary L, Chee Melissa J
Department of Neuroscience, Carleton University, Ottawa, ON, K1S 5B6, Canada.
Department of Neuroscience, Carleton University, Ottawa, ON, K1S 5B6, Canada.
Mol Metab. 2025 Jul 11;99:102209. doi: 10.1016/j.molmet.2025.102209.
Fructose is a naturally-occurring sugar, consumed in excess as sweeteners, and is linked to the development of obesity. Fructose is consumed with glucose (dextrose) in added sugars, but while dextrose produces satiety, excessive fructose intake promotes hyperphagia through the brain. However, the neurological effects of dietary fructose are not clearly defined. We fed male and female mice standard chow, a 60% high fructose, or 60% high dextrose diet and found that fructose- and dextrose-fed mice ate more calories and gained more body fat despite increasing fat oxidation and energy expenditure. Furthermore, their metabolic syndromes were more prominent in male mice, who also developed glucose intolerance. To define the neurological effects underlying the obesogenic actions of fructose, we performed ex vivo patch-clamp recordings from orexigenic Neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons in the arcuate nucleus. Fructose feeding uniquely increased synaptic excitation at NPY/AgRP neurons, which remained elevated with sustained fructose exposure; this excitation may arise from glutamatergic neurons in the dorsomedial hypothalamic nucleus. Terminating fructose feeding reversed this synaptic excitation at male but not female NPY/AgRP neurons. Furthermore, chronic but not acute fructose feeding in male mice also irreversibly activated NPY/AgRP neurons even following fructose withdrawal. Interestingly, despite sex-dependent fructose-mediated plasticity at NPY/AgRP neurons, a prolonged fructose withdrawal increased innate fructose preference in both male and female mice. Taken together, these findings showed that fructose elicited synaptic and neuronal excitation at NPY/AgRP neurons that can be long-lasting. These actions are consistent with that seen during hunger and may thus promote hyperphagia in the expression of fructose-mediated obesity.
果糖是一种天然存在的糖，作为甜味剂过量食用时，会与肥胖的发生有关。果糖在添加糖中与葡萄糖（右旋糖）一起被摄入，但葡萄糖会产生饱腹感，而过量摄入果糖会通过大脑促进食欲亢进。然而，膳食果糖的神经学效应尚不清楚。我们给雄性和雌性小鼠喂食标准饲料、60%高果糖或60%高葡萄糖饮食，发现喂食果糖和葡萄糖的小鼠尽管脂肪氧化和能量消耗增加，但摄入了更多热量并增加了体脂。此外，它们的代谢综合征在雄性小鼠中更为突出，雄性小鼠还出现了葡萄糖不耐受。为了确定果糖致肥胖作用背后的神经学效应，我们对弓状核中促食欲的神经肽Y/刺鼠相关肽（NPY/AgRP）神经元进行了离体膜片钳记录。喂食果糖独特地增加了NPY/AgRP神经元的突触兴奋性，持续暴露于果糖时这种兴奋性仍然升高；这种兴奋可能源于下丘脑背内侧核中的谷氨酸能神经元。停止喂食果糖可逆转雄性而非雌性NPY/AgRP神经元的这种突触兴奋。此外，雄性小鼠长期而非急性喂食果糖，即使在停止喂食果糖后，也会不可逆地激活NPY/AgRP神经元。有趣的是，尽管NPY/AgRP神经元存在性别依赖性的果糖介导的可塑性，但长期停止喂食果糖会增加雄性和雌性小鼠对果糖的固有偏好。综上所述，这些发现表明果糖在NPY/AgRP神经元上引发了可持久的突触和神经元兴奋。这些作用与饥饿时的情况一致，因此可能在果糖介导的肥胖表达中促进食欲亢进。
