The preclinical multicomponent free-choice high-fat high-sucrose (fcHFHS) diet has strong validity to model diet-induced obesity (DIO) and associated maladaptive molecular changes in the central nervous system. fcHFHS-induced obese rats demonstrate increased sensitivity to intracerebroventricular infusion of the orexigenic Neuropeptide Y (NPY). The brain region-specific effects of NPY signaling on fcHFHS diet component selection are not completely understood. For example, fcHFHS-fed rats have increased intake of chow and fat following intracerebroventricular NPY infusion, whereas NPY administration in the nucleus accumbens, a key hub of the reward circuitry, specifically increases fat intake. Here, we investigated whether NPY infusion in the lateral hypothalamic area (LHA), which is crucially involved in the regulation of intake, regulates fcHFHS component selection, and if LHA NPY receptor subtypes 1 or 5 (NPYR1/5) are involved. Male Wistar rats were fed a chow or fcHFHS diet for at least seven days, and received intra-LHA vehicle or NPY infusions in a cross-over design. Diet component intake was measured two hours later. Separate experimental designs were used to test the efficacy of NPY1R- or NPY5R antagonism to prevent the orexigenic effects of intra-LHA NPY. Intra-LHA NPY increased caloric intake in chow- and fcHFHS-fed rats. This effect was mediated specifically by chow intake in fcHFHS-fed rats. The orexigenic effects of intra-LHA NPY were prevented by NPY1R and NPY5R antagonism in chow-fed rats, but only by NPY5R antagonism in fcHFHS-fed rats. Thus, NPY signaling has brain region-specific effects on fcHFHS component selection and LHA NPYR sensitivity is dysregulated during consumption of a fcHFHS diet.

中文翻译：

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下丘脑外侧神经肽 Y 信号调节饮食成分选择，并在饮食诱导的肥胖模型中失调。

临床前多组分自由选择高脂高蔗糖 (fcHFHS) 饮食对模拟饮食诱导的肥胖 (DIO) 和中枢神经系统中相关的适应不良分子变化具有很强的有效性。fcHFHS 诱导的肥胖大鼠表现出对脑室内输注促食欲神经肽 Y (NPY) 的敏感性增加。NPY 信号传导对 fcHFHS 饮食成分选择的大脑区域特异性影响尚不完全清楚。例如，在脑室内输注 NPY 后，喂食 fcHFHS 的大鼠增加了食物和脂肪的摄入，而在伏隔核（奖励电路的关键枢纽）中施用 NPY 会特别增加脂肪摄入。在这里，我们调查了在下丘脑外侧区 (LHA) 输注 NPY 是否与摄入量的调节至关重要，调节 fcHFHS 成分选择，以及是否涉及 LHA NPY 受体亚型 1 或 5 (NPYR1/5)。给雄性 Wistar 大鼠喂食 chow 或 fcHFHS 饮食至少 7 天，并在交叉设计中接受 LHA 内载体或 NPY 输注。两小时后测量饮食成分的摄入量。使用单独的实验设计来测试 NPY1R 或 NPY5R 拮抗作用以防止 LHA 内 NPY 的促食欲作用。Intra-LHA NPY 增加了食物和 fcHFHS 喂养大鼠的热量摄入。这种效应是由 fcHFHS 喂养的大鼠的食物摄入量特异性介导的。LHA 内 NPY 的促食欲作用通过 NPY1R 和 NPY5R 拮抗作用在食物喂养的大鼠中得到阻止，但在 fcHFHS 喂养的大鼠中仅通过 NPY5R 拮抗作用。因此，