Fibroblast growth factor 21 (FGF21) is an endocrine hormone produced by the liver that regulates nutrient and metabolic homeostasis. FGF21 production is increased in response to macronutrient imbalance and signals to the brain to suppress sugar intake and sweet-taste preference. However, the central targets mediating these effects have been unclear. Here, we identify FGF21 target cells in the hypothalamus and reveal that FGF21 signaling to glutamatergic neurons is both necessary and sufficient to mediate FGF21-induced sugar suppression and sweet-taste preference. Moreover, we show that FGF21 acts directly in the ventromedial hypothalamus (VMH) to specifically regulate sucrose intake, but not non-nutritive sweet-taste preference, body weight, or energy expenditure. Finally, our data demonstrate that FGF21 affects neuronal activity by increasing activation and excitability of neurons in the VMH. Thus, FGF21 signaling to glutamatergic neurons in the VMH is an important component of the neurocircuitry that functions to regulate sucrose intake.

成纤维细胞生长因子 21 (FGF21) 是一种由肝脏产生的内分泌激素，可调节营养和代谢稳态。FGF21 的产生是由于大量营养素失衡而增加，并向大脑发出信号以抑制糖摄入量和甜味偏好。然而，调节这些影响的中心目标尚不清楚。在这里，我们确定了下丘脑中的 FGF21 靶细胞，并揭示了 FGF21 向谷氨酸能神经元的信号传导对于介导 FGF21 诱导的糖抑制和甜味偏好既必要又充分。此外，我们表明 FGF21 直接作用于腹内侧下丘脑 (VMH)，专门调节蔗糖摄入量，但不调节非营养性甜味偏好、体重或能量消耗。最后，我们的数据表明 FGF21 通过增加 VMH 中神经元的激活和兴奋性来影响神经元活动。因此，向 VMH 中的谷氨酸能神经元发送 FGF21 信号是神经回路的重要组成部分，其功能是调节蔗糖摄入。