HHMI, The Rockefeller University, New York, NY 10065.
Laboratory of Molecular Genetics, The Rockefeller University, New York, NY 10065.
Proc Natl Acad Sci U S A. 2021 Mar 30;118(13). doi: 10.1073/pnas.2100194118.
Leptin-deficient ob/ob mice eat voraciously, and their food intake is markedly reduced by leptin treatment. In order to identify potentially novel sites of leptin action, we used PhosphoTRAP to molecularly profile leptin-responsive neurons in the hypothalamus and brainstem. In addition to identifying several known leptin responsive populations, we found that neurons in the dorsomedial hypothalamus (DMH) of ob/ob mice expressing protein phosphatase 1 regulatory subunit 17 (PPP1R17) constitutively express cFos and that this is suppressed by leptin treatment. Because ob mice are hyperphagic, we hypothesized that activating PPP1R17 neurons would increase food intake. However, chemogenetic activation of PPP1R17 neurons decreased food intake and body weight of ob/ob mice while inhibition of PPP1R17 neurons increased them. Similarly, in a scheduled feeding protocol that elicits increased consumption, mice also ate more when PPP1R17 neurons were inhibited and ate less when they were activated. Finally, we found that pair-feeding of ob mice reduced cFos expression to a similar extent as leptin and that reducing the amount of food available during scheduled feeding in DMH neurons also decreased cFos in DMH neurons. Finally, these neurons do not express the leptin receptor, suggesting that the effect of leptin on these neurons is indirect and secondary to reduced food intake. In aggregate, these results show that PPP1R17 neurons in the DMH are activated by increased food intake and in turn restrict intake to limit overconsumption, suggesting that they function to constrain binges of eating.
瘦素缺乏型 ob/ob 小鼠食欲旺盛，而瘦素治疗可显著减少其食物摄入量。为了确定瘦素作用的潜在新靶点，我们使用 PhosphoTRAP 对下丘脑和脑干中瘦素反应神经元进行了分子特征分析。除了鉴定出几种已知的瘦素反应群体外，我们还发现 ob/ob 小鼠的下丘脑背内侧核（DMH）中表达蛋白磷酸酶 1 调节亚基 17（PPP1R17）的神经元持续表达 cFos，而瘦素治疗可抑制其表达。由于 ob 小鼠食欲过盛，我们假设激活 PPP1R17 神经元会增加食物摄入量。然而，化学遗传学激活 PPP1R17 神经元会减少 ob/ob 小鼠的食物摄入量和体重，而抑制 PPP1R17 神经元则会增加它们的摄入量。同样，在一项引发增加消耗的定时喂养方案中，当抑制 PPP1R17 神经元时，小鼠也会吃得更多，而当激活它们时则会吃得更少。最后，我们发现，ob 小鼠的等量喂养会将 cFos 表达减少到与瘦素相似的程度，并且在 DMH 神经元中限制定时喂养时的食物供应也会减少 DMH 神经元中的 cFos。最后，这些神经元不表达瘦素受体，这表明瘦素对这些神经元的作用是间接的，并且是由于食物摄入量减少所致。总之，这些结果表明，DMH 中的 PPP1R17 神经元会因食物摄入量增加而被激活，进而限制摄入量以限制过度进食，这表明它们的功能是限制暴食。
