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Chronic Gq signaling in AgRP neurons does not cause obesity.
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2020-08-25 , DOI: 10.1073/pnas.2004941117
Sedona N Ewbank 1, 2 , Carlos A Campos 1, 2 , Jane Y Chen 2, 3 , Anna J Bowen 2, 3 , Stephanie L Padilla 2, 3 , Joseph L Dempsey 4 , Julia Yue Cui 4 , Richard D Palmiter 1, 2
Affiliation  

Maintaining energy homeostasis requires coordinating physiology and behavior both on an acute timescale to adapt to rapid fluctuations in caloric intake and on a chronic timescale to regulate body composition. Hypothalamic agouti-related peptide (AgRP)-expressing neurons are acutely activated by caloric need, and this acute activation promotes increased food intake and decreased energy expenditure. On a longer timescale, AgRP neurons exhibit chronic hyperactivity under conditions of obesity and high dietary fat consumption, likely due to leptin resistance; however, the behavioral and metabolic effects of chronic AgRP neuronal hyperactivity remain unexplored. Here, we use chemogenetics to manipulate Gq signaling in AgRP neurons in mice to explore the hypothesis that chronic activation of AgRP neurons promotes obesity. Inducing chronic Gq signaling in AgRP neurons initially increased food intake and caused dramatic weight gain, in agreement with published data; however, food intake returned to baseline levels within 1 wk, and body weight returned to baseline levels within 60 d. Additionally, we found that, when mice had elevated body weight due to chronic Gq signaling in AgRP neurons, energy expenditure was not altered but adiposity and lipid metabolism were both increased, even under caloric restriction. These findings reveal that the metabolic and behavioral effects of chronic Gq signaling in AgRP neurons are distinct from the previously reported effects of acute Gq signaling and also of leptin insensitivity.



中文翻译:

AgRP 神经元中的慢性 Gq 信号传导不会导致肥胖。

维持能量稳态需要在短期内协调生理和行为以适应热量摄入的快速波动,并在长期内调节身体成分。下丘脑刺鼠相关肽(AgRP)表达神经元因热量需求而急剧激活,这种急性激活会促进食物摄入量增加和能量消耗减少。在较长的时间尺度上,AgRP 神经元在肥胖和高膳食脂肪消耗的条件下表现出慢性过度活跃,这可能是由于瘦素抵抗;然而,慢性 AgRP 神经元过度活跃对行为和代谢的影响仍有待探索。在这里,我们使用化学遗传学来操纵小鼠 AgRP 神经元中的 G q信号传导,以探索 AgRP 神经元的慢性激活促进肥胖的假设。在 AgRP 神经元中诱导慢性 G q信号传导最初会增加食物摄入量并导致体重急剧增加,这与已发表的数据一致;然而,食物摄入量在 1 周内恢复到基线水平,体重在 60 天内恢复到基线水平。此外,我们发现,当小鼠由于AgRP 神经元中的慢性 G q信号传导而体重增加时,即使在热量限制下,能量消耗也不会改变,但肥胖和脂质代谢都会增加。这些发现表明,AgRP 神经元中慢性 G q信号传导的代谢和行为影响不同于之前报道的急性 G q信号传导以及瘦素不敏感的影响。

更新日期:2020-08-26
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