The current obesity epidemic faces a lack of mechanistic insights. It is known that the acute activity changes of a growing number of brain neurons rapidly alter feeding behaviour; however, how these changes translate to obesity development and the fundamental mechanism underlying brain neurons in controlling body weight remain elusive. Here, we show that chronic activation of hypothalamic arcuate GABAergic (GABA⁺), agouti-related protein (AgRP) neurons or arcuate non-AgRP GABA⁺ neurons leads to obesity, which is similar to the obese phenotype observed in ob/ob mice. Conversely, chronic inhibition of arcuate GABA⁺, but not AgRP, neurons reduces ageing-related weight gain and corrects ob/ob obesity. These results demonstrate that the modulation of Arc GABA⁺ neuron activity is a fundamental mechanism of body-weight regulation, and that arcuate GABA⁺ neurons are the major mediator of leptin action, with a profound and redundant role in obesity development.

当前的肥胖流行病缺乏机制性的见解。众所周知，越来越多的大脑神经元的急剧活动变化会迅速改变进食行为。然而，这些变化如何转化为肥胖的发展以及大脑神经元控制体重的基本机制仍然难以捉摸。在这里，我们发现下丘脑弓状 GABA 能（GABA ⁺ ）、刺鼠相关蛋白（AgRP）神经元或弓状非 AgRP GABA ⁺神经元的慢性激活会导致肥胖，这与ob / ob小鼠中观察到的肥胖表型相似。相反，长期抑制弓形 GABA ⁺神经元（而非 AgRP）可减少与衰老相关的体重增加并纠正ob / ob肥胖。这些结果表明，弓形 GABA ⁺神经元活性的调节是体重调节的基本机制，并且弓形 GABA ⁺神经元是瘦素作用的主要介质，在肥胖发展中具有深远而多余的作用。