The melanocortin action is well perceived for its ability to regulate body weight bidirectionally with its gain of function reducing body weight and loss of function promoting obesity. However, this notion cannot explain the difficulty in identifying effective therapeutics toward treating general obesity via activation of the melanocortin action. Here, we provide evidence that altered melanocortin action is only able to cause one-directional obesity development. We demonstrate that chronic inhibition of arcuate neurons expressing proopiomelanocortin (POMC) or paraventricular hypothalamic neurons expressing melanocortin receptor 4 (MC4R) causes massive obesity. However, chronic activation of these neuronal populations failed to reduce body weight. Furthermore, gain of function of the melanocortin action through overexpression of MC4R, POMC or its derived peptides had little effect on obesity prevention or reversal. These results reveal a bias of the melanocortin action towards protection of weight loss and provide a neural basis behind the well-known, but mechanistically ill-defined, predisposition to obesity development.

黑皮质素的作用因其双向调节体重的能力而广为人知，其功能获得可减轻体重，而功能丧失则可促进肥胖。然而，这一概念无法解释通过激活黑皮质素作用来确定治疗一般性肥胖症的有效疗法的困难。在这里，我们提供的证据表明，改变黑皮质素的作用只能导致单向肥胖的发展。我们证明，长期抑制表达阿黑皮质素原 (POMC) 的弓状神经元或表达黑皮质素受体 4 (MC4R) 的室旁下丘脑神经元会导致严重肥胖。然而，这些神经元群的长期激活未能减轻体重。此外，通过MC4R、POMC或其衍生肽的过度表达获得黑皮质素作用的功能对预防或逆转肥胖几乎没有影响。这些结果揭示了黑皮质素对保护体重减轻的作用的偏向，并为众所周知但机制上不明确的肥胖发展倾向提供了神经基础。