Shimada M, Tritos N A, Lowell B B, Flier J S, Maratos-Flier E
Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.
Nature. 1998 Dec 17;396(6712):670-4. doi: 10.1038/25341.
Feeding is influenced by hypothalamic neuropeptides that promote (orexigenic peptides) or inhibit feeding. Of these, neuropeptide Y (NPY) in the arcuate nucleus and melanin-concentrating hormone (MCH) and orexins/hypocretins in the lateral hypothalamus have received attention because their expression is increased during fasting and because they promote feeding when administered centrally. Surprisingly, absence of the orexigenic neuropeptide NPY fails to alter feeding or body weight in normal mice. As deficiency of a single component of the pathway that limits food intake (such as leptin or receptors for melanocortin-4) causes obesity, it has been suggested that orexigenic signals are more redundant than those limiting food intake. To define further the physiological role of MCH and to test the redundancy of orexigenic signals, we generated mice carrying a targeted deletion of the MCH gene. MCH-deficient mice have reduced body weight and leanness due to hypophagia (reduced feeding) and an inappropriately increased metabolic rate, despite their reduced amounts of both leptin and arcuate nucleus pro-opiomelanocortin messenger RNA. Our results show that MCH is a critical regulator of feeding and energy balance which acts downstream of leptin and the melanocortin system, and that deletion of a gene encoding a single orexigenic peptide can result in leanness.
进食受到下丘脑神经肽的影响，这些神经肽可促进（促食欲肽）或抑制进食。其中，弓状核中的神经肽Y（NPY）以及下丘脑外侧的黑色素浓缩激素（MCH）和食欲素/下丘脑泌素受到了关注，因为它们在禁食期间表达增加，并且在中枢给药时会促进进食。令人惊讶的是，缺乏促食欲神经肽NPY并不会改变正常小鼠的进食或体重。由于限制食物摄入途径的单个成分（如瘦素或黑皮质素-4受体）的缺乏会导致肥胖，因此有人提出促食欲信号比那些限制食物摄入的信号更具冗余性。为了进一步明确MCH的生理作用并测试促食欲信号的冗余性，我们培育出了携带MCH基因靶向缺失的小鼠。尽管MCH缺陷小鼠的瘦素和弓状核阿片-促黑素皮质素原信使核糖核酸含量均降低，但由于摄食减少（进食减少）和代谢率不适当升高，它们的体重减轻且体型消瘦。我们的研究结果表明，MCH是进食和能量平衡的关键调节因子，其作用于瘦素和黑皮质素系统的下游，并且单个促食欲肽编码基因的缺失可导致消瘦。
