A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors
A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors
复制标题
DOI：
10.1073/pnas.220409497
复制
发表时间：
2000-10-24
影响因子：
11.1
通讯作者：
Palmiter, RD
中科院分区：
文献类型：
--
作者：
Ste Marie, L;Miura, GI;Palmiter, RD
黑皮质素-4受体（Mc 4 r）缺失小鼠表现出迟发性肥胖。为了确定异常代谢是否导致肥胖，将Mc 4 r缺失小鼠的食物消耗限制为野生型（WT）小鼠消耗的食物（成对喂养）。配对喂养的Mc 4 r缺失雌性小鼠的体重保持在WT和非配对喂养的Mc 4 r缺失雌性小鼠的体重中间，而配对喂养使Mc 4 r缺失雄性小鼠的体重正常化。与野生型小鼠相比，雄性和雌性配对喂养的Mc 4 r基因敲除小鼠的脂肪垫和循环瘦素水平均升高。体重与WT对照相似的Mc 4 r缺失小鼠的耗氧量降低了20%。年轻非肥胖Mc 4 r缺失雄性的运动活动显着低于WT雄性;然而，年轻非肥胖雌性的运动正常。Mc 4 r基因敲除小鼠的核心体温是正常的，并且它们对冷暴露的反应正常。年轻的非肥胖的Mc 4 r-null女性不能诱导解偶联蛋白1（UCP 1）在棕色脂肪组织中响应外周瘦素管理，而UCP 1 mRNA增加了60%的WT女性。这些结果表明，Mc 4 r缺乏增强热量效率，类似于在无食欲肥胖综合征和黑皮质素-3受体缺失小鼠中所见。
Melanocortin-4 receptor (Mc4r)-null mice exhibit late-onset obesity. To determine whether aberrant metabolism contributes to the obesity, food consumption by Mc4r-null mice was restricted to (pair-fed to) that consumed by wild-type (WT) mice. Pair-fed Mc4r-null females maintained body weights intermediate to that of WT and nonpair-fed Mc4r-null females, whereas pairfeeding normalized the body weights of Mc4r-null male mice. Fat pad and circulating leptin levels were elevated in both male and female pair-fed Mc4r-null mice compared with WT mice. Oxygen consumption of Mc4r-null mice with similar body weights as WT controls was reduced by 20%. Locomotor activity of young nonobese Mc4r-null males was significantly lower than that of WT males; however, locomotion of young nonobese females was normal. Core body temperature of Mc4r-null mice was normal, and they responded normally to cold exposure. Young nonobese Mc4r-null females were unable to induce uncoupling protein 1 (UCP1) in brown adipose tissue in response to peripheral leptin administration, whereas UCP1 mRNA was increased by 60% in the WT females. These results indicate that Mc4r deficiency enhances caloric efficiency, similar to that seen in the agouti obesity syndrome and in melanocortin-3 receptor-null mice.