Corticotropin-releasing factor receptor-2-deficient mice display abnormal homeostatic responses to challenges of increased dietary fat and cold
Corticotropin-releasing factor receptor-2-deficient mice display abnormal homeostatic responses to challenges of increased dietary fat and cold
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DOI：
10.1210/en.2002-0091
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发表时间：
2003-06-01
期刊：
影响因子：
4.8
通讯作者：
Vale, WW
中科院分区：
文献类型：
--
作者：
Bale, TL;Anderson, KR;Vale, WW
促肾上腺皮质激素释放因子（CRF）及其配体家族是能量平衡的关键调节因子。这些配体通过激活其两种受体CRFR 1和CRFR 2发挥作用。CRFR 1已被证明是下丘脑-垂体-肾上腺轴在应激反应中激活的主要受体，也是边缘系统中焦虑的关键介质。为了具体检查CRFR 2在能量平衡中的作用，将CRFR 2缺陷的小鼠暴露于稳态的生理扰动，包括高脂饮食、反复冷应激以及葡萄糖和胰岛素挑战，并测量它们的反应。在高脂肪饮食中，CRFR 2突变小鼠消耗更多的食物并保持相同的体重，但与野生型同窝小鼠相比，其体脂和血浆脂质显著降低。这些小鼠也不太倾向于发展饮食诱导的胰岛素抵抗，对血糖变化更敏感，表明胰岛素敏感性增加。重复冷应激后，突变小鼠的体脂显著降低，饲料效率短暂降低，尽管体重相似，这表明可能偏好脂肪作为能量底物。CRFR 2突变小鼠棕色脂肪组织以及较小的白色和棕色脂肪细胞中解偶联蛋白-1水平升高表明交感神经张力可能增加。这些结果表明，CRFR 2在调节能量消耗中起着关键作用，并且对于应对稳态挑战很重要。
Corticotropin-releasing factor (CRF) and its family of ligands are key regulators of energy balance. These ligands function via activation of their two receptors, CRFR1 and CRFR2. CRFR1 has been shown to be the dominant receptor in activation of the hypothalamic-pituitary-adrenal axis in response to stress as well as a key mediator of anxiety in the limbic system. To specifically examine the role of CRFR2 in energy balance, mice deficient for CRFR2 were exposed to physiological perturbations of homeostasis, including high-fat diet, repeated cold stress, and glucose and insulin challenges, and their responses measured. While on a high-fat diet, CRFR2-mutant mice consumed substantially more food and maintaining the same weight but had significantly lower body fat and lower plasma lipids than their wild-type littermates. These mice were also less inclined to develop diet-induced insulin resistance and more sensitive to changes in plasma glucose, indicating increased insulin sensitivity. Following repeated cold stress, mutant mice had significantly lower body fat and a transient reduction in feed efficiency, despite similar body weights, suggesting a possible preference for fat as an energy substrate. Elevated levels of uncoupling protein-1 in brown adipose tissue as well as smaller white and brown adipocytes from CRFR2-mutant mice were indications of possible increased sympathetic tone. These results demonstrate that CRFR2 plays a critical role in regulation of energy expenditure and is important for responses to homeostatic challenges.