Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.
Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
Diabetes. 2020 Jun;69(6):1110-1125. doi: 10.2337/db19-0849. Epub 2020 Mar 9.
Amylin, a pancreatic hormone and neuropeptide, acts principally in the hindbrain to decrease food intake and has recently been shown to act as a neurotrophic factor to control the development of area postrema → nucleus of the solitary tract and arcuate hypothalamic nucleus → paraventricular nucleus axonal fiber outgrowth. Amylin is also able to activate ERK signaling specifically in POMC neurons independently of leptin. For investigation of the physiological role of amylin signaling in POMC neurons, the core component of the amylin receptor, calcitonin receptor (CTR), was depleted from POMC neurons using an inducible mouse model. The loss of CTR in POMC neurons leads to increased body weight gain, increased adiposity, and glucose intolerance in male knockout mice, characterized by decreased energy expenditure (EE) and decreased expression of uncoupling protein 1 (UCP1) in brown adipose tissue. Furthermore, a decreased spontaneous locomotor activity and absent thermogenic reaction to the application of the amylin receptor agonist were observed in male and female mice. Together, these results show a significant physiological impact of amylin/calcitonin signaling in CTR-POMC neurons on energy metabolism and demonstrate the need for sex-specific approaches in obesity research and potentially treatment.
胰岛淀粉样多肽是一种胰腺激素和神经肽，主要在后脑中发挥作用，以减少食物摄入，最近已被证明其作为一种神经营养因子来控制后脑区（迷走神经背核-孤束核复合体）和弓状核-室旁核投射纤维的发育。胰岛淀粉样多肽还能够独立于瘦素激活 POMC 神经元中的 ERK 信号。为了研究胰岛淀粉样多肽信号在 POMC 神经元中的生理作用，使用诱导型小鼠模型使 POMC 神经元中的胰岛淀粉样多肽受体核心成分降钙素受体（CTR）耗竭。POMC 神经元中 CTR 的缺失导致雄性敲除小鼠体重增加、肥胖和葡萄糖耐量受损，其特征为能量消耗减少（EE）和棕色脂肪组织中解偶联蛋白 1（UCP1）的表达减少。此外，还观察到雄性和雌性小鼠的自发性运动活动减少，以及应用胰岛淀粉样多肽受体激动剂时的产热反应缺失。总之，这些结果表明，CTR-POMC 神经元中的胰岛淀粉样多肽/降钙素信号对能量代谢有重要的生理影响，并表明在肥胖研究和潜在治疗中需要采用性别特异性方法。
