Wang Mengjie, Czernik Piotr J, Lecka-Czernik Beata, Xu Yong, Hill Jennifer W
Center for Diabetes and Endocrine Research, Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio, USA.
USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
bioRxiv. 2024 Sep 20:2024.09.20.614140. doi: 10.1101/2024.09.20.614140.
Leptin receptor (LepRb)-expressing neurons are known to link body growth and reproduction, but whether these functions are mediated via insulin-like growth factor 1 receptor (IGF1R) signaling is unknown. IGF-1 and insulin can bind to each other's receptors, permitting IGF-1 signaling in the absence of IGF1R. Therefore, we created mice lacking IGF1R exclusively in LepRb neurons (IGF1R mice) and simultaneously lacking IGF1R and insulin receptor (IR) in LepRb neurons (IGF1R/IR mice) and then characterized their body growth, bone morphology, reproductive and metabolic functions. We found that IGF1R and IR in LepRb neurons were required for normal timing of pubertal onset, while IGF1R in LepRb neurons played a predominant role in regulating adult fertility and exerted protective effects against reproductive aging. Accompanying these reproductive deficits, IGF1R mice and IGF1R/IR mice had transient growth retardation. Notably, IGF1R in LepRb neurons was indispensable for normal trabecular and cortical bone mass accrual in both sexes. These findings suggest that IGF1R in LepRb neurons is involved in the interaction among body growth, bone development, and reproduction. Though only mild changes in body weight were detected, simultaneous deletion of IGF1R and IR in LepRb neurons caused dramatically increased fat mass composition, decreased lean mass composition, lower energy expenditure, and locomotor activity in both sexes. Male IGF1R/IR mice exhibited impaired insulin sensitivity. These findings suggest that IGF1R and IR in LepRb neurons jointly regulated body composition, energy balance, and glucose homeostasis. Taken together, our studies identified the sex-dependent complex roles of IGF1R and IR in LepRb neurons in regulating body growth, reproduction, and metabolism.
已知表达瘦素受体（LepRb）的神经元可连接身体生长与生殖，但这些功能是否通过胰岛素样生长因子1受体（IGF1R）信号介导尚不清楚。IGF-1和胰岛素可相互结合对方受体，使得在缺乏IGF1R时仍能进行IGF-1信号传导。因此，我们构建了仅在LepRb神经元中缺乏IGF1R的小鼠（IGF1R小鼠）以及在LepRb神经元中同时缺乏IGF1R和胰岛素受体（IR）的小鼠（IGF1R/IR小鼠），然后对它们的身体生长、骨骼形态、生殖和代谢功能进行了表征。我们发现，LepRb神经元中的IGF1R和IR是青春期正常启动时间所必需的，而LepRb神经元中的IGF1R在调节成年生育能力方面起主要作用，并对生殖衰老具有保护作用。伴随着这些生殖缺陷，IGF1R小鼠和IGF1R/IR小鼠出现了短暂的生长发育迟缓。值得注意的是，LepRb神经元中的IGF1R对于两性正常的小梁骨和皮质骨量积累不可或缺。这些发现表明，LepRb神经元中的IGF1R参与了身体生长、骨骼发育和生殖之间的相互作用。尽管仅检测到体重有轻微变化，但LepRb神经元中IGF1R和IR的同时缺失导致两性脂肪量组成显著增加、瘦体重组成减少、能量消耗降低以及运动活动减少。雄性IGF1R/IR小鼠表现出胰岛素敏感性受损。这些发现表明，LepRb神经元中的IGF1R和IR共同调节身体组成、能量平衡和葡萄糖稳态。综上所述，我们的研究确定了IGF1R和IR在LepRb神经元中调节身体生长、生殖和代谢方面的性别依赖性复杂作用。
