Section of Reproductive Endocrinology, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA.
Frank H. Netter School of Medicine, Quinnipiac University, North Haven, Connecticut, USA.
J Endocrinol. 2022 Aug 9;254(3):121-135. doi: 10.1530/JOE-21-0447. Print 2022 Sep 1.
Girls with obesity are at increased risk of early puberty. Obesity is associated with insulin resistance and hyperinsulinemia. We hypothesized that insulin plays a physiological role in pubertal transition, and super-imposed hyperinsulinemia due to childhood obesity promotes early initiation of puberty in girls. To isolate the effect of hyperinsulinemia from adiposity, we compared pre-pubertal and pubertal states in hyperinsulinemic, lean muscle (M)-insulin-like growth factor 1 receptor (IGF-1R)-lysine (K)-arginine (R) (MKR) mice to normoinsulinemic WT, with puberty onset defined by vaginal opening (VO). Our results show MKR had greater insulin resistance and higher insulin levels (P < 0.05) than WT despite lower body weight (P < 0.0001) and similar IGF-1 levels (P = NS). Serum luteinizing hormone (LH) levels were higher in hyperinsulinemic MKR (P = 0.005), and insulin stimulation induced an increase in LH levels in WT. VO was earlier in hyperinsulinemic MKR vs WT (P < 0.0001). When compared on the day of VO, kisspeptin expression was higher in hyperinsulinemic MKR vs WT (P < 0.05), and gonadotropin-releasing hormone and insulin receptor isoform expression was similar (P = NS). Despite accelerated VO, MKR had delayed, disordered ovarian follicle and mammary gland development. In conclusion, we found that hyperinsulinemia alone without adiposity triggers earlier puberty. In our study, hyperinsulinemia also promoted dyssynchrony between pubertal initiation and progression, urging future studies in girls with obesity to assess alterations in transition to adulthood.
肥胖女孩青春期提前的风险增加。肥胖与胰岛素抵抗和高胰岛素血症有关。我们假设胰岛素在青春期过渡中发挥生理作用，而儿童肥胖引起的高胰岛素血症会促进女孩青春期的早期启动。为了将高胰岛素血症的影响与肥胖分开，我们比较了高胰岛素血症、瘦肌肉（M）-胰岛素样生长因子 1 受体（IGF-1R）-赖氨酸（K）-精氨酸（R）（MKR）小鼠的青春期前和青春期状态与正常胰岛素血症 WT 相比，青春期的开始由阴道开口（VO）定义。我们的结果表明，尽管体重较低（P < 0.0001）且 IGF-1 水平相似（P = NS），但 MKR 的胰岛素抵抗和胰岛素水平更高（P < 0.05）。血清黄体生成素（LH）水平在高胰岛素血症 MKR 中更高（P = 0.005），胰岛素刺激可诱导 WT 中 LH 水平升高。高胰岛素血症 MKR 比 WT 更早出现 VO（P < 0.0001）。在 VO 当天进行比较时，高胰岛素血症 MKR 中的 kisspeptin 表达高于 WT（P < 0.05），而促性腺激素释放激素和胰岛素受体同工型的表达相似（P = NS）。尽管 VO 提前，但 MKR 的卵巢卵泡和乳腺发育延迟且紊乱。总之，我们发现，没有肥胖症的单纯高胰岛素血症会引发更早的青春期。在我们的研究中，高胰岛素血症还促进了青春期开始和进展之间的不同步，敦促对肥胖女孩进行未来的研究以评估向成年期过渡的改变。
