Hyperinsulinemia induces early and dyssynchronous puberty in lean female mice

in Journal of Endocrinology
Authors:
Farrah L Saleh 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

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https://orcid.org/0000-0002-3704-3309
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Aditi A Joshi Section of Reproductive Endocrinology, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA

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Aya Tal Section of Reproductive Endocrinology, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA

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Patricia Xu Section of Reproductive Endocrinology, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA

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Julie R Hens Section of Endocrinology, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA

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Serena L Wong Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA

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Clare A Flannery Section of Reproductive Endocrinology, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA
Section of Endocrinology, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA

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Correspondence should be addressed to C A Flannery: clare.flannery@yale.edu
DOI:
https://doi.org/10.1530/JOE-21-0447
Volume/Issue:
Volume 254: Issue 3
Article Type:
Research Article
Page Range:
121–135
Online Publication Date:
09 Aug 2022
Copyright:
© Society for Endocrinology 2022
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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.

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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© Society for Endocrinology 2022
Page(s):
15
Article Type:
Research Article
Received Date:
20 May 2022
Accepted Date:
27 Jun 2022
Print Publication Date:
01 Sep 2022
Online Publication Date:
09 Aug 2022
Keywords:
puberty; insulin; insulin receptor; obesity

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