Roles of Insulin Receptors and IGF-1 Receptors in Leptin-Responsive Neurons in Regulation of Body Weight, Growth, Pubertal Development and Fertility

Presentation Number: SAT 422
Date of Presentation: April 1st, 2017

Mengjie Wang*1 and Jennifer Wootton Hill2
1University of Toledo, Toledo, OH, 2University of Toledo School of Medicine, Toledo, OH

Abstract

Growth and reproduction are tightly linked. Growth hormone deficiency results in a profound suppression of postnatal growth accompanied by delayed puberty (of a week or more in mice) and delayed reproductive senescence, while GH excess is correlated with the reverse (1). The specific mechanism underlying this delay is undefined. IGF-1 administration advances pubertal timing, however deletion of IGF-1R from GnRH neurons only delays puberty by 3-4 days (2). Thus, upstream, metabolically active neurons may play a role in the effects of IGF-1 on pubertal timing. Although neurons in the hypothalamus that express leptin receptors (LepRb) are known to modulate the timing of puberty, whether IGF-1 receptor (IGF-1R) signaling in these neurons controls pubertal development is unknown. To test whether IGF-1 action specifically in LepRb expressing cells affects pubertal development and fertility, we used Cre-loxp technology to generate female transgenic mice lacking IGF-1R exclusively in LepRb expressing cells (termed IGF-1RLepRb). Because IGF-1R and insulin receptor (IR) signaling overlap, we also generated double knockout female mice (termed IGF-1R/IRLepRb) (3). IGF-1RLepRb mice experienced delayed pubertal development and impaired fertility. Surprisingly, the vaginal opening age, first estrus age, and fertility were comparable between the IGF-1RLepRb and IGF-1R/IRLepRb female mice. IGF-1RLepRb mice also exhibited metabolic abnormalities including reduced body weight and body growth. However, the body weight and body length in IGF-1R/IRLepRb female mice were significantly lower than IGF-1RLepRb mice. These findings identify divergent roles of IR and IGF-1R signaling in LepRb neurons. IGF-1R signaling in leptin responsive neurons plays a dominant role in the control of body weight, body length, and pubertal development and fertility, while IR signaling contributes to the control of body weight and body length.

 

Nothing to Disclose: MW, JWH