Neither Signal Transducer and Activator of Transcription 3 (STAT3) or STAT5 Signaling Pathways Are Required for Leptin's Effects on Fertility in Mice

Abstract

The hormone leptin is critical for the regulation of energy balance and fertility. The long-form leptin receptor (LepR) regulates multiple intracellular signaling cascades, including the classic Janus kinase-signal transducer and activator of transcription (STAT) pathways. Previous studies have shown that deletion of STAT3 or the closely related STAT5 from the brain results in an obese phenotype, but their roles in fertility regulation are not clear. This study tested whether STAT3 and STAT5 pathways of leptin signaling are required for fertility, and whether absence of one pathway might be compensated for by the other in a redundant manner. A Cre-loxP approach was used to generate 3 models of male and female transgenic mice with LepR-specific deletion of STAT3, STAT5, or both STAT3 and STAT5. Body weight, puberty onset, estrous cyclicity, and fertility were measured in all knockout (KO) mice and their control littermates. Knocking out STAT3 or both STAT3 and 5 from LepR expressing cells, but not STAT5 alone, led to significant increase in body weight. All STAT3 and STAT5 single KO mice exhibited normal puberty onset and subsequent fertility compared to their control littermates. Surprisingly, all STAT3 and STAT5 double KO mice also exhibited normal puberty onset, estrous cyclicity, and fertility, although they had severely disrupted body weight regulation. These results suggest that, although STAT3 signaling is crucial for body weight regulation, neither STAT3 nor STAT5 is required for the regulation of fertility by leptin. It remains to be determined what other signaling molecules mediate this effect of leptin, and whether they interact in a redundant manner.

PI3Kα inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction

“…This approach has produced important data on the role of JAK/STAT, IRS2, and PTEN signaling downstream of leptin action (14,25,26). We were able to dissociate the effects of PI3Kα and PI3Kβ in metabolic regulation and demonstrate the requirement for PI3Kα in LR for growth and reproduction.…”

“…To dissociate the effects of both hormones and gain insights into the role of PI3K downstream of leptin action, we deleted PI3K catalytic subunits only in LR cells. A similar approach has produced compelling data on the requirement of STAT3, STAT5, and PTEN actions downstream of leptin signaling (14,23,26). Because the coexpression of LR and InsR has not been systematically investigated, we assessed if lack of insulin signaling in LR cells accounts for the phenotype observed following LR PI3K deletion.…”

“…However, they show improved glucose homeostasis, growth, and fertility compared with leptin signaling-deficient (db/db, Lepr db ) mice. Likewise, lack of either leptin-induced SHP2/ERK or STAT5 pathways caused only mild metabolic and neuroendocrine phenotypes (24)(25)(26). Here, we used single and dual deletion of PI3Kα and PI3Kβ in LR cells to dissect the role of individual PI3K catalytic subunits in energy homeostasis, growth, and reproductive function.…”

Leptin promotes the proliferation and migration of human breast cancer through the extracellular-signal regulated kinase pathway

“…It has been reported that leptin levels are positively correlated with weight gain (14). Furthermore, studies have observed that leptin is capable of modulating several other processes, including angiogenesis (15), fertility (16) and immune response (17). In addition, evidence suggests that leptin may be involved in tumorigenesis, particularly in the development of breast, colorectal and prostate cancer (8).…”

Neuroendocrine integration of nutritional signals on reproduction

“…Mice lacking LepR from GABA neurons were profoundly obese and exhibited delayed puberty and subfertility , whereas mice lacking InsR from GABA neurons exhibited a very mild metabolic phenotype and normal pubertal development and fertility (Evans et al 2014b). Although it remains a possibility that the reproductive impairments observed in the GABA-specific LepR-knockout mice were directly related to their obesity phenotype, our lab and others have demonstrated that reproductive competency can be maintained despite profound obesity (Bates et al 2003, Singireddy et al 2013, suggesting leptin-GABA signaling is directly involved in the control of HPG axis function. In contrast, insulin-GABA signaling does not appear to be critically involved in regulating fertility.…”