Loss of PI3K p110αin the Adipose Tissue Results in Infertility and Delayed Puberty Onset in Male Mice

Abstract

Deletion of PI3K catalytic subunit p110α in adipose tissue (aP2-Cre/p110αflx/flx, α−/− hereafter) results in increased adiposity, glucose intolerance, and liver steatosis. Because this endocrine organ releases hormones like leptin, which are important in reproductive physiology, we investigated the reproductive phenotype of α−/− males. Compared to controls, α−/− males displayed delayed onset of puberty accompanied by a reduction in plasma LH levels and testicular weight. At postnatal day 30, α−/− mice exhibited normal body weight but elevated fasted plasma leptin levels. Testicular leptin gene expression was increased, whereas expression of the cholesterol transporter StAR and of P450 cholesterol side chain cleavage enzyme was decreased. Adult α−/− males were infertile and exhibited hyperandrogenemia with normal basal LH, FSH, and estradiol levels. However, neither sperm counts nor sperm motility was different between genotypes. The mRNA levels of leptin and of 17-beta-dehydrogenase 3, and enzyme important for testosterone production, were significantly higher in the testis of adult α−/− males. The mRNA levels of ERα, an important regulator of intratesticular steroidogenesis, were lower in the testis of adult and peripubertal α−/− males. We propose that chronic hyperleptinemia contributes to the negative impact that disrupting PI3K signaling in adipocytes has on puberty onset, steroidogenesis, and fertility in males.

PI3K signalling in leptin receptor cells: Role in growth and reproduction

“…Whether deletion of PI3K subunits in LR cells of peripheral tissues may have impacted the growth and reproductive phenotypes observed in our studies needs further evaluation. However, it should be noted that deletion of p110α only in adipocytes resulted in a very distinct phenotype compared to that observed in our studies, such that delayed puberty and infertility were observed only in male (not female) mice . The mechanism(s) associated with this phenotype remain unknown.…”

“…However, it should be noted that deletion of p110α only in adipocytes resulted in a very distinct phenotype compared to that observed in our studies, such that delayed puberty and infertility were observed only in male (not female) mice. 104 The mechanism(s) associated with this phenotype remain unknown. Moreover, no reproductive or linear growth deficits have been described in mice with deletion of LR or disruption of PI3K class I in the liver.…”

The Regulation of the Male Hypothalamic-Pituitary-Gonadal Axis and Testosterone Production by Adipokines

“…The deterioration of reproductive functions was found in mice with a knockout of the gene encoding the catalytic p110α-subunit of PI3K in the adipose tissue [106]. In the testes of 30-day knockout mice with severe hyperleptinemia, the expression of the gene encoding leptin was increased, while the expression of the genes encoding StAR and P450 scc was reduced.…”

“…Adult knockout mice had a severe form of hyperleptinemia, obesity, hepatic steatosis and the impaired glucose tolerance, and were infertile. It was quite unexpected that in the testes of knockout animals the expression of the ob gene and the Hsd17b3 gene encoding 17β-hydroxysteroid dehydrogenase 3 (17β-HSD) was significantly increased, and the plasma level of T was also increased, indicating a pronounced hyperandrogenemia [106]. A possible cause for this was the reduced activity of estrogen receptor-α (Esr1), since in animals lacking the Esr1 gene a similar phenotype with hyperandrogenemia and infertility was described [107,108].…”

Lin28 gene and mammalian puberty

“…The onset of puberty is also gated by body energy reserves and nutritional cues (Vazquez, Velasco, & Tena‐Sempere, 2019), and in which, the adipose hormone leptin is an essential signal to the hypothalamic GnRH pulse generator that there are sufficient energy stores in the adipose tissue for fertility to commence, which is necessary for the initiation of puberty (Ahmed, Ong, & Dunger, 2009; Biro, Khoury, & Morrison, 2006; Egan, Inglis, & Anderson, 2017). Leptin stimulates GnRH secretion by binding to the leptin receptor to activates several signaling pathways, including the 5′ adenosine monophosphate‐activated protein kinase (Roa et al, 2018; Xie et al, 2018), mammalian target of rapamycin (mTOR; Roa & Tena‐Sempere, 2010; Roa et al, 2009), phosphoinositide 3‐kinase (PI3K; Garcia‐Galiano, Borges, Allen, & Elias, 2019; Garcia‐Galiano et al, 2017; Nelson et al, 2017; Nguyen, Zacchi, Schulz, Moore, & Fortes, 2018).…”