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Published on: June 3, 2016
Loss of PI3K p110α in the Adipose Tissue Results in Infertility and Delayed Puberty Onset in Male Mice
Victoria L Boughton Nelson1, Ariel L Negrón2, Inefta Reid1
1Department of Physiology and Biophysics, Stony Brook University Medical Center, Stony Brook, NY, USA.
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.
Insights
Deleting PI3K p110α in fat tissue impairs male reproduction, causing delayed puberty and infertility. Chronic high leptin levels likely contribute to these reproductive issues in mice.
Area of Science:
- Endocrinology
- Reproductive Biology
- Metabolic Syndrome
Background:
- Phosphoinositide 3-kinase (PI3K) signaling is crucial for metabolic regulation.
- Adipose tissue plays a key role in endocrine functions, influencing reproductive health.
- PI3K p110α deletion in adipocytes leads to metabolic disturbances like obesity and glucose intolerance.
Purpose of the Study:
- To investigate the reproductive phenotype of male mice lacking PI3K catalytic subunit p110α in adipose tissue.
- To determine the impact of disrupted PI3K signaling in adipocytes on male puberty, fertility, and hormone levels.
- To explore the role of leptin in mediating reproductive dysfunction.
Main Methods:
- Generation of adipose-specific PI3K p110α knockout mice (aP2-Cre/p110αflx/flx).
- Assessment of reproductive parameters including puberty onset, testicular weight, hormone levels (LH, FSH, estradiol, leptin), sperm parameters, and gene expression.
- Analysis of key steroidogenic genes (StAR, P450scc, 17β-HSD3) and estrogen receptor alpha (ERα) in testicular tissue.
Main Results:
- aP2-Cre/p110α-/- males exhibited delayed puberty, reduced testicular weight, and infertility.
- Elevated plasma leptin levels and increased testicular leptin gene expression were observed.
- Hyperandrogenemia was present, with decreased StAR and P450scc expression but increased 17β-HSD3 expression; ERα levels were reduced.
Conclusions:
- Disruption of PI3K signaling in adipose tissue negatively impacts male reproductive function.
- Chronic hyperleptinemia is implicated as a contributing factor to impaired puberty onset, steroidogenesis, and fertility.
- Adipose PI3K p110α is essential for maintaining normal male reproductive physiology.
