Loss of PI3K p110 Alpha in the Adipose Tissue Results in Infertility and Delayed Puberty Onset in Male Mice

Presentation Number: THR-128
Date of Presentation: March 5th, 2015

Maricedes Acosta-Martínez*1, Victoria Boughton Nelson2, Ariel L. Negrón3 and Richard Z Lin2
1Stony Brook University Medical Center, Stony Brook, NY, 2Stony Brook University, Medical Center, Stony Brook, NY, 3Stony Brook University, Stony Brook, NY

Abstract

There is a strong association between obesity and a higher risk for infertility in males.  Several factors contribute to the detrimental effects of obesity on male fertility, including alterations in hormonal profiles and reduced sperm quality.  Despite the increasing prevalence of obesity worldwide, a paucity of studies has examined the underlying mechanisms of obesity-associated male infertility.  White adipose tissue is a major mediator of inflammation and metabolism, and an important source of hormones and proteins, such as estrogen and leptin. Hence, excessive fat accumulation is thought to contribute not only to the metabolic imbalance but also to the impaired reproductive function observed in obese patients.   In adipose tissue, the enzyme phosphatidylinositol-3-kinase (PI3K) plays a critical role in the regulation of systemic glucose and lipid homeostasis, and is a major mediator of insulin responsiveness in this organ.  Using Cre recombinase driven by the aP2 (fatty acid binding protein 4) promoter, we generated mice in which the gene encoding class IA PI3K catalytic subunit, p110α is deleted in white and brown adipose tissue.  aP2-Cre/p110αflx/flx mice have increased adiposity, glucose intolerance, and liver steatosis.  In addition, these mice exhibited low energy expenditure due to low cellular respiration in brown adipocytes.  In the present study we describe the reproductive phenotype of aP2-Cre/p110αflx/flx male mice.  Compared to WT littermates, aP2-Cre/p110αflx/flx males displayed delayed onset of puberty, as determined by the age of balanopreputial separation and anogenital distance.  This was accompanied by a significant reduction in testis weight at postnatal day 30 (PD30).  However, serum testosterone (T) levels were not significantly different between WT and aP2-Cre/p110αflx/flx males at PD30 (15.5 ± 8.8 ng/ml vs. 6.4 ± 1.8 ng/ml, KO (n= 5) and WT (n = 4), respectively).  In contrast, fasted leptin levels were significantly increased in aP2-Cre/p110αflx/flx at PD30 (1.21 ± 0.05 ng/ml (n=5) vs. 1.03 ± 0.02 ng/ml (n=4), KO and WT respectively).  In contrast to WT littermates, aP2-Cre/p110aflx/flx males (2.5 – 3 months of age) were unable to sire pups in proven fertile WT females (mating success of 0 % (n=5) and 60% (n=5) for KO and WT, respectively).   Basal luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels were similar between WT and KO at 2 months of age.  In contrast, serum T levels were significantly increased in aP2-Cre/p110αflx/flx males  (12.8 ± 1.2 ng/ml (n=7) vs. 4.5 ± 1.2 ng/ml (n=10), KO and WT respectively).  No genotype effect was observed on testis weight in adult males.  Our studies suggest that compromised PI3K signaling in adipose tissue is involved in the subfertility associated with impaired metabolic status.

 

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