Dataset Information

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

ABSTRACT: Deletion of PI3K catalytic subunit p110? in adipose tissue (aP2-Cre/p110?^flx/flx, ?-/- 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 ?-/- males. Compared to controls, ?-/- males displayed delayed onset of puberty accompanied by a reduction in plasma LH levels and testicular weight. At postnatal day 30, ?-/- 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 ?-/- 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 ?-/- males. The mRNA levels of ER?, an important regulator of intratesticular steroidogenesis, were lower in the testis of adult and peripubertal ?-/- 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.

SUBMITTER: Nelson VL

PROVIDER: S-EPMC5357525 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Loss of PI3K p110α in the Adipose Tissue Results in Infertility and Delayed Puberty Onset in Male Mice.

Nelson Victoria L Boughton VL Negrón Ariel L AL Reid Inefta I Thomas Justin A JA Yang Leon L Lin Richard Z RZ Acosta-Martínez Maricedes M

BioMed research international 20170305

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 a ...[more]

PMID: 28357399

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Project description:Delayed pubertal onset has many etiologies, but on average two-thirds of patients presenting with late puberty have self-limited (or constitutional) delayed puberty. Self-limited delayed puberty often has a strong familial basis. Segregation analyses from previous studies show complex models of inheritance, most commonly autosomal dominant, but also including autosomal recessive, bilineal, and X-linked. Sporadic cases are also observed. Despite this, the neuroendocrine mechanisms and genetic regulation remain unclear in the majority of patients with self-limited delayed puberty. Only rarely have mutations in genes known to cause aberrations of the hypothalamic-pituitary-gonadal axis been identified in cases of delayed puberty, and the majority of these are in relatives of patients with congenital hypogonadotropic hypogonadism (CHH), for example in the FGFR1 and GNRHR genes. Using next generation sequencing in a large family with isolated self-limited delayed puberty, a pathogenic mutation in the CHH gene HS6ST1 was found as the likely cause for this phenotype. Additionally, a study comparing the frequency of mutations in genes that cause GnRH deficiency between probands with CHH and probands with isolated self-limited delayed puberty identified that a significantly higher proportion of mutations with a greater degree of oligogenicity were seen in the CHH group. Mutations in the gene IGSF10 have been implicated in the pathogenesis of familial late puberty in a large Finnish cohort. IGSF10 disruption represents a fetal origin of delayed puberty, with dysregulation of GnRH neuronal migration during embryonic development presenting for the first time in adolescence as late puberty. Some patients with self-limited delayed puberty have distinct constitutional features of growth and puberty. Deleterious variants in FTO have been found in families with delayed puberty with extremely low BMI and maturational delay in growth in early childhood. Recent exciting evidence highlights the importance of epigenetic up-regulation of GnRH transcription by a network of miRNAs and transcription factors, including EAP1, during puberty. Whilst a fascinating heterogeneity of genetic defects have been shown to result in delayed and disordered puberty, and many are yet to be discovered, genetic testing may become a realistic diagnostic tool for the differentiation of conditions of delayed puberty.

Dataset Information

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

Publications

Loss of PI3K p110<i>α</i> in the Adipose Tissue Results in Infertility and Delayed Puberty Onset in Male Mice.

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