Impaired steroidogenesis in the testis of leptin-deficient mice (ob/ob -/-)

Martins, Fabiane Ferreira; Águila, Márcia Barbosa; Mandarim-de-Lacerda, Carlos Alberto

doi:10.1016/j.acthis.2017.05.003

Cited by 23 publications

(22 citation statements)

References 27 publications

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“…The testicular steroidogenesis and proliferation are regulated by adipokine through the autocrine and paracrine mechanisms (El‐Hefnawy, Ioffe, & Dym, 2000), and the expression and levels of adipokines are altered in the diabetic conditions (Verrijn Stuart et al, 2012). Ob‐R are involved in the modulation of testicular steroidogenesis and the proliferation of testicular cells (Herrid et al, 2008; Martins et al, 2017). However, the localization pattern of Ob‐R along with levels of intratesticular leptin has not been evaluated in the diabetic testis, Type I diabetes in particular.…”

Section: Discussionmentioning

confidence: 99%

“…Both leptin, the most important adipokine (Zhang et al, 1994), and the leptin receptor (LEPR/Ob‐R; Zhang et al, 1997), through which leptin realizes its regulatory effects on the target cells are expressed in the testes of mammals (Herrid, O'Shea, & McFarlane, 2008). In DM1, in humans and experimental animals the plasma levels of leptin are decreased significantly (Kraus, Herman, & Kahn, 2010), and a leptin deficiency leads to the reduced testicular activity (Martins, Aguila, & Mandarim‐de‐Lacerda, 2017). Since leptin has a significant effect on the steroidogenesis and spermatogenesis (Hoffmann et al, 2016; Shpakov, Ryzhov, Bakhtyukov, & Derkach, 2018), the leptin monotherapy causes their improvement in DM1 (Schoeller et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Effect of metformin on testicular expression and localization of leptin receptor and levels of leptin in the diabetic mice

Annie

Jeremy

Gurusubramanian

et al. 2020

Molecular Reproduction Devel

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Diabetes mellitus impairs testicular activity and leads to infertility. Leptin is one of the endogenous regulators of the male reproductive functions, but the role of leptin and its receptor (LEPR/Ob-R) in the control of testosterone production and testicular proliferation has not been investigated so far, especially in the Type 1 diabetes mellitus (DM1). Metformin is an anti-hyperglycemic drug which is beneficial for treating the both DM2 and DM1. The aim of this work was to study the possible role of leptin and Ob-R in the regulation of steroidogenesis and proliferation in the testes of mice with streptozotocin-induced DM1 (75 mg/kg/day, 4 days) and to estimate the restoring effect of metformin treatment (500 mg/kg, 2 weeks) on the diabetic testes. In the diabetic testes, the plasma and intratesticular leptin levels and plasma testosterone levels were reduced and completely restored by metformin treatment. Metformin also restored the expression of the steroidogenic transport protein steroidogenic acute regulatory protein reduced in DM1. In the diabetic testes, the expression of Ob-R was downregulated and the immunolocalization of Ob-R showed weak staining in the Leydig cells, the primary spermatocytes and the round spermatids. The germ cell proliferation was also reduced in DM1, as noticed with proliferating cell nuclear antigen (PCNA) expression. Metformin increased the Ob-R expression and immunostaining in the different cell types and improved the PCNA expression. Thus, DM1 impairs the testicular steroidogenesis and proliferation by inhibiting the leptin signaling, causing a decrease in leptin levels and Ob-R expression in the testes of diabetic mice, while metformin improves the leptin signaling and restores testosterone production and testicular proliferation. K E Y W O R D S diabetes mellitus, leptin, metformin, Ob-R, testes, testosterone 1 | INTRODUCTION The Types 1 and 2 diabetes mellitus (DM1 and DM2) are widespread metabolic diseases. The DM1 is characterized by insulin deficiency and severe hyperglycemia, while the DM2 is characterized by insulin resistance and impaired glucose tolerance (American Diabetes Association, 2013). In DM, the prolonged hyperglycemia, the pathological changes in energy metabolism and

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of metformin on testicular expression and localization of leptin receptor and levels of leptin in the diabetic mice

Annie

Jeremy

Gurusubramanian

et al. 2020

Molecular Reproduction Devel

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“…A recent study showed testicular atrophy in an ob/ob mice model, with testis weight 13% less than the control group ( p < 0.0001) despite higher body weight [ 40 ]. Likewise, this model displayed a decrease in the nuclear volume of Sertoli cells, spermatogonia, and spermatocytes.…”

Section: Introductionmentioning

confidence: 99%

Adipokines in Semen: Physiopathology and Effects on Spermatozoas

Elfassy

Bastard

McAvoy

et al. 2018

International Journal of Endocrinology

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Adipokines are secreted by adipose tissue and could be the link between obesity and infertility. Different studies investigated the involvement of adipokines in reproductive functions but only a few have looked into the male part. This review assesses adipokine functions on male reproductive parameters. Adiponectin seems to have a positive effect on sperm parameters, whereas other adipokines such as resistin or chemerin would have a rather deleterious effect on spermatogenesis. Semen parameters seem to be impacted when resistin and chemerin are increased: indeed, there is a decrease of sperm motility. Sperm morphology is improved when adiponectin is increased. The most studied adipokine, leptin, has a dual effect with a positive effect on sperm at physiological levels and a negative one for high seminal concentrations. Many semen parameters and fertility itself are disturbed according to semen adipokine levels, even if it is not the only interfering element. Taken together, adipokines are found in human and animal semen and most of them or their receptors are expressed in male genital tract. Although the pathophysiological role of adipokines in semen is not clearly elucidated, the adipokines could influence sperm functionality and could be potential biomarkers of male fertility.

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“…PCNA is associated with DNA replication during the cell cycle and considered a useful marker for cell proliferation (Wang, 2014). Obese mice have a low expression level of PCNA in testis (Martins, Aguila, & Mandarim‐de‐Lacerda, 2017). Together, these evidence further support the potential role of increasing adenosine in affecting spermatogenesis in obese testes.…”

Section: Discussionmentioning

confidence: 99%

Adenosine accumulation causes metabolic disorders in testes and associates with lower testosterone level in obese mice

Yang

Zhao

Sun

et al. 2020

Molecular Reproduction Devel

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Overweight and obese men face numerous health problems, including type 2 diabetes, subfertility, and even infertility. However, few studies have focused on the effects of nutritional status and obesity‐related regulatory signals on fertility deficiency. Our previous observations have shown that the elevation of plasma 5'‐adenosine monophosphate (5'‐AMP) and the accumulation of adenosine in liver and muscle of obese diabetic db/db mice are related to insulin resistance. Here, we found that adenosine accumulation in testis is a common marker of both genetic obesity and high‐fat‐diet induced obese mice. An messenger RNA sequencing analysis indicated that 78 upregulated genes and 155 downregulated genes in the testis of 5'‐AMP‐treated mice overlapped with the same genes in the testis of ob/ob mice, and these genes belonged to the clusters of steroid metabolic process and regulation of hormone levels, respectively. Serum testosterone was reduced in ob/ob and 5'‐AMP‐treated mice. Metabolomic analysis based on 1H nuclear magnetic resonance showed that the testicular metabolic profiles of ob/ob mice were similar to those of 5'‐AMP treated mice. Exogenous 5'‐AMP inhibited the phosphorylation of AKT and mammalian target of rapamycin signal transduction and reduced the proliferating cell nuclear antigen expressions in testes. Our results suggest that the accumulation of adenosine causes metabolic disorders in testes and associates lower testosterone level in obese mice.

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Impaired steroidogenesis in the testis of leptin-deficient mice (ob/ob -/-)

Cited by 23 publications

References 27 publications

Effect of metformin on testicular expression and localization of leptin receptor and levels of leptin in the diabetic mice

Effect of metformin on testicular expression and localization of leptin receptor and levels of leptin in the diabetic mice

Adipokines in Semen: Physiopathology and Effects on Spermatozoas

Adenosine accumulation causes metabolic disorders in testes and associates with lower testosterone level in obese mice

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