Leptin Within the Subphysiological to Physiological Range Dose Dependently Improves Male Reproductive Function in an Obesity Mouse Model

Abstract

Obesity has recently been linked with reduced fertility, and the mechanisms underpinning this effect are currently unknown. The adipokine leptin is dysregulated in obesity and affects reproductive tracts; therefore, we investigated the dose-dependent effects of leptin on Leydig cell function and spermatogenesis. Eight-week-old leptin-deficient obese (ob/ob) male mice were treated with subphysiological (0.1- or 0.5-mg/kg body weight [BW]/d) or physiological (3.0-mg/kg BW/d) doses of leptin or saline for 12 weeks (chronic treatment) or 72 hours (acute treatment). We then evaluated male reproductive function markers. Mean testis weight increased significantly in the 0.1- and 3.0-mg/kg BW/d groups compared with saline controls (both P < .05). Intratesticular testosterone levels relative to testis weight significantly increased in the 0.5-mg/kg BW/d group compared with saline controls (P < .05). FSH levels increased in a dose-dependent manner with leptin treatment, whereas LH levels did not change. Leptin treatment significantly up-regulated both mRNA and protein expression of the steroidogenic enzyme cytochrome P450 17A1. Spermatogenesis improved in leptin-treated animals. Significantly more seminiferous tubules were observed in stages I-VIII (P < .01), and there were fewer abnormal seminiferous tubule structures (P < .01). Acute treatment with physiological leptin doses partially improved male reproductive markers without changing BW. Administration of subphysiological to physiological doses of leptin improves Leydig cell function and spermatogenesis.

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

“…In addition to adipose-derived leptin, testicular leptin regulates T production from Leydig cells through its ability to regulate steroidogenic enzymes [2, 33, 34]. Furthermore, obesity-associated hyperleptinemia negatively impacts testicular function and T production in males [35–37].…”

“…For example, mice with congenital deficiency of leptin ( ob/ob mice) exhibit hyperphagia, reduced energy expenditure, obesity, and infertility [41]. Administration of leptin to ob/ob mice restores their fertility [33, 42, 43], and in normal animals, it can advance puberty onset [44]. On the other hand, deregulated leptin production, especially at an early developmental stage, can have detrimental effects on the maturation and function of the HPG axis [45].…”

“…The actions of leptin on the HPG axis are complex and whether its effects are stimulatory or inhibitory depends on the concentration and duration, as well as the developmental state. For example, in vivo and in vitro studies suggest that at low concentrations leptin induces testicular T secretion, whereas high leptin concentrations are inhibitory [9, 33, 45, 47, 48]. The LepR is expressed in the testis and circulating leptin can cross the blood-testis barrier [49–52].…”

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

“…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). However, there is less information available on the intratesticular expression of leptin and its receptor in the conditions of DM1.…”

Normalization of adiponectin concentrations by leptin replacement in ob/ob mice is accompanied by reductions in systemic oxidative stress and inflammation

“…In this sense, leptin-deficient ob/ob mice, in which leptin’s effect are absent, exhibit either decreased 18, 19 , increased 20, 21 , or unchanged 22 adiponectin circulating concentrations. Moreover, many previous studies have used supraphysiological or even pharmacological doses of leptin 18, 23 that may overestimate its effects or, alternatively, exert no effect since it has been reported that pharmacological doses of leptin may lose its effect due to saturation or downregulation of receptors 24 or even elicit opposite effects to those observed after the administration of a low leptin dose around the physiological level 25 .…”