Obesity is a chronic illness associated with several metabolic derangements and comorbidities (i.e., insulin resistance, leptin resistance, diabetes, etc.) and often leads to impaired testicular function and male subfertility. Several mechanisms may indeed negatively affect the hypothalamic–pituitary–gonadal health, such as higher testosterone conversion to estradiol by aromatase activity in the adipose tissue, increased ROS production, and the release of several endocrine molecules affecting the hypothalamus–pituitary–testis axis by both direct and indirect mechanisms. In addition, androgen deficiency could further accelerate adipose tissue expansion and therefore exacerbate obesity, which in turn enhances hypogonadism, thus inducing a vicious cycle. Based on these considerations, we propose an overview on the relationship of adipose tissue dysfunction and male hypogonadism, highlighting the main biological pathways involved and the current therapeutic options to counteract this condition.

Excess circulating fatty acids contributes to the association between metabolic disorders and hormonal alterations. Indeed, obesity and diabetes mellitus are frequently associated with functional hypogonadism characterised by reduced testosterone levels. Although a high-fat-diet is known to negatively affect testicular function, its specific impact on steroidogenesis remains unclear. Therefore, the aim of this study has been to investigate the effects of different FFAs, with or without human chorionic gonadotropin (hCG) stimulation, on steroidogenesis and apoptosis in a murine Leydig cell line (mLTC1). mLTC1 cells were exposed with increasing concentrations of palmitate (PA) or oleate (OA), in the presence or absence of 0.2 IU/mL hCG. The expression of the Steroidogenic Acute Regulatory (STAR) protein, a key marker of steroidogenesis, was evaluated by immunoblotting. Testosterone secretion was measured by ELISA, while apoptosis was evaluated by cleaved caspase-3 (C3C) protein expression using immunoblotting. Exposure to PA significantly reduced hCG-induced STAR protein expression in a dose-dependent manner after 6h and 15h, respectively, compared with PA-free conditions. Similarly, exposure to OA reduced STAR protein expression at all concentrations tested (0.4-1 mM). Prolonged treatment with PA (96 hours) further compromised steroidogenic capacity, leading to a reduction in testosterone production. Furthermore, PA significantly increased C3C levels. Notably, hCG stimulation during the last 6h of incubation significantly reduced PA-induced C3C levels at all concentrations. In conclusion, both PA and OA impair hCG-induced steroidogenesis, while PA additionally promotes Leydig cell apoptosis. These findings suggest a direct detrimental role of excess FFAs on testicular function in obesity and indicate a potential protective role of hCG in preserving Leydig cell viability under conditions of metabolic stress.

Objective: The insulin receptor (IR) and the insulin‐like growth factor I receptor (IGF‐IR) regulate adipose tissue (AT) differentiation. This study investigated the expression of IGF‐IR, IR, and the IR isoforms (IRa and IRb) in human subcutaneous (S‐ASC) and visceral (V‐ASC) adipose‐derived stem cells. Methods: S‐AT and V‐AT biopsies were obtained from human donors and ASC were differentiated into adipocytes. mRNA levels of all receptors were quantified by qPCR at baseline and after differentiation. IR protein expression and adipogenic efficiency were assessed by flow cytometry. Results: In undifferentiated ASC, IGF‐IR transcripts exceeded IR and were higher in S‐ASC than V‐ASC. Upon differentiation, IGF‐IR decreased in S‐ASC but remained unchanged in V‐ASC, whereas IR increased in both depots. S‐ASC displayed ~twofold higher IRa expression and greater insulin‐induced Akt activation. During adipogenesis, IR expression rose in both depots, with IRb exceeding IRa particularly in V‐ASC (+50%). In whole AT, IR exceeded IGF‐IR, and no depot‐specific differences were observed between IR isoforms. Adipogenic conversion was higher in S‐ASC (60%) than V‐ASC (20%). Only ~77% of S‐ASC‐ and ~61% of V‐ASC‐derived adipocytes expressed surface IR. Conclusions: Depot‐specific dynamics of IR isoforms may influence adipogenic capacity and insulin responsiveness and suggest partially receptor‐independent pathways of adipocyte differentiation. image