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

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 ¹ H 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.