Prevention of Diet-Induced Obesity by Phytoecdysteroids 20-Hydroxyecdysone and Calonysterone—Unexpected Modulation of Androgen Balance in Normal and Obese Rats

Background: Calonysterone (CAL) is a natural derivative of 20-hydroxyecdysone (20E) with enhanced bioactivity on skeletal muscle cells in vitro, but its in vivo physiological actions remain less well characterized. This study aimed to compare the effects of 20E and CAL on metabolic, muscular, and endocrine parameters in normal and obese male rats, with a particular focus on androgen balance. Methods: Male rats were treated with 20E or CAL under normal (ND) or high-fat, high-sugar dietary (HFHSD) conditions for 12 weeks. Body weight, food intake, skeletal and androgen-sensitive muscle mass, and testicular weight were measured. Testicular expression of androgen receptor (Ar) and aromatase (Cyp19a1) mRNA was assessed by RT-PCR. ELISA was used to determine the plasma corticosterone, testosterone and ERβ level in testes. Results: 20E and CAL prevented HFHSD-induced weight gain and skeletal muscle atrophy. CAL uniquely preserved testicular and levator ani muscle mass in obese rats. CAL increased the expression of Cyp19a1 and ERβ in testicles. Decreased Ar mRNA expression was regulated in 20E- and CAL-treated obese animals. While 20E treatment significantly reduced plasma testosterone levels in the normal diet group compared to controls, both 20E and CAL interventions elicited significant reductions in the obese group relative to both the ND and HFHSD groups. HFHSD-induced increase in plasma corticosterone levels was normalized by 20E or CAL treatment. Conclusions: 20E and CAL exhibit beneficial metabolic and anabolic effects by preventing HFHSD-induced obesity and consequential muscle atrophy. CAL counteracts obesity-induced testicular atrophy in terms of tissue mass. Based on our results, we hypothesized that CAL enhances testicular aromatase levels, which may lead to increased compensatory androgen receptor mRNA expression and increased ERβ levels. These complex, not yet fully understood results underscore the need for caution in the use of phytoecdysteroids as dietary supplements.