Leptin Fragment Modulates Stimulatory Effects of Chorionic Gonadotropin on Testicular Steroidogenesis in a Rat Model of Diet-Induced Obesity

Leptin, secreted by adipose tissue, indirectly stimulatesthe activity of GnRH-producing neurons in the hypothalamus and thusregulates the functional activity of the hypothalamic–pituitary–testicular (HPT)axis. Obesity is known to be accompanied by a systemic hyperleptinemiaand impaired leptin transport in the central nervous system, whichlimits the use of full-length leptin as a drug. It was previouslyshown that the intranasally administered (i.n.) leptin fragmentMA-[D-Leu4]-OB3 (LF) enhances the steroidogenic effect of humanchorionic gonadotropin (hCG) in rats fed a standard diet. An evenmore urgent task is to assess its effect on testicular steroidogenesisin obesity that reduces reproductive functions in men. This workwas aimed to study the ability of LF (200 µg/kg, i.n., for 3 days)to modulate the effect of hCG (10 IU/rat, s.c., once) on testicularsteroidogenesis in male Wistar rats with obesity induced by a 20-weekhigh-fat/high-carb diet (HFHCD), as well as to evaluate the impactof the GnRH receptor antagonist Cetrorelix (ANT, 75 µg/kg, s.c.,for 3 days) on the effects of LF in these animals. Obese rats demonstratedreduced testicular levels of the luteinizing hormone receptor (LHR)and a compensatorily upregulated expression of the Cyp11a1 gene encoding the steroidogenic enzymecytochrome P450scc. LF administration enhanced hCG effects on bloodtestosterone levels and testicular expression of the Star gene encoding the cholesteroltransporter protein StAR, which suggests the ability of LF to positivelymodulate HPT axis activity under obesity. ANT and LF co-administration, bycontrast, reduced the stimulatory effect of hCG on blood testosteronelevels and testicular Star gene expression,which may be due to the testicular effects of LF. Our data indicatethe ability of LF to influence different components of the malegonadal axis under conditions of diet-induced obesity.