Leptin fragment modulates the stimulatory effects of chorionic gonadotropin on testicular steroidogenesis in a model of diet-induced obesity in rats

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Abstract

Leptin, secreted by adipose tissue, indirectly stimulates the activity of GnRH-producing neurons of the hypothalamus and thus regulates the functional activity of the hypothalamic-pituitary-testicular (HPT) axis. As is known, the obesity is accompanied by systemic hyperleptinemia and impaired leptin transport in the central nervous system, which limits the use of full-length leptin as a drug. It was previously shown that intranasally administered leptin fragment MA-[D-Leu4]-OB3 (LF) enhances the steroidogenic effect of human chorionic gonadotropin (hCG) in rats fed a standard diet. An even more urgent task is to assess its effect on testicular steroidogenesis in conditions of obesity, which reduces reproductive functions in men. The aim of the work was to study the ability of LF (200 μg/kg, intranasally, 3 days) to modulate the effect of hCG (10 IU/rat, subcutaneously, once) on testicular steroidogenesis in rats with obesity induced by a high-fat/high-carbohydrate diet (HFHCD), and also to evaluate influence of the GnRH receptor antagonist cetrorelix (ANT, 75 µg/kg, subcutaneously, 3 days) on the effects of LF. Male Wistar rats were used for the study and received HFHCD for 20 weeks. In obese rats, the level of the luteinizing hormone (LH) receptor in the testes was reduced and the expression of the Cyp11a1 gene, encoding the steroidogenic enzyme cytochrome P450scc, was compensatory increased. LF administration enhanced the effect of hCG on the testosterone level in the blood and the expression of the Star gene, encoding the cholesterol transport protein StAR, which indicates the ability of LF to positively modulate the activity of the HPT axis in obesity. Co-administration of ANT and LF, on the contrary, reduced the stimulating effect of hCG on testosterone levels and Star gene expression, which may be due to the testicular effects of LF. Our data indicate the ability of LF to influence various components of the male gonadal axis under conditions of diet-induced obesity.

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About the authors

A. A. Bakhtyukov

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Author for correspondence.
Email: bahtyukov@gmail.com
Russian Federation, St. Petersburg

I. A. Lebedev

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: bahtyukov@gmail.com
Russian Federation, St. Petersburg

I. Yu. Morina

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: bahtyukov@gmail.com
Russian Federation, St. Petersburg

V. S. Kuznetsova

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: bahtyukov@gmail.com
Russian Federation, St. Petersburg

A. O. Shpakov

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: bahtyukov@gmail.com
Russian Federation, St. Petersburg

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2. Fig. 1. Effect of three-day administration of the leptin fragment MA-[D-Leu4]-OB3 and/or cetrorelix and a single injection of hCG on the blood testosterone level of male rats consuming VZVD.

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3. Fig. 2. Levels of mRNA of the Star and Cyp11a1 genes in the testes of rats treated with VZVUD, against the background of the introduction of the leptin fragment MA-[D-Leu4]-OB3 and/or cetrorelix, as well as stimulation of steroidogenesis with hCG.

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4. Fig. 3. LH receptor protein content (a, b) and immunohistochemical reaction to the LH receptor (c) in the testes of rats treated with VLDL after three days of administration of the leptin fragment MA-[D-Leu4]-OB3 and/or cetrorelix, as well as a single injection of hCG.

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