Neurotensin receptor-1 antagonist SR48692 modulation of high-fat diet induced reproductive impairment in male mice.

Neurotensin (NTS), a tridecapeptide of the gastrointestinal tract, has been implicated in the facilitation of lipid absorption on ingestion of a high-fat diet (HFD) especially via NTS receptors, NTSR1, NTSR2, and NTSR3, to cause lipid metabolic dysregulation and imbalance of the oxidant-antioxidant system. Oxidative stress induced a negative impact on reproductive function, affecting the reproductive organ and related reproductive hormones. The present study elucidated the efficacy of NTSR1 antagonist SR48692 in the modulation of HFD-induced reproductive impairment in male mice. Swiss albino mice (male, 23 ± 2 g) were maintained (6/group) for eight weeks; Group-I chow diet (CD), Group-II HFD, Group-III (HFD+SR48692 L), Group-IV (HFD+SR48692 H), Group-V (CD+SR48692 L) and Group-VI (CD+SR48692 H). SR48692 low (100 µg/kg b.w./SR48692 L) and high-dose (400 µg/kg b.w./SR48692 H) were given intraperitoneally for the last four weeks. Treatment with low-dose (SR48692 L) to HFD-fed mice showed some efficacy in mitigating lipid dysregulation, oxidative stress, and reproductive impairment as evidenced by decreased triglycerides, total cholesterol, low-density lipoprotein cholesterol, leptin, and increased high-density lipoprotein cholesterol, increased antioxidant defense enzymes, reduction of histopathological scores in testis and increase in plasma level of LH, FSH and testosterone compared to that of HFD, but not up to CD. With the high-dose of antagonist (SR48692 H) showed more adverse effects even from that of HFD. Treatment of both doses of SR48692 to CD-fed mice these effects become more extended. Less effectiveness of NTSR1 antagonist with the doses tried (low and high) in normalizing the lipid dysregulation and reproductive impairments might be due to the persistence of NTSR2/NTSR3-mediated lipid absorption. • High fat diet consumption causes lipid dysregulation and reproductive impairment. • Histopathological alteration was reflected due to increased oxidative stress effect. • SR48692 exposure shown partial efficacy in HFD induced reproductive impairment. • Varied NTS receptors might be responsible for NTS-NTSR mediated lipid absorption. [ABSTRACT FROM AUTHOR]