Neuropeptide S receptor gene Asn107 polymorphism in obese male individuals in Pakistan

Abstract

Neuropeptide S (NPS) is a naturally occurring appetite stimulant, associated with anxiety, stress, and excitement regulation. Neuropeptide S serves as a hypothalamic energy regulator that enhances food intake with a reduced level of satiety. NPS activates fat angiogenesis and the proliferation of new adipocytes in obesity. NPS has an established role in energy regulation by many pre-clinical investigations; however we have limited data available to support this notion in humans. We found significant association of Neuropeptide S receptor (NPSR1) Asn107Ile (rs324981, A>T) polymorphism with obese male participants. The current investigation carried out genotype screening of NPSR1 allele to assess the spectrum of the Asn107Ile polymorphism in obese and healthy Pakistani individuals. We revealed a significant (p = 0.04) difference between AA vs TT + AT genotype distribution of NPSR1 (SNP rs324981,) between obese and healthy individuals (p = 0.04). In this genotype analysis of (SNP rs324981) of the NPSR1 gene, T allele was marked as risk allele with higher frequency in the obese (38%) compared to its frequency in the controls (25%). Single Nucleotide Polymorphism (SNP, rs324981) Asn107Ile of NPSR1gene, that switches an amino acid from Asn to Ile, has been found associated with increased susceptibility to obesity in Pakistani individuals. Furthermore, molecular simulation studies predicted a lower binding affinity of NPSR1 Asn107Ile variant to NPS than the wild-type consistent with the genotype studies. These molecular simulation studies predict a possible molecular mechanism of this interaction by defining the key amino acid residues. However, a significantly (p<0.0001) lower concentration of NPS was recorded independent of genotype frequencies in obese subjects compared to healthy controls. We believe that large scale polymorphism data of population for important gene players including NPSR1 will be more useful to understand obesity and its associated risk factors.

Relationship of Neuropeptide S with Clinical and Metabolic Parameters of Patients during Rehabilitation Therapy for Schizophrenia

“…The NPS T2 results and the NPS T2–T1 difference were not related to the body mass index (BMI), total cholesterol, HDL, LDL, triglycerides, glycemia, and AlAT. The role of NPS/NPSR1 in food intake and metabolic regulation is not clear, and our trial did not support any of the anabolic or anorectic hypotheses [ 16 , 17 ].…”

“…The anorexigenic effect of NPS was demonstrated in CNS animal studies; however, once injected through the orexin system, it could show a rebound effect [ 15 ]. The specific NPSR1 polymorphism was revealed in obese males, but a lower concentration of NPS was recorded independent of genotype in obesity [ 16 ].…”

The Neural Network of Neuropeptide S (NPS): Implications in Food Intake and Gastrointestinal Functions

“…The Asn 107 Ile mutation results in a gain of NPSR function, considering that NPS activates the NPSR Ile 107 with approximately 10-fold higher potency, compared to the NPSR Asn 107 , conversely to the alternatively spliced C-terminal variant, which does not influence pharmacological properties of the receptor protein [ 29 ]. Interestingly, the Asn 107 Ile SNP revealed not only to affect the in vitro properties of the NPSR, but also a gender-specific association of this genotype with panic disorder, mainly observed in male patients [ 32 ] and recently, a study performed in male obese Pakistani individuals, highlighted the presence of this SNP as a risk factor for the development of obesity [ 20 ].…”

“…The first investigation of the behavioral effects induced by the NPS demonstrated that it was able to promote wakefulness, locomotor activity, arousal and to exert anxiolytic-like effects in rodents [ 15 ], but interestingly, several following studies highlighted the potent inhibitory effect of NPS on food intake, in different animal species [ 16 , 17 , 18 , 19 ]. Moreover, in humans, polymorphisms of the NPSR gene were recently associated with an increased susceptibility to obesity, and NPS serum levels were found lower in individuals with a high body mass index [ 20 ]. The influence of NPS on food intake is consistent with the presence of the NPS receptor (NPSR) in feeding-related brain areas, such as the Arcuate Nucleus of the hypothalamus (ARC), lateral hypothalamic area, paraventricular nucleus of the hypothalamus (PVN) and the dorsomedial hypothalamic nucleus (DMN) [ 15 , 21 ], and with the interconnection between NPS and the other neurotransmitters implicated in feeding behavior.…”