A Review of Single-Nucleotide Polymorphisms in Orexigenic Neuropeptides Targeting G Protein-Coupled Receptors

ACS Chem Neurosci. 2018 Jun 20;9(6):1235-1246. doi: 10.1021/acschemneuro.8b00151. Epub 2018 May 11.


Many physiological pathways are involved in appetite, food intake, and the maintenance of energy homeostasis. In particular, neuropeptides within the central nervous system have been demonstrated to be critical signaling molecules for modulating appetite. Both anorexigenic (appetite-decreasing) and orexigenic (appetite-stimulating) neuropeptides have been described. The biological effects of these neuropeptides can be observed following central administration in animal models. This review focuses on single nucleotide polymorphisms (SNPs) in six orexigenic neuropeptides: agouti-related protein (AGRP), galanin, melanin concentrating hormone (MCH), neuropeptide Y (NPY), orexin A, and orexin B. Following a brief summary of the neuropeptides and their orexigenic activities, reports associating SNPs within the orexigenic neuropeptides to energy homeostasis, food intake, obesity, and BMI in humans are reviewed. Additionally, the NIH tool Variation Viewer was utilized to identify missense SNPs within the mature, biologically active neuropeptide sequences. For SNPs found through Variation Viewer, a concise discussion on relevant pharmacological structure-activity relationship studies for select SNPs is included. This review is meant to update reported orexigenic neuropeptide SNPs and demonstrate the potential utility of genomic sequence databases for finding SNPs that may result in altered receptor signaling for neuropeptide pathways associated with appetite.

Keywords: GPCR; SNP; Single-nucleotide polymorphisms; agouti-related protein; galanin; hormone; melanocyte concentrating hormone; neuropeptide Y; orexin A; orexin B; peptide; pharmacogenomics; polypharmacology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Humans
  • Hypothalamic Hormones / genetics
  • Hypothalamic Hormones / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Melanins / genetics
  • Melanins / metabolism
  • Neuropeptides / genetics*
  • Neuropeptides / metabolism
  • Orexins / genetics
  • Orexins / metabolism
  • Pituitary Hormones / genetics
  • Pituitary Hormones / metabolism
  • Polymorphism, Single Nucleotide / genetics*
  • Receptors, G-Protein-Coupled / genetics*
  • Receptors, G-Protein-Coupled / metabolism


  • Hypothalamic Hormones
  • Intracellular Signaling Peptides and Proteins
  • Melanins
  • Neuropeptides
  • Orexins
  • Pituitary Hormones
  • Receptors, G-Protein-Coupled
  • melanin-concentrating hormone