title: Functional consequences of the human leptin receptor (LEPR) Q223R transversion.
abstract: Perturbations in the functional integrity of the leptin axis are obvious candidates for mediation of altered adiposity. In a large number of genetic association studies in humans, the nonconservative LEPR Q223R allele has been inconsistently associated with adiposity. Subtle, long-term effects of such genetic variants can be obscured by effects of the environment and other confounders that render definitive inferences difficult to reach. We directly assessed the biological effects of this variant in 129P3/J mice segregating for the humanized Lepr allele at codon 223. No effects of this allele were detected on body weight, composition, or energy expenditure in animals fed diets of varying fat content over periods as long as 235 days. In vitro, Q223R did not affect leptin signaling as reflected by activation of STAT3. We conclude that Q223R is unlikely to play a significant role in regulation of human adiposity. This approach to vetting of human allelic variation might be more widely used.
authors.affiliation: Department of Pediatrics, Division of Molecular Genetics, Naomi Berrie Diabetes Center, Columbia University, New York, New York, USA.
authors.forename: George
authors.initials: G
authors.lastname: Stratigopoulos
authors.forename: Charles A
authors.initials: CA
authors.lastname: LeDuc
authors.forename: Naoki
authors.initials: N
authors.lastname: Matsuoka
authors.forename: Roee
authors.initials: R
authors.lastname: Gutman
authors.forename: Richard
authors.initials: R
authors.lastname: Rausch
authors.forename: Scott A
authors.initials: SA
authors.lastname: Robertson
authors.forename: Martin G
authors.initials: MG
authors.lastname: Myers
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.forename: Streamson C
authors.initials: SC
authors.lastname: Chua
authors.forename: Rudolph L
authors.initials: RL
authors.lastname: Leibel
mesh_terms: D000273:Adipose Tissue / Q000502:physiology*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001823:Body Composition / Q000235:genetics*; D017931:DNA Primers; D018752:Diet, Fat-Restricted; D053595:Embryonic Stem Cells / Q000502:physiology; D005091:Exons; D005260:Female; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009765:Obesity / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D054411:Receptors, Leptin / Q000235:genetics*
chemical_list: D017931:DNA Primers; D054411:Receptors, Leptin