Two related RabGAPs, TBC1D1 and TBC1D4 (=AS160) have been described to be associated with obesity-related traits and type 2 diabetes in both mice and humans.
To address this question, we generated a mouse model harboring a TBC1D1(Ser231Ala) knockin (KI) mutation and found that the KI mice developed obesity on a normal chow diet.
HTR2C, LEP, FTO and TBC1D1 represented the top genes for weight gain during treatment with a SGAP and/or MS. A genome-wide signal (FTO rs9930506) associated previously with obesity was associated with psychotropic-induced weight gain.
Our analysis suggests that R125W in TBC1D1 plays a role in the binding of an effector protein, but we find no evidence that the R125W variant is related to mean BMI or odds of obesity in a general population sample.
Analysis of 16 microsatellite markers on chromosome 4 restricted to the 42 pedigrees carrying the TBC1D1R125W variant allele also revealed a suggestive evidence of linkage with obesity (maximum likelihood binomial LOD of 2.73, P = 0.0002) on chromosome 4p14, where resides TBC1D1.