The TUB variant impairs leptin sensitivity and AgRP neuronal response, leading to obesity

Obesity exhibits a high heritability with heterogeneity; however, the genetic variants identified as obesity-causing factors are still underexplored. By performing deep sequencing on 2295 cases of young-onset obesity from East Asian populations and 2292 lean controls, we identified five genes (TUB, NR4A3, HIST1H4D, DXO, and TELO2) with an excess burden of rare predicted loss-of-function (LoF) variants in cases. Among the variants, TUB p.R364G was identified as a potential deleterious variant that disrupted TUB protein's subcellular localization. Knock-in mice carrying the homologous p.R363G variant exhibited hyperphagia and obesity in an allele dose-dependent manner when fed a high-fat diet. The TUB p.R363G variant also blunted responses to leptin-induced suppression of food intake, leading to leptin resistance in mice. Furthermore, we demonstrated that TUB acted as a positive regulator of the leptin pathway through its interaction with STAT3, and this interaction was impaired by the p.R364G variant. TUB silencing mitigated the inhibitory effects of leptin on the activities of agouti-related protein (AgRP)-expressing neurons. Consistently, conditional ablation of TUB in AgRP⁺ neurons in mice led to hyperphagic obesity and attenuated leptin-induced appetite suppression in mice. Thus, our study demonstrates that rare LoF variants in TUB predispose to young-onset obesity in humans, likely through impairing leptin sensitivity in AgRP⁺ neurons.