An endocytic pathway as a target of tubby for regulation of fat storage

Abstract

The tubby loci provide a unique opportunity to study adult‐onset obesity. Mutation in either mammalian tubby or its homologue in Caenorhabditis elegans , tub‐1 , results in increased fat storage. Previously, we have shown that TUB‐1 interacts with a new Rab GTPase‐activating protein, RBG‐3, for the regulation of fat storage. To understand further the molecular mechanism of TUB‐1, we identified the Rab GTPase downstream of RBG‐3. We found that RBG‐3 preferentially stimulates the intrinsic GTPase activity of RAB‐7 in both human and C. elegans . Importantly, either mutation or RNA interference knockdown in rab‐7 reduces stored fat in wild type and tub‐1 mutants. In addition, the small GTPase rab‐5 and genes that regulate Rab membrane localization and nucleotide recycling are required for the regulation of fat storage, thereby defining a role for endocytic recycling in this process. We propose that TUB‐1 controls receptor or sensory molecule degradation in neurons by regulating a RAB‐7‐mediated endocytic pathway.