The primary cilium is a small, antenna‐like sensory organelle that protrudes from most mammalian cells and mediates signaling pathways. Cilia are built by intraflagellar transport (IFT) protein complexes B and A, which have separate roles. Dysfunction of IFT and cilia results in ciliopathies, disease syndromes which commonly cause renal cystic disease and can also lead to obesity.Intriguingly, in mice, deletion of Ift‐B genes, which causes loss of primary cilia, can markedly attenuate Autosomal Dominant Polycystic Kidney Disease (ADPKD), the most common renal cystic disease and a leading cause of renal failure. These data indicate that targeting primary cilia genes can have immense therapeutic potential in ADPKD through mechanisms that remain elusive. To help elucidate these mechanisms, we have ablated an Ift‐A gene in ADPKD mouse models. IFT‐A dysfunction partially rescues the ADPKD elongated renal ciliary phenotype and attenuates the disease in a renal tubular‐ and maturation‐dependent manner.In adult mice, Ift gene deletion causes hyperphagia‐induced obesity. We have found that prior to an obese phenotype, IFT‐A dysfunction misregulates expression of appetite‐controlling neuropeptides in the hypothalamus. Additionally, in a pre‐obese state and through a non‐cell autonomous mechanism, hyperphagia induces hepatic insulin resistance, which drives systemic insulin resistance. These data uncouple obesity and insulin resistance, and indicate that hyperphagia is a major driver of both phenotypes. Thus, we are examining methods to counter hyperphagia. In collaboration with Zafgen Inc., we have found that pharmacological inhibition of MetAP2, which cleaves the N‐terminal methionine of nascent proteins, reduces food intake and body weight, and substantially improves metabolic parameters in an Ift‐A mutant mouse. To our knowledge, this is the first demonstration of rescue of an obese phenotype in a ciliopathy mouse model.Support or Funding InformationThis research is supported by NIH/NIDDK R01DK103033