Intraflagellar-transport A dysfunction causes hyperphagia-induced systemic insulin resistance in a pre-obese state.

Deletion of murine Thm1, an intraflagellar transport A (IFT-A) component that mediates ciliary protein trafficking, causes hyperphagia, obesity, and metabolic syndrome. The role of Thm1 or IFT-A in adipogenesis and insulin sensitivity is unknown. Here, we report that Thm1 knockdown in 3T3-L1 pre-adipocytes promotes adipogenesis and enhances insulin sensitivity in vitro. Yet, pre-obese Thm1 conditional knockout mice show systemic insulin resistance. While insulin-induced AKT activation in Thm1 mutant adipose depots and skeletal muscle are similar to those of control littermates, an attenuated insulin response arises in the mutant liver. Insulin treatment of control and Thm1 mutant primary hepatocytes results in similar AKT activation. Moreover, pair-feeding Thm1 conditional knockout mice produces a normal insulin response, both in the liver and systemically. Thus, hyperphagia caused by a cilia defect, induces hepatic insulin resistance via a non-cell autonomous mechanism. In turn, hepatic insulin resistance drives systemic insulin resistance prior to an obese phenotype. These data demonstrate that insulin signaling across cell types is regulated differentially, and that the liver is particularly susceptible to hyperphagia-induced insulin resistance and a critical determinant of systemic insulin resistance.

Transglutaminase-1 mutations in Omani families with lamellar ichthyosis.

OBJECTIVE: To determine the molecular basis of familial ichthyosis in three Omani families. SUBJECTS AND METHODS: Nine patients from three consanguineous families, A, B, and C, were born with typical features of lamellar ichthyosis subtype including collodion membrane and maintained ectropion, and epidermal scaling through their childhood. The 4 patients from family B had more severe symptoms requiring neonatal critical care and subsequent regular treatment with emollients, eye lubricants, and low-dose acitretin. DNA was extracted from peripheral blood by standard methods. The samples were initially genotyped to screen known loci linked to recessive ichthyosis on chromosomes 2q33-32 (ABCA12), 14q11 (TGM1), and 19p12-q12 using commercially supplied polymorphic fluorescent microsatellite markers. TGM1 was analyzed by direct sequencing for disease-associated mutations. RESULTS: Two known pathogenic mutations in TGM1 were detected: p.Gly278Arg in families A and B and p.Arg396His in family C. These two mutations were segregating in an autosomal recessive mode of inheritance. CONCLUSION: Two known pathogenic TGM1 mutations were detected in three large consanguineous Omani families with lamellar ichthyosis. This study confirmed the geographic distribution of known mutations to an apparently unrelated population.