Knockdown of the Alstrom syndrome-associated gene Alms1 in 3T3-L1 preadipocytes impairs adipogenesis but has no effect on cell-autonomous insulin action

Alstrom syndrome is a rare genetic syndrome associated with early-onset obesity, severe insulin resistance (IR) that is disproportionate to the degree of adiposity and premature diabetes. The ALMS1 gene, which is mutated in Alstrom syndrome, encodes a giant 460 kDa centrosome-and basal body-associated protein. Its function is unknown, although roles in primary cilia formation and function, intracellular organelle trafficking and, most recently, adipocyte differentiation have been mooted. We now test the hypothesis that the severe IR and dyslipidaemia in Alstrom syndrome are accounted for by a partial defect in adipogenesis and/or insulin action in mature adipocytes, leading to relative failure of adipose tissue to discharge its role in metabolic homeostasis. Stable knockdown of Alms1 expression by >80% in 3T3-L1 preadipocytes was associated with impairment of lipid accumulation and at least a twofold reduction in adipocyte gene expression following hormonal induction of adipogenesis. This was accompanied by a commensurate defect in insulin-stimulated glucose uptake. Proximal signalling events in response to insulin were unaffected. These results suggest that partial impairment of adipogenesis in Alstrom syndrome may contribute to the severity of the associated metabolic phenotype, whereas the ability of insulin to stimulate glucose uptake into adipocytes is grossly unimpaired. International Journal of Obesity (2010) 34, 1554-1558; doi:10.1038/ijo.2010.92; published online 1 June 2010