Knockdown of the Alström syndrome-associated gene Alms1 in 3T3-L1 preadipocytes impairs adipogenesis but has no effect on cell-autonomous insulin action.
Alström 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 Alström 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 Alström 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 Alström 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.
Huang-Doran
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University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
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D041721:3T3-L1 Cells / Q000378:metabolism; D017667:Adipocytes / Q000502:physiology*; D050156:Adipogenesis / Q000235:genetics*; D056769:Alstrom Syndrome / Q000235:genetics*; D000818:Animals; D018797:Cell Cycle Proteins; D055786:Gene Knockout Techniques; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D051379:Mice; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D011506:Proteins / Q000235:genetics*
C490729:ALMS1 protein, human; D018797:Cell Cycle Proteins; D011506:Proteins