Abstract
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.
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References
Garg A . Acquired and inherited lipodystrophies. N Engl J Med 2004; 350: 1220–1234.
O'Rahilly S, Farooqi IS . Human obesity as a heritable disorder of the central control of energy balance. Int J Obes (Lond) 2008; 32 (Suppl 7): S55–S61.
Virtue S, Vidal-Puig A . It's not how fat you are, it's what you do with it that counts. PLoS Biol 2008; 6: e237.
Marshall JD, Beck S, Maffei P, Naggert JK . Alstrom syndrome. Eur J Hum Genet 2007; 15: 1193–1202.
Minton JA, Owen KR, Ricketts CJ, Crabtree N, Shaikh G, Ehtisham S et al. Syndromic obesity and diabetes: changes in body composition with age and mutation analysis of ALMS1 in 12 United Kingdom kindreds with Alstrom syndrome. J Clin Endocrinol Metab 2006; 91: 3110–3116.
Collin GB, Marshall JD, Ikeda A, So WV, Russell-Eggitt I, Maffei P et al. Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alstrom syndrome. Nat Genet 2002; 31: 74–78.
Hearn T, Renforth GL, Spalluto C, Hanley NA, Piper K, Brickwood S et al. Mutation of ALMS1, a large gene with a tandem repeat encoding 47 amino acids, causes Alstrom syndrome. Nat Genet 2002; 31: 79–83.
Hearn T, Spalluto C, Phillips VJ, Renforth GL, Copin N, Hanley NA et al. Subcellular localization of ALMS1 supports involvement of centrosome and basal body dysfunction in the pathogenesis of obesity, insulin resistance, and type 2 diabetes. Diabetes 2005; 54: 1581–1587.
Rochford JJ, Semple RK, Laudes M, Boyle KB, Christodoulides C, Mulligan C et al. ETO/MTG8 is an inhibitor of C/EBPbeta activity and a regulator of early adipogenesis. Mol Cell Biol 2004; 24: 9863–9872.
Payne VA, Grimsey N, Tuthill A, Virtue S, Gray SL, Dalla Nora E et al. The human lipodystrophy gene BSCL2/seipin may be essential for normal adipocyte differentiation. Diabetes 2008; 57: 2055–2060.
Urso B, Cope DL, Kalloo-Hosein HE, Hayward AC, Whitehead JP, O'Rahilly S et al. Differences in signaling properties of the cytoplasmic domains of the insulin receptor and insulin-like growth factor receptor in 3T3-L1 adipocytes. J Biol Chem 1999; 274: 30864–30873.
Romano S, Milan G, Veronese C, Collin GB, Marshall JD, Centobene C et al. Regulation of Alstrom syndrome gene expression during adipogenesis and its relationship with fat cell insulin sensitivity. Int J Mol Med 2008; 21: 731–736.
Qiu Z, Wei Y, Chen N, Jiang M, Wu J, Liao K . DNA synthesis and mitotic clonal expansion is not a required step for 3T3-L1 preadipocyte differentiation into adipocytes. J Biol Chem 2001; 276: 11988–11995.
Tang QQ, Otto TC, Lane MD . Mitotic clonal expansion: a synchronous process required for adipogenesis. Proc Natl Acad Sci USA 2003; 100: 44–49.
Singla V, Reiter JF . The primary cilium as the cell's antenna: signaling at a sensory organelle. Science 2006; 313: 629–633.
Badano JL, Mitsuma N, Beales PL, Katsanis N . The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genomics Hum Genet 2006; 7: 125–148.
Li G, Vega R, Nelms K, Gekakis N, Goodnow C, McNamara P et al. A role for Alstrom syndrome protein, alms1, in kidney ciliogenesis and cellular quiescence. PLoS Genet 2007; 3: e8.
Spalding KL, Arner E, Westermark PO, Bernard S, Buchholz BA, Bergmann O et al. Dynamics of fat cell turnover in humans. Nature 2008; 453: 783–787.
de Ferranti S, Mozaffarian D . The perfect storm: obesity, adipocyte dysfunction, and metabolic consequences. Clin Chem 2008; 54: 945–955.
Khan T, Muise ES, Iyengar P, Wang ZV, Chandalia M, Abate N et al. Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol Cell Biol 2009; 29: 1575–1591.
Delaval B, Doxsey SJ . Pericentrin in cellular function and disease. J Cell Biol 2010; 188: 181–190.
Acknowledgements
IHD is supported by the Sackler Fund for Medical Science and the James Baird Fund; RKS is supported by the Wellcome Trust (Intermediate Clinical Fellowship 080952/Z/06/Z). Support was also provided by the UK Medical Research Council Centre for Obesity and Related Disorders, and the National Institute for Health Research Cambridge Biomedical Research Centre.
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Huang-Doran, I., Semple, R. Knockdown of the Alström syndrome-associated gene Alms1 in 3T3-L1 preadipocytes impairs adipogenesis but has no effect on cell-autonomous insulin action. Int J Obes 34, 1554–1558 (2010). https://doi.org/10.1038/ijo.2010.92
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DOI: https://doi.org/10.1038/ijo.2010.92
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