👤 Olga Aksanov

Bardet-Biedl syndrome (BBS) is a pleiotropic autosomal recessive disorder associated with marked obesity, increased susceptibility to insulin resistance and type 2 diabetes. However, it is unknown whether the link between BBS and diabetes is indirect or direct. Adipogenesis and adipocyte function are regulated by hormonal stimuli, with insulin and insulin growth factor (IGF) playing an important role both in normal and impaired conditions. We have previously shown augmented transcript levels of BBS genes upon induction of adipogenesis. The aim of this study was to investigate the role of insulin in BBS. Through in vitro studies in adipocytes in which Bbs4 expression was either silenced (SiBbs4) or overexpressed (OEBbs4), we showed that insulin and IGF dose- and time-dependently decrease transcription and protein expression of BBS genes during adipogenesis. Silencing of Bbs4 expression in adipocytes significantly impaired and reduced glucose uptake. This effect was reversed by Bbs4 overexpression. Inhibition of PI 3-kinase resulted in upregulation of Bbs transcripts, suggesting that the PI3K pathway is involved in the regulation of these genes. In conclusion, we showed that insulin is a direct regulator of Bbs1, 2, 4 and 6. This hormonal regulation might indicate a metabolic link of these genes to obesity and metabolic syndrome. © 2017 IUBMB Life, 69(7):489-499, 2017. Show less

BBS4 is one of several proteins whose defects cause Bardet-Biedl syndrome (BBS), a multi-systemic disorder, manifesting with marked obesity. BBS4 polymorphisms have been associated with common non-syndromic morbid obesity. BBS4 obesity molecular mechanisms, and the role of the BBS4 gene in adipocyte differentiation and function are not entirely known. We now show that Bbs4 plays a direct and essential role in proliferation and adipogenesis: silencing of Bbs4 in 3T3F442A preadipocytes induced accelerated cell division and aberrant differentiation, evident through morphologic studies (light, scanning and transmission electron microscopy), metabolic analyses (fat accumulation, fatty acid profile and lipolysis) and adipogenic markers transcripts (Cebpα, Pparγ, aP2, ADRP, Perilipin). Throughout adipogenesis and when challenged with fat load, Bbs4 silenced cells accumulate significantly more triglycerides than control adipocytes, albeit in smaller (yet greater in number) droplets containing modified fatty acid profiles. Thus, greater fat accumulation in the silenced cells is a consequence of both a higher rate of adipocyte proliferation and of aberrant differentiation leading to augmented aberrant accumulation of fat per cell. Our findings suggest that the BBS obesity might be partly due to a direct role of BBS4 in physiological and pathophysiological mechanisms that underlie adipose tissue formation relevant to obesity. Show less