Insulin regulates Bbs4 during adipogenesis

Abstract

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.

Bardet‐Biedl syndrome: A focus on genetics, mechanisms and metabolic dysfunction

“…49 Insulin suppresses Bbs4 expression, putatively through a PI3 kinase-dependent mechanism, and studies in which Bbs4 has been either silenced or overexpressed have shown that Bbs4 regulates glucose uptake into adipocytes. 50 In addition, Bbs4 silencing drives preadipocyte proliferation as well as enhancing triglyceride accumulation. 51 In parallel, overexpression of Bbs4 in a rodent preadipocyte cell line decreased cell proliferation.…”

Role of EZH2 in adipogenesis and obesity: Current state of the art and implications – A review

“…The capacity for adipocyte differentiation in adipose tissue cellularity remains in adult humans, with a significant proportion of multipotent cells capable of undergoing adipocyte differentiation. [16,17] During the early stage of adipocyte differentiation, preadipocytes originate from MSCs or progenitor cells that restrict their fate to the adipocyte lineage through cell proliferation, clonal expansion, and growth arrest, without significant changes in phenotype. [17] Early adipocyte commitment factors that drive the differentiation process include bone morphogenetic protein 2 (BMP2), BMP4, BMP7, and the binding proteins CCAAT/ enhancer β (C/EBPβ) and C/EBPδ.…”

“…The capacity for adipocyte differentiation in adipose tissue cellularity remains in adult humans, with a significant proportion of multipotent cells capable of undergoing adipocyte differentiation. [16,17]…”

Loss of the ciliary gene Bbs4 results in defective thermogenesis due to metabolic inefficiency and impaired lipid metabolism

“…Gerdes et al previously reported that loss of Bbs4 contributes to impaired glucose metabolism due to an insulin secretion defect in pancreatic beta cells and perturbations of overall islet architecture in diabetic rats 20 . Insulin‐dependent regulation of Bbs4 was further linked to regulation of adipocyte differentiation, as it was shown that insulin inhibits Bbs expression during early adipogenesis and that silencing of Bbs4 impaired glucose uptake into adipocytes 21 . Furthermore, absence of functional Bbs4 led to accelerated preadipocyte proliferation, resulting in abnormal adipocyte differentiation by suppression of adipogenic marker expression 22 .…”

“…20 Insulin-dependent regulation of Bbs4 was further linked to regulation of adipocyte differentiation, as it was shown that insulin inhibits Bbs expression during early adipogenesis and that silencing of Bbs4 impaired glucose uptake into adipocytes. 21 Furthermore, absence of functional Bbs4 led to accelerated preadipocyte proliferation, resulting in abnormal adipocyte differentiation by suppression of adipogenic marker expression. 22 To this end, aberrant function of the BBS4 protein may result in aberrant triglyceride accumulation in mature adipocytes, where lipids are stored in smaller lipid droplets, but in larger number.…”