Endocrine Abstracts

A defining trait of modern civilization is easy access to food combined with minimum energy expenditure. This unbalance is responsible for the emergence of considerable wide-spread obesity and its harrowing cortege of life-threatening complications such as type-2 diabetes. Rare genetic disorders that manifest with obesity are of great value in discovering new pieces of the jigsaw on the origins of obesity as they allow us to link a phenotype with a specific protein or group of proteins. Among these disorders is a ciliopathy, the Bardet Biedl Syndrome caused by a defect of genetic origin in the primary cilium. It is characterized by the occurrence of obesity, but curiously enough, diabetes is neither a defining nor obligatory trait of this syndrome. Using a combination of clinical, in vitro and in vivo studies, we showed that the recruitment of the mesenchymal stem cells towards the adipogenic faith is controlled by a transient primary cilium. We show that BBS12 inactivation repressed the anti-adipogenic pathways, thereby favoring adipogenesis. The transient BBS12 inactivation during adipogenesis resulted in a particular genetic unique imprinting of the mature adipocytes characterized by higher expression levels of key actors in insulin detection and glucose absorption. This could explain the unexpected low occurrence of diabetes in the BBS patients after years of threatening obesity. Through a comparative study between the Bbs12 knock-out mouse model (Bbs12-/-), the hyperphagic mouse Ob/Ob and the pharmacologically activated adipogenic mouse model treated with two PPARγ-agonists Thiazolidinediones (TZD), we showed that the Bbs12-/- adipose tissue was similar to the TZD-treated adipose tissue, with increased expression of the insulin receptor and GLUT4. These findings cast new light on the regulatory events controlling differentiation of the adipocytes’ progenitors and open new potential ciliary targets for pharmacological applications, to regulate insulin sensitivity and glucose absorption in the mature adipocyte.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.