Faculty Collaboration Database

The BBSome Controls Energy Homeostasis by Mediating the Transport of the Leptin Receptor to the Plasma Membrane. PLoS Genet 2016 Feb;12(2):e1005890

Date

03/02/2016

Pubmed ID

26926121

Pubmed Central ID

PMC4771807

DOI

10.1371/journal.pgen.1005890

Scopus ID

2-s2.0-84959876003 (requires institutional sign-in at Scopus site)   107 Citations

Abstract

Bardet-Biedl syndrome (BBS) is a highly pleiotropic autosomal recessive disorder associated with a wide range of phenotypes including obesity. However, the underlying mechanism remains unclear. Here, we show that neuronal BBSome is a critical determinant of energy balance through its role in the regulation of the trafficking of the long signaling form of the leptin receptor (LRb). Targeted disruption of the BBSome by deleting the Bbs1 gene from the nervous system causes obesity in mice, and this phenotype is reproduced by ablation of the Bbs1 gene selectively in the LRb-expressing cells, but not from adipocytes. Obesity developed as a consequence of both increased food intake and decreased energy expenditure in mice lacking the Bbs1 gene in LRb-expressing cells. Strikingly, the well-known role of BBS proteins in the regulation of ciliary formation and function is unlikely to account for the obesogenic effect of BBS1 loss as disruption of the intraflagellar transport (IFT) machinery required for ciliogenesis by deleting the Ift88 gene in LRb-expressing cells caused a marginal increase in body weight and adiposity. Instead, we demonstrate that silencing BBS proteins, but not IFT88, impair the trafficking of the LRb to the plasma membrane leading to central leptin resistance in a manner independent of obesity. Our data also demonstrate that postnatal deletion of the Bbs1 gene in the mediobasal hypothalamus can cause obesity in mice, arguing against an early neurodevelopmental origin of obesity in BBS. Our results depict a novel mechanism underlying energy imbalance and obesity in BBS with potential implications in common forms of human obesity.

Author List

Guo DF, Cui H, Zhang Q, Morgan DA, Thedens DR, Nishimura D, Grobe JL, Sheffield VC, Rahmouni K

Author

Justin L. Grobe PhD Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Bardet-Biedl Syndrome
Cell Membrane
Energy Metabolism
Female
Hypothalamus
Mice, Mutant Strains
Mice, Transgenic
Microtubule-Associated Proteins
Multiprotein Complexes
Obesity
Protein Transport
Receptors, Leptin
Tumor Suppressor Proteins