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The BBSome in POMC and AgRP Neurons Is Necessary for Body Weight Regulation and Sorting of Metabolic Receptors. Diabetes 2019 08;68(8):1591-1603

Date

05/28/2019

Pubmed ID

31127052

Pubmed Central ID

PMC6692817

DOI

10.2337/db18-1088

Scopus ID

2-s2.0-85070184998   19 Citations

Abstract

The BBSome, a complex of eight Bardet-Biedl syndrome (BBS) proteins involved in cilia function, has emerged as an important regulator of energy balance, but the underlying cellular and molecular mechanisms are not fully understood. Here, we show that the control of energy homeostasis by the anorexigenic proopiomelanocortin (POMC) neurons and orexigenic agouti-related peptide (AgRP) neurons require intact BBSome. Targeted disruption of the BBSome by Bbs1 gene deletion in POMC or AgRP neurons increases body weight and adiposity. We demonstrate that obesity in mice lacking the Bbs1 gene in POMC neurons is associated with hyperphagia. Mechanistically, we present evidence implicating the BBSome in the trafficking of G protein-coupled neuropeptide Y Y2 receptor (NPY2R) and serotonin 5-hydroxytryptamine (HT)2C receptor (5-HT2CR) to cilia and plasma membrane, respectively. Consistent with this, loss of the BBSome reduced cell surface expression of the 5-HT2CR, interfered with serotonin-evoked increase in intracellular calcium and membrane potential, and blunted the anorectic and weight-reducing responses evoked by the 5-HT2cR agonist, lorcaserin. Finally, we show that disruption of the BBSome causes the 5-HT2CR to be stalled in the late endosome. Our results demonstrate the significance of the hypothalamic BBSome for the control of energy balance through regulation of trafficking of important metabolic receptors.

Author List

Guo DF, Lin Z, Wu Y, Searby C, Thedens DR, Richerson GB, Usachev YM, Grobe JL, Sheffield VC, Rahmouni K

Author

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




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

Adiposity
Agouti-Related Protein
Animals
Body Weight
Calcium
Cell Line
Cell Membrane
Hyperphagia
Hypothalamus
Mice
Mice, Knockout
Microtubule-Associated Proteins
Neurons
Obesity
Pro-Opiomelanocortin
Protein Transport
Receptors, Neuropeptide Y
Receptors, Serotonin, 5-HT2