The BBSome in POMC and AgRP Neurons Is Necessary for Body Weight Regulation and Sorting of Metabolic Receptors. Diabetes 2019 Aug;68(8):1591-1603
Date
05/28/2019Pubmed ID
31127052Pubmed Central ID
PMC6692817DOI
10.2337/db18-1088Scopus ID
2-s2.0-85070184998 (requires institutional sign-in at Scopus site) 41 CitationsAbstract
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 KAuthor
Justin L. Grobe PhD Professor in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdiposityAgouti-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