Journal article
The BBSome in POMC and AgRP Neurons Is Necessary for Body Weight Regulation and Sorting of Metabolic Receptors
Diabetes (New York, N.Y.), Vol.68(8), pp.1591-1603
08/2019
DOI: 10.2337/db18-1088
PMCID: PMC6692817
PMID: 31127052
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
gene deletion in POMC or AgRP neurons increases body weight and adiposity. We demonstrate that obesity in mice lacking the
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 (NPY
R) and serotonin 5-hydroxytryptamine (HT)
receptor (5-HT
R) to cilia and plasma membrane, respectively. Consistent with this, loss of the BBSome reduced cell surface expression of the 5-HT
R, interfered with serotonin-evoked increase in intracellular calcium and membrane potential, and blunted the anorectic and weight-reducing responses evoked by the 5-HT
R agonist, lorcaserin. Finally, we show that disruption of the BBSome causes the 5-HT
R 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.
Details
- Title: Subtitle
- The BBSome in POMC and AgRP Neurons Is Necessary for Body Weight Regulation and Sorting of Metabolic Receptors
- Creators
- Deng-Fu Guo - Department of Pharmacology, University of Iowa, Iowa City, IAZhihong Lin - Department of Pharmacology, University of Iowa, Iowa City, IAYuanming Wu - Department of Neurology, University of Iowa, Iowa City, IACharles Searby - Department of Pediatrics, University of Iowa, Iowa City, IADaniel R Thedens - Department of Radiology, University of Iowa, Iowa City, IAGeorge B Richerson - Department of Neurology, University of Iowa, Iowa City, IAYuriy M Usachev - Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IAJustin L Grobe - Obesity Education and Research Initiative, University of Iowa, Iowa City, IAVal C Sheffield - Obesity Education and Research Initiative, University of Iowa, Iowa City, IAKamal Rahmouni - Department of Internal Medicine, University of Iowa, Iowa City, IA
- Resource Type
- Journal article
- Publication Details
- Diabetes (New York, N.Y.), Vol.68(8), pp.1591-1603
- Publisher
- United States
- DOI
- 10.2337/db18-1088
- PMID
- 31127052
- PMCID
- PMC6692817
- ISSN
- 0012-1797
- eISSN
- 1939-327X
- Grant note
- R01 NS096246 / NINDS NIH HHS S10 RR025439 / NCRR NIH HHS I01 BX004249 / BLRD VA
- Language
- English
- Date published
- 08/2019
- Academic Unit
- Neurology; Electrical and Computer Engineering; Medical Genetics and Genomics; Anesthesia; Roy J. Carver Department of Biomedical Engineering; Radiology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Neurosurgery; Internal Medicine; Ophthalmology and Visual Sciences
- Record Identifier
- 9984070877202771
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