Subcellular localization of MC4R with ADCY3 at neuronal primary cilia underlies a common pathway for genetic predisposition to obesity
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Most monogenic cases of obesity in humans have been linked to mutations in genes encoding members of the leptin-melanocortin pathway. Specifically, mutations in MC4R, the melanocortin-4 receptor gene, account for 3-5% of all severe obesity cases in humans 1-3. Recently, ADCY3 (adenylyl cyclase 3) gene mutations have been implicated in obesity 4,5. ADCY3 localizes to the primary cilia of neurons 6 , organelles that function as hubs for select signaling pathways. Mutations that disrupt the functions of primary cilia cause ciliopathies, rare recessive pleiotropic diseases in which obesity is a cardinal manifestation 7 . We demonstrate that MC4R colocalizes with ADCY3 at the primary cilia of a subset of hypothalamic neurons, that obesity-associated MC4R mutations impair ciliary localization and that inhibition of adenylyl cyclase signaling at the primary cilia of these neurons increases body weight. These data suggest that impaired signaling from the primary cilia of MC4R neurons is a common pathway underlying genetic causes of obesity in humans.
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NPY has an important role in the central regulation of food intake and energy expenditure.
“NPY also has an important role in the central regulation of food intake and energy expenditure 181.”
From Cellular signalling by primary cilia in development, organ function and disease (2019) · cites this paper as [181]
The Main Text (page unavailable) discusses MC4R-expressing neurons, their ligands αMSH and AGRP, and regulation of feeding and energy homeostasis. Searches for “NPY” and “neuropeptide Y” found no passage in our copy addressing NPY’s role in food intake or energy expenditure. (LLM, conf=0.76)
Experimental — accuracy not yet measuredThe paraventricular nucleus has been implicated in body weight regulation of AC3.
“A specific ventromedial hypothalamus deletion resulted in the same effect (301), although a different subregion of the hypothalamus, the paraventricular nucleus, has also been implicated in the body weight regulation of AC3 (302).”
From Physiological roles of mammalian transmembrane adenylyl cyclase isoforms (2022) · cites this paper as [302]
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- Authors
- Siljee, J. E., Wang, Y., Bernard, A. A., Ersoy, B. A., Zhang, S., Marley, A., Von Zastrow, M., Reiter, J. F., & Vaisse, C.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Vaisse, Christian
- Venue
- Nature Genetics
- Published
- 2018-01-08
- Volume
- 50
- Issue
- 2
- Pages
- 180-185
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC5805646
- OpenAlex
- W2781875842
- Cited by
- 247
- References
- 30
- Citations by year
- 2026: 24 · 2025: 30 · 2024: 27 · 2023: 22 · 2022: 25 · 2021: 40 · 2020: 33 · 2019: 22 · 2018: 24
- FWCI
- 18.21
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute on Drug Abuse (P01DA010154, R01DA010711, R01DA012864)
- National Institute of General Medical Sciences (R01GM095941)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK098722, R01DK060540, P30DK063720, R01DK106404)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR054396)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- melanocortin-4 receptor, ADCY3, primary cilia, obesity, leptin-melanocortin pathway, hypothalamic neurons, ciliopathies, adenylyl cyclase signaling, genetic predisposition to obesity, body weight, receptor subcellular localization
- MeSH terms
- Adenylyl Cyclases, Animals, Cells, Cultured, Cilia, Female, Humans, Male, Mice, Transgenic, Mutation, Neurons, Obesity, Signal Transduction, Genetic Predisposition to Disease, NIH 3T3 Cells, Intracellular Space, Receptor, Melanocortin, Type 4, Mice, HEK293 Cells
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