Dysfunction of the adhesion G protein-coupled receptor latrophilin 1 (ADGRL1/LPHN1) increases the risk of obesity.
Journal
Signal transduction and targeted therapy
ISSN: 2059-3635
Titre abrégé: Signal Transduct Target Ther
Pays: England
ID NLM: 101676423
Informations de publication
Date de publication:
26 Apr 2024
26 Apr 2024
Historique:
received:
21
08
2023
accepted:
20
03
2024
revised:
04
03
2024
medline:
26
4
2024
pubmed:
26
4
2024
entrez:
25
4
2024
Statut:
epublish
Résumé
Obesity is one of the diseases with severe health consequences and rapidly increasing worldwide prevalence. Understanding the complex network of food intake and energy balance regulation is an essential prerequisite for pharmacological intervention with obesity. G protein-coupled receptors (GPCRs) are among the main modulators of metabolism and energy balance. They, for instance, regulate appetite and satiety in certain hypothalamic neurons, as well as glucose and lipid metabolism and hormone secretion from adipocytes. Mutations in some GPCRs, such as the melanocortin receptor type 4 (MC4R), have been associated with early-onset obesity. Here, we identified the adhesion GPCR latrophilin 1 (ADGRL1/LPHN1) as a member of the regulating network governing food intake and the maintenance of energy balance. Deficiency of the highly conserved receptor in mice results in increased food consumption and severe obesity, accompanied by dysregulation of glucose homeostasis. Consistently, we identified a partially inactivating mutation in human ADGRL1/LPHN1 in a patient suffering from obesity. Therefore, we propose that LPHN1 dysfunction is a risk factor for obesity development.
Identifiants
pubmed: 38664368
doi: 10.1038/s41392-024-01810-7
pii: 10.1038/s41392-024-01810-7
doi:
Substances chimiques
Receptors, G-Protein-Coupled
0
Receptors, Peptide
0
ADGRL1 protein, human
0
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
103Subventions
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 209933838 B10
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 421152132 C04
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 209933838 B06
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 246212759 P04
Informations de copyright
© 2024. The Author(s).
Références
NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128·9 million children, adolescents, and adults. Lancet (London, England). 390, 2627–2642 (2017).
Brown, W. V., Fujioka, K., Wilson, P. W. F. & Woodworth, K. A. Obesity: why be concerned? Am. J. Med. 122, S4–S11 (2009).
pubmed: 19410676
doi: 10.1016/j.amjmed.2009.01.002
Golden, A. & Kessler, C. Obesity and genetics. J. Am. Assoc. Nurse Pract. 32, 493–496 (2020).
pubmed: 32658169
doi: 10.1097/JXX.0000000000000447
Elias, C. F. et al. Leptin activates hypothalamic CART neurons projecting to the spinal cord. Neuron. 21, 1375–1385 (1998).
pubmed: 9883730
doi: 10.1016/S0896-6273(00)80656-X
Morton, G. J. et al. Central nervous system control of food intake and body weight. Nature. 443, 289–295 (2006).
pubmed: 16988703
doi: 10.1038/nature05026
Schwartz, M. W. et al. Central nervous system control of food intake. Nature. 404, 661–671 (2000).
pubmed: 10766253
doi: 10.1038/35007534
Krashes, M. J., Shah, B. P., Koda, S. & Lowell, B. B. Rapid versus delayed stimulation of feeding by the endogenously released AgRP neuron mediators GABA, NPY, and AgRP. Cell Metab. 18, 588–595 (2013).
pubmed: 24093681
doi: 10.1016/j.cmet.2013.09.009
Olson, B. R. et al. Oxytocin and an oxytocin agonist administered centrally decrease food intake in rats. Peptides. 12, 113–118 (1991).
pubmed: 1646995
doi: 10.1016/0196-9781(91)90176-P
Ramirez-Virella, J. & Leinninger, G. M. The role of central neurotensin in regulating feeding and body weight. Endocrinology. 162, bqab038 (2021).
pubmed: 33599716
pmcid: 7951050
doi: 10.1210/endocr/bqab038
Hillebrand, J. J. G., Wied, D. D. & Adan, R. A. H. Neuropeptides, food intake and body weight regulation: a hypothalamic focus. Peptides. 23, 2283–2306 (2002).
pubmed: 12535710
doi: 10.1016/S0196-9781(02)00269-3
Krashes, M. J. et al. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J. Clin. Invest. 121, 1424–1428 (2011).
pubmed: 21364278
pmcid: 3069789
doi: 10.1172/JCI46229
Nakajima, K.-I. et al. Gs-coupled GPCR signalling in AgRP neurons triggers sustained increase in food intake. Nat. Commun. 7, 10268 (2016).
pubmed: 26743492
pmcid: 4729878
doi: 10.1038/ncomms10268
Üner, A. G. et al. Role of POMC and AgRP neuronal activities on glycaemia in mice. Sci. Rep. 9, 13068 (2019).
pubmed: 31506541
pmcid: 6736943
doi: 10.1038/s41598-019-49295-7
Nakazato, M. et al. A role for ghrelin in the central regulation of feeding. Nature. 409, 194–198 (2001).
pubmed: 11196643
doi: 10.1038/35051587
Broberger, C. et al. Subtypes Y1 and Y2 of the neuropeptide Y receptor are respectively expressed in pro-opiomelanocortin- and neuropeptide-Y-containing neurons of the rat hypothalamic arcuate nucleus. Neuroendocrinology. 66, 393–408 (1997).
pubmed: 9430445
doi: 10.1159/000127265
Burke, L. K. et al. Sex difference in physical activity, energy expenditure and obesity driven by a subpopulation of hypothalamic POMC neurons. Mol. Metab. 5, 245–252 (2016).
pubmed: 26977396
pmcid: 4770275
doi: 10.1016/j.molmet.2016.01.005
Doslikova, B. et al. 5-HT2C receptor agonist anorectic efficacy potentiated by 5-HT1B receptor agonist coapplication: an effect mediated via increased proportion of pro-opiomelanocortin neurons activated. J. Neurosci. 33, 9800–9804 (2013).
pubmed: 23739976
pmcid: 3717514
doi: 10.1523/JNEUROSCI.4326-12.2013
Takayasu, S., Usutani, M., Makita, K. & Daimon, M. The activation of G protein-coupled receptor 30 increases pro-opiomelanocortin gene expression through cAMP/PKA/NR4A pathway in mouse pituitary corticotroph AtT-20 cells. Neurosci. Lett. 739, 135468 (2020).
pubmed: 33152456
doi: 10.1016/j.neulet.2020.135468
Marks, D. L., Hruby, V., Brookhart, G. & Cone, R. D. The regulation of food intake by selective stimulation of the type 3 melanocortin receptor (MC3R). Peptides. 27, 259–264 (2006).
pubmed: 16274853
doi: 10.1016/j.peptides.2005.01.025
Campfield, L. A. et al. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science. 269, 546–549 (1995).
pubmed: 7624778
doi: 10.1126/science.7624778
Tovar, S. et al. Central administration of resistin promotes short-term satiety in rats. Eur. J. Endocrinol. 153, R1–R5 (2005).
pubmed: 16131594
doi: 10.1530/eje.1.01999
Dragano, N. R. V. et al. Polyunsaturated fatty acid receptors, GPR40 and GPR120, are expressed in the hypothalamus and control energy homeostasis and inflammation. J. Neuroinflammation. 14, 91 (2017).
pubmed: 28446241
pmcid: 5405534
doi: 10.1186/s12974-017-0869-7
Bachman, E. S. et al. betaAR signaling required for diet-induced thermogenesis and obesity resistance. Science. 297, 843–845 (2002).
pubmed: 12161655
doi: 10.1126/science.1073160
Eisenstein, A., Chitalia, S. V. & Ravid, K. Bone marrow and adipose tissue adenosine receptors effect on osteogenesis and adipogenesis. Int. J. Mol. Sci. 21, 7470 (2020).
pubmed: 33050467
pmcid: 7589187
doi: 10.3390/ijms21207470
Gnad, T. et al. Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors. Nature. 516, 395–399 (2014).
pubmed: 25317558
doi: 10.1038/nature13816
Hong, Y.-H. et al. Acetate and propionate short chain fatty acids stimulate adipogenesis via GPCR43. Endocrinology. 146, 5092–5099 (2005).
pubmed: 16123168
doi: 10.1210/en.2005-0545
Kimura, T. et al. Adipocyte Gq signaling is a regulator of glucose and lipid homeostasis in mice. Nat. Commun. 13, 1652 (2022).
pubmed: 35351896
pmcid: 8964770
doi: 10.1038/s41467-022-29231-6
Amisten, S. Quantification of the mRNA expression of G protein-coupled receptors in human adipose tissue. Methods Cell Biol. 132, 73–105 (2016).
pubmed: 26928540
doi: 10.1016/bs.mcb.2015.10.004
Nogueira, P. A. S. et al. The orphan receptor GPR68 is expressed in the hypothalamus and is involved in the regulation of feeding. Neurosci. Lett. 781, 136660 (2022).
pubmed: 35489647
doi: 10.1016/j.neulet.2022.136660
Nogueira, P. A. S. et al. The orphan G protein-coupled receptor, GPR139, is expressed in the hypothalamus and is involved in the regulation of body mass, blood glucose, and insulin. Neurosci. Lett. 792, 136955 (2022).
pubmed: 36347339
doi: 10.1016/j.neulet.2022.136955
Hamann, J. et al. International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors. Pharmacol. Rev. 67, 338–367 (2015).
pubmed: 25713288
pmcid: 4394687
doi: 10.1124/pr.114.009647
Piao, X. et al. G protein-coupled receptor-dependent development of human frontal cortex. Science. 303, 2033–2036 (2004).
pubmed: 15044805
doi: 10.1126/science.1092780
Chiang, N.-Y. et al. Disease-associated GPR56 mutations cause bilateral frontoparietal polymicrogyria via multiple mechanisms. J. Biol. Chem. 286, 14215–14225 (2011).
pubmed: 21349848
pmcid: 3077623
doi: 10.1074/jbc.M110.183830
Arcos-Burgos, M. et al. A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication. Mol. Psychiatry. 15, 1053–1066 (2010).
pubmed: 20157310
doi: 10.1038/mp.2010.6
Scholz, N. Cancer cell mechanics: adhesion G protein-coupled receptors in action? Front. Oncol. 8, 59 (2018).
pubmed: 29594040
pmcid: 5859372
doi: 10.3389/fonc.2018.00059
Kaczmarek, I. et al. The relevance of adhesion G protein-coupled receptors in metabolic functions. Biol. Chem. 403, 195–209 (2022).
pubmed: 34218541
doi: 10.1515/hsz-2021-0146
Suchý, T. et al. The repertoire of Adhesion G protein-coupled receptors in adipocytes and their functional relevance. Int. J. Obes. (Lond). 44, 2124–2136 (2020).
pubmed: 32203115
pmcid: 7508673
doi: 10.1038/s41366-020-0570-2
Matsushita, H., Lelianova, V. G. & Ushkaryov, Y. A. The latrophilin family: multiply spliced G protein-coupled receptors with differential tissue distribution. FEBS Lett. 443, 348–352 (1999).
pubmed: 10025961
doi: 10.1016/S0014-5793(99)00005-8
Sugita, S., Ichtchenko, K., Khvotchev, M. & Südhof, T. C. Alpha-Latrotoxin receptor CIRL/latrophilin 1 (CL1) defines an unusual family of ubiquitous G-protein-linked receptors. G-protein coupling not required for triggering exocytosis. J. Biol. Chem. 273, 32715–32724 (1998).
pubmed: 9830014
doi: 10.1074/jbc.273.49.32715
Vysokov, N. V. et al. Proteolytically released Lasso/teneurin-2 induces axonal attraction by interacting with latrophilin-1 on axonal growth cones. ELife. 7, e37935 (2018).
pubmed: 30457553
pmcid: 6245728
doi: 10.7554/eLife.37935
Meza-Aguilar, D. G. & Boucard, A. A. Latrophilins updated. Biomol. Concepts. 5, 457–478 (2014).
pubmed: 25429599
doi: 10.1515/bmc-2014-0032
Tobaben, S., Südhof, T. C. & Stahl, B. Genetic analysis of alpha-latrotoxin receptors reveals functional interdependence of CIRL/latrophilin 1 and neurexin 1 alpha. J. Biol. Chem. 277, 6359–6365 (2002).
pubmed: 11741895
doi: 10.1074/jbc.M111231200
Berger, C. et al. A novel compound heterozygous leptin receptor mutation causes more severe obesity than in Leprdb/db mice. J. Lipid Res. 62, 100105 (2021).
pubmed: 34390703
pmcid: 8450258
doi: 10.1016/j.jlr.2021.100105
Moreno-Salinas, A. L. et al. Latrophilins: a neuro-centric view of an evolutionary conserved adhesion G protein-coupled receptor subfamily. Front Neurosci. 13, 700 (2019).
pubmed: 31354411
pmcid: 6629964
doi: 10.3389/fnins.2019.00700
Henry, F. E. et al. Cell type-specific transcriptomics of hypothalamic energy-sensing neuron responses to weight-loss. ELife. 4, e09800 (2015).
pubmed: 26329458
pmcid: 4595745
doi: 10.7554/eLife.09800
Steppan, C. M. et al. The hormone resistin links obesity to diabetes. Nature. 409, 307–312 (2001).
pubmed: 11201732
doi: 10.1038/35053000
Perakakis, N., Farr, O. M. & Mantzoros, C. S. Leptin in leanness and obesity: JACC state-of-the-art review. J. Am. Coll. Cardio. 77, 745–760 (2021).
doi: 10.1016/j.jacc.2020.11.069
Kern, P. A. et al. Adiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-alpha expression. Diabetes. 52, 1779–1785 (2003).
pubmed: 12829646
doi: 10.2337/diabetes.52.7.1779
Stinson, S. E. et al. Fasting plasma GLP-1 is associated with overweight/obesity and cardiometabolic risk factors in children and adolescents. J Clin. Endocrinol. Metab. 106, 1718–1727 (2021).
pubmed: 33596309
pmcid: 8118577
doi: 10.1210/clinem/dgab098
Lijnen, H. R. et al. On the role of plasminogen activator inhibitor-1 in adipose tissue development and insulin resistance in mice. J. Thromb. Haemost. 3, 1174–1179 (2005).
pubmed: 15946208
doi: 10.1111/j.1538-7836.2005.01390.x
Karczewski, K. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 581, 434–443 (2020).
pubmed: 32461654
pmcid: 7334197
doi: 10.1038/s41586-020-2308-7
Vitobello, A. et al. ADGRL1 haploinsufficiency causes a variable spectrum of neurodevelopmental disorders in humans and alters synaptic activity and behavior in a mouse model. Am. J. Hum. Genet. 109, 1436–1457 (2022).
pubmed: 35907405
pmcid: 9388395
doi: 10.1016/j.ajhg.2022.06.011
Knierim, A. B. et al. Genetic basis of functional variability in adhesion G protein-coupled receptors. Sci Rep. 9, 11036 (2019).
pubmed: 31363148
pmcid: 6667449
doi: 10.1038/s41598-019-46265-x
Müller, A. et al. Oriented Cell Division in the C. elegans Embryo Is Coordinated by G-Protein Signaling Dependent on the Adhesion GPCR LAT-1. PLoS Genet. 11, e1005624 (2015).
pubmed: 26505631
pmcid: 4624771
doi: 10.1371/journal.pgen.1005624
Lefkowitz, R. J., Cotecchia, S., Samama, P. & Costa, T. Constitutive activity of receptors coupled to guanine nucleotide regulatory proteins. Trends Pharmacol. Sci. 14, 303–307 (1993).
pubmed: 8249148
doi: 10.1016/0165-6147(93)90048-O
Röthe, J. et al. Involvement of the adhesion GPCRs latrophilins in the regulation of insulin release. Cell Rep. 26, 1573–1584.e1575 (2019).
pubmed: 30726739
doi: 10.1016/j.celrep.2019.01.040
Nazarko, O. et al. A Comprehensive Mutagenesis Screen of the Adhesion GPCR Latrophilin-1/ADGRL1. iScience. 3, 264–278 (2018).
pubmed: 30428326
pmcid: 6137404
doi: 10.1016/j.isci.2018.04.019
Chhabra, K. H. et al. ADGRL1 is a glucose receptor involved in mediating energy and glucose homeostasis. Diabetologia. 67, 170–189 (2023).
Chehab, F. F., Lim, M. E. & Lu, R. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat Genet. 12, 318–320 (1996).
pubmed: 8589726
doi: 10.1038/ng0396-318
Silva, J.-P. & Ushkaryov, Y. A. The latrophilins, “split-personality” receptors. Adv. Exp. Med. Biol. 706, 59–75 (2010).
pubmed: 21618826
pmcid: 3145135
doi: 10.1007/978-1-4419-7913-1_5
Simpson, K. A., Martin, N. M. & Bloom, S. R. Hypothalamic regulation of food intake and clinical therapeutic applications. Arq Bras Endocrinol Metabol. 53, 120–128 (2009).
pubmed: 19466203
doi: 10.1590/S0004-27302009000200002
Choi, H.-M. et al. An age-dependent alteration of the respiratory exchange ratio in the db/db mouse. Lab. Anim. Res. 31, 1–6 (2015).
pubmed: 25806077
pmcid: 4371472
doi: 10.5625/lar.2015.31.1.1
Schoiswohl, G. et al. Impact of Reduced ATGL-Mediated Adipocyte Lipolysis on Obesity-Associated Insulin Resistance and Inflammation in Male Mice. Endocrinology. 156, 3610–3624 (2015).
pubmed: 26196542
pmcid: 4588821
doi: 10.1210/en.2015-1322
Haemmerle, G. et al. Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science. 312, 734–737 (2006).
pubmed: 16675698
doi: 10.1126/science.1123965
Wu, J. W. et al. Fasting energy homeostasis in mice with adipose deficiency of desnutrin/adipose triglyceride lipase. Endocrinology. 153, 2198–2207 (2012).
pubmed: 22374972
doi: 10.1210/en.2011-1518
Moreno, C. et al. Regulation of peripheral metabolism by substrate partitioning in the brain. Endocrinol. Metab. Clin. North Am. 42, 67–80 (2013).
pubmed: 23391240
pmcid: 4501378
doi: 10.1016/j.ecl.2012.11.007
Wang, Q. et al. Ventromedial hypothalamic OGT drives adipose tissue lipolysis and curbs obesity. Sci. Adv. 8, eabn8092 (2022).
pubmed: 36044565
pmcid: 9432828
doi: 10.1126/sciadv.abn8092
Pedersen, S. B. et al. Estrogen controls lipolysis by up-regulating alpha2A-adrenergic receptors directly in human adipose tissue through the estrogen receptor alpha. Implications for the female fat distribution. J. Clin. Endocrinol. Metab. 89, 1869–1878 (2004).
pubmed: 15070958
doi: 10.1210/jc.2003-031327
Dalgaard, K. et al. Trim28 haploinsufficiency triggers bi-stable epigenetic obesity. Cell. 164, 353–364 (2016).
pubmed: 26824653
pmcid: 4735019
doi: 10.1016/j.cell.2015.12.025
Landgraf, K. et al. Evidence of early alterations in adipose tissue biology and function and its association with obesity-related inflammation and insulin resistance in children. Diabetes. 64, 1249–1261 (2015).
pubmed: 25392242
doi: 10.2337/db14-0744
Meyre, D. et al. A genome-wide scan for childhood obesity-associated traits in French families shows significant linkage on chromosome 6q22.31-q23.2. Diabetes. 53, 803–811 (2004).
pubmed: 14988267
doi: 10.2337/diabetes.53.3.803
Schöneberg, T. & Liebscher, I. Mutations in G protein-coupled receptors: mechanisms, pathophysiology and potential therapeutic approaches. Pharmacol. Rev. 73, 89–119 (2021).
pubmed: 33219147
doi: 10.1124/pharmrev.120.000011
Wittlake, A., Prömel, S. & Schöneberg, T. The evolutionary history of vertebrate adhesion GPCRs and its implication on their classification. Int. J. Mol. Sci. 22, 11803 (2021).
pubmed: 34769233
pmcid: 8584163
doi: 10.3390/ijms222111803
Piñero, J. et al. DisGeNET: a discovery platform for the dynamical exploration of human diseases and their genes. Database (Oxford). 2015, bav028 (2015).
pubmed: 25877637
pmcid: 4397996
doi: 10.1093/database/bav028
Mina, A. I. et al. CalR: a web-based analysis tool for indirect calorimetry experiments. Cell Metab. 28, 656–666.e651 (2018).
pubmed: 30017358
pmcid: 6170709
doi: 10.1016/j.cmet.2018.06.019
Péronnet, F. & Massicotte, D. Table of nonprotein respiratory quotient: an update. Can. J. Sport Sci. 16, 23–29 (1991).
pubmed: 1645211
Le Duc, D. et al. Reduced lipolysis in lipoma phenocopies lipid accumulation in obesity. Int. J. Obes. (Lond). 45, 565–576 (2021).
pubmed: 33235355
doi: 10.1038/s41366-020-00716-y
Jäger, E. et al. Dendritic Cells Regulate GPR34 through mitogenic signals and undergo apoptosis in its absence. J. Immunol. 196, 2504–2513 (2016).
pubmed: 26851221
doi: 10.4049/jimmunol.1501326
Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 29, 15–21 (2013).
pubmed: 23104886
doi: 10.1093/bioinformatics/bts635
van der Auwera, G. & O’Connor, B. D. (eds) Genomics in the cloud: Using Docker, GATK, and WDL in Terra. First edition edn, (O’Reilly Media, 2020).
Cingolani, P. et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin). 6, 80–92 (2012).
pubmed: 22728672
pmcid: 3679285
doi: 10.4161/fly.19695
Stäubert, C., Broom, O. J. & Nordström, A. Hydroxycarboxylic acid receptors are essential for breast cancer cells to control their lipid/fatty acid metabolism. Oncotarget. 6, 19706–19720 (2015).
pubmed: 25839160
pmcid: 4637315
doi: 10.18632/oncotarget.3565