{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T22:29:40Z","timestamp":1791239380541,"version":"4.1.0"},"reference-count":51,"publisher":"The Endocrine Society","issue":"10","license":[{"start":{"date-parts":[[2021,6,7]],"date-time":"2021-06-07T00:00:00Z","timestamp":1623024000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100004690","name":"French Ministry of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004690","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,9,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Context<\/jats:title>\n                  <jats:p>Unlike homozygous variants, the implication of heterozygous variants on the leptin\u2013melanocortin pathway in severe obesity has not been established.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>To describe the frequency, the phenotype, and the genotype\u2013phenotype relationship for heterozygous variants in LEP, LEPR, POMC, and PCSK1 in severe obesity.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>In this retrospective study, genotyping was performed on at least 1 of the LEP, LEPR, POMC, and PCSK1 genes in 1486 probands with severe obesity (600 children, 886 adults). The phenotype was collected in 60 subjects with heterozygous variants and 16 with homozygous variants. We analyzed variant frequency, body mass index (BMI), age of obesity onset, food impulsivity, and endocrine abnormalities.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The frequency of subjects with homozygous variants was 1.7% (n = 26), and 6.7% (n = 100) with heterozygous variants. Adults with homozygous variants had a higher BMI (66 vs 53 kg\/m2, P = .015), an earlier onset of obesity (0.4 vs 5.4 years, P &amp;lt; .001), more often food impulsivity (83% vs 42%, P = .04), and endocrine abnormalities (75% vs 26%, P &amp;lt; .01). The BMI was higher for subjects with high-impact heterozygous variants (61 vs 50 kg\/m\u00b2, P = .045) and those with a second heterozygous variant on the pathway (65 vs 49 kg\/m\u00b2, P &amp;lt; .01). In children, no significant differences were found for the age of obesity onset and BMI.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Heterozygous variants in LEP, LEPR, POMC, and PCSK1 are frequent in severe obesity and sometimes associated with a phenotype close to that of homozygotes. These data suggest a systematic search for variants in severe early-onset obesity, to discuss therapy that targets this key pathway.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/clinem\/dgab404","type":"journal-article","created":{"date-parts":[[2021,6,7]],"date-time":"2021-06-07T18:35:13Z","timestamp":1623090913000},"page":"2991-3006","source":"Crossref","is-referenced-by-count":57,"title":["Implication of Heterozygous Variants in Genes of the Leptin\u2013Melanocortin Pathway in Severe Obesity"],"prefix":"10.1210","volume":"106","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6581-4107","authenticated-orcid":false,"given":"Sophie","family":"Courbage","sequence":"first","affiliation":[{"name":"Assistance Publique-H\u00f4pitaux de Paris (AP-HP), Reference Centre for Rare Diseases (PRADORT, Prader-Willi Syndrome and other Rare Forms of Obesity with Eating Behavior Disorders), Pediatric Nutrition and Gastroenterology Department, Armand-Trousseau Hospital, Sorbonne University, Paris, France"},{"name":"Sorbonne Universit\u00e9, INSERM, Nutrition and Obesities; Systemic Approaches (NutriOmics) Research Unit, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7769-6331","authenticated-orcid":false,"given":"Christine","family":"Poitou","sequence":"additional","affiliation":[{"name":"Assistance Publique-H\u00f4pitaux de Paris (AP-HP), Reference Centre for Rare Diseases (PRADORT, Prader-Willi Syndrome and other Rare Forms of Obesity with Eating Behavior Disorders), Nutrition Department, Piti\u00e9-Salp\u00eatri\u00e8re Hospital, Paris, France"},{"name":"Sorbonne Universit\u00e9, INSERM, Nutrition and Obesities; Systemic Approaches (NutriOmics) Research Unit, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5647-2002","authenticated-orcid":false,"given":"Johanne","family":"Le Beyec-Le Bihan","sequence":"additional","affiliation":[{"name":"Assistance Publique-H\u00f4pitaux de Paris (AP-HP), Endocrine and Oncological Biochemistry Department, Piti\u00e9-Salp\u00eatri\u00e8re Hospital, Sorbonne University, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Karsenty","sequence":"additional","affiliation":[{"name":"Assistance Publique-H\u00f4pitaux de Paris (AP-HP), Reference Centre for Rare Diseases (PRADORT, Prader-Willi Syndrome and other Rare Forms of Obesity with Eating Behavior Disorders), Pediatric Nutrition and Gastroenterology Department, Armand-Trousseau Hospital, Sorbonne University, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4979-1822","authenticated-orcid":false,"given":"Julie","family":"Lemale","sequence":"additional","affiliation":[{"name":"Assistance Publique-H\u00f4pitaux de Paris (AP-HP), Reference Centre for Rare Diseases (PRADORT, Prader-Willi Syndrome and other Rare Forms of Obesity with Eating Behavior Disorders), Pediatric Nutrition and Gastroenterology Department, Armand-Trousseau Hospital, Sorbonne University, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e9ronique","family":"Pelloux","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, Nutrition and Obesities; Systemic Approaches (NutriOmics) Research Unit, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Marc","family":"Lacorte","sequence":"additional","affiliation":[{"name":"Assistance Publique-H\u00f4pitaux de Paris (AP-HP), Endocrine and Oncological Biochemistry Department, Piti\u00e9-Salp\u00eatri\u00e8re Hospital, Sorbonne University, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0424-6767","authenticated-orcid":false,"given":"Jean-Claude","family":"Carel","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, F-75019, Paris, France; AP-HP.Nord Universit\u00e9 de Paris. H\u00f4pital Universitaire Robert-Debr\u00e9, Service d\u2019Endocrinologie Diab\u00e9tologie P\u00e9diatrique F-75019, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Lecomte","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, F-75019, Paris, France; AP-HP.Nord Universit\u00e9 de Paris. H\u00f4pital Universitaire Robert-Debr\u00e9, Service d\u2019Endocrinologie Diab\u00e9tologie P\u00e9diatrique F-75019, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Storey","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, F-75019, Paris, France; AP-HP.Nord Universit\u00e9 de Paris. H\u00f4pital Universitaire Robert-Debr\u00e9, Service d\u2019Endocrinologie Diab\u00e9tologie P\u00e9diatrique F-75019, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1313-5599","authenticated-orcid":false,"given":"Gianpaolo","family":"De Filippo","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, F-75019, Paris, France; AP-HP.Nord Universit\u00e9 de Paris. H\u00f4pital Universitaire Robert-Debr\u00e9, Service d\u2019Endocrinologie Diab\u00e9tologie P\u00e9diatrique F-75019, Paris, France"},{"name":"Assistance Publique-H\u00f4pitaux de Paris (AP-HP), Bic\u00eatre Hospital, Medicine for Adolescents Department, Le Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muriel","family":"Coupaye","sequence":"additional","affiliation":[{"name":"Assistance Publique-H\u00f4pitaux de Paris (AP-HP), Reference Centre for Rare Diseases (PRADORT, Prader-Willi Syndrome and other Rare Forms of Obesity with Eating Behavior Disorders), Nutrition Department, Piti\u00e9-Salp\u00eatri\u00e8re Hospital, Paris, France"},{"name":"Assistance Publique-H\u00f4pitaux de Paris (AP-HP), Explorations Fonctionnelles Department, Louis-Mourier Hospital, Centre Int\u00e9gr\u00e9 Nord Francilien de l\u2019Ob\u00e9sit\u00e9 (CINFO) and Universit\u00e9 de Paris, Centre de Recherche sur l\u2019Inflammation, Inserm UMRS 1149, Paris, 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