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Obesity Due to Steroid Receptor Coactivator-1 Deficiency Is Associated With Endocrine and Metabolic Abnormalities.
Cacciottolo, Tessa M; Henning, Elana; Keogh, Julia M; Bel Lassen, Pierre; Lawler, Katherine; Bounds, Rebecca; Ahmed, Rachel; Perdikari, Aliki; Mendes de Oliveira, Edson; Smith, Miriam; Godfrey, Edmund M; Johnson, Elspeth; Hodson, Leanne; Clément, Karine; van der Klaauw, Agatha A; Farooqi, I Sadaf.
Afiliação
  • Cacciottolo TM; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
  • Henning E; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
  • Keogh JM; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
  • Bel Lassen P; Sorbonne Université, INSERM, Nutrition and Obesities: Systemic Approaches (NutriOmics) Research Group and Assistance Publique hôpitaux de Paris, Nutrition Department, Pitié-Salpêtrière Hospital, 75013 Paris, France.
  • Lawler K; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
  • Bounds R; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
  • Ahmed R; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
  • Perdikari A; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
  • Mendes de Oliveira E; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
  • Smith M; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
  • Godfrey EM; Department of Radiology, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
  • Johnson E; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital and National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals Foundation Trust, Headington, Oxford OX3 7LE, UK.
  • Hodson L; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital and National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals Foundation Trust, Headington, Oxford OX3 7LE, UK.
  • Clément K; Sorbonne Université, INSERM, Nutrition and Obesities: Systemic Approaches (NutriOmics) Research Group and Assistance Publique hôpitaux de Paris, Nutrition Department, Pitié-Salpêtrière Hospital, 75013 Paris, France.
  • van der Klaauw AA; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
  • Farooqi IS; University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
J Clin Endocrinol Metab ; 107(6): e2532-e2544, 2022 05 17.
Article em En | MEDLINE | ID: mdl-35137184
CONTEXT: Genetic variants affecting the nuclear hormone receptor coactivator steroid receptor coactivator, SRC-1, have been identified in people with severe obesity and impair melanocortin signaling in cells and mice. As a result, obese patients with SRC-1 deficiency are being treated with a melanocortin 4 receptor agonist in clinical trials. OBJECTIVE: Here, our aim was to comprehensively describe and characterize the clinical phenotype of SRC-1 variant carriers to facilitate diagnosis and clinical management. METHODS: In genetic studies of 2462 people with severe obesity, we identified 23 rare heterozygous variants in SRC-1. We studied 29 adults and 18 children who were SRC-1 variant carriers and performed measurements of metabolic and endocrine function, liver imaging, and adipose tissue biopsies. Findings in adult SRC-1 variant carriers were compared to 30 age- and body mass index (BMI)-matched controls. RESULTS: The clinical spectrum of SRC-1 variant carriers included increased food intake in children, normal basal metabolic rate, multiple fractures with minimal trauma (40%), persistent diarrhea, partial thyroid hormone resistance, and menorrhagia. Compared to age-, sex-, and BMI-matched controls, adult SRC-1 variant carriers had more severe adipose tissue fibrosis (46.2% vs 7.1% respectively, P = .03) and a suggestion of increased liver fibrosis (5/13 cases vs 2/13 in controls, odds ratio = 3.4), although this was not statistically significant. CONCLUSION: SRC-1 variant carriers exhibit hyperphagia in childhood, severe obesity, and clinical features of partial hormone resistance. The presence of adipose tissue fibrosis and hepatic fibrosis in young patients suggests that close monitoring for the early development of obesity-associated metabolic complications is warranted.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Obesidade Mórbida / Coativador 1 de Receptor Nuclear Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Female / Humans / Male Idioma: En Revista: J Clin Endocrinol Metab Ano de publicação: 2022 Tipo de documento: Article País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Obesidade Mórbida / Coativador 1 de Receptor Nuclear Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Female / Humans / Male Idioma: En Revista: J Clin Endocrinol Metab Ano de publicação: 2022 Tipo de documento: Article País de publicação: Estados Unidos