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Obesity Due to Steroid Receptor Coactivator-1 Deficiency Is Associated With Endocrine and Metabolic Abnormalities
Tessa M Cacciottolo1, Elana Henning1, Julia M Keogh1
1University 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.
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.
Insights
Genetic variants in steroid receptor coactivator (SRC-1) are linked to severe obesity and hormone resistance. Early monitoring for metabolic complications is crucial in affected children and adults.
Area of Science:
- Genetics and Endocrinology
- Metabolic Disorders
- Nuclear Hormone Receptors
Background:
- Genetic variants in the steroid receptor coactivator (SRC-1) gene are associated with severe obesity.
- SRC-1 deficiency impairs melanocortin signaling, affecting appetite regulation.
- Obese patients with SRC-1 deficiency are being investigated for treatment with melanocortin 4 receptor agonists.
Purpose of the Study:
- To comprehensively describe and characterize the clinical phenotype of SRC-1 variant carriers.
- To facilitate the diagnosis and clinical management of individuals with SRC-1 variants.
- To identify potential health complications associated with SRC-1 deficiency.
Main Methods:
- Genetic screening of 2462 individuals with severe obesity identified 23 rare heterozygous SRC-1 variants.
- Clinical phenotyping of 29 adult and 18 child SRC-1 variant carriers.
- Measurements included metabolic and endocrine function, liver imaging, and adipose tissue biopsies, with comparisons to matched controls.
Main Results:
- SRC-1 variant carriers presented with childhood hyperphagia, severe obesity, multiple fractures (40%), persistent diarrhea, partial thyroid hormone resistance, and menorrhagia.
- Adult carriers showed significantly higher rates of adipose tissue fibrosis (46.2% vs 7.1%, P=.03) compared to controls.
- A trend towards increased liver fibrosis was observed in adult carriers, though not statistically significant.
Conclusions:
- SRC-1 variant carriers exhibit hyperphagia, severe obesity, and partial hormone resistance.
- The presence of fibrosis in adipose and liver tissues suggests a need for close monitoring of metabolic complications in young patients.
- Characterizing the SRC-1 phenotype aids in early diagnosis and management strategies for obesity and related disorders.
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