Marta Díaz1,2, Gemma Carreras-Badosa3, Joan Villarroya1,4,5, Aleix Gavaldà-Navarro1,4,5, Judit Bassols3, Francis de Zegher6, Abel López-Bermejo3, Francesc Villarroya7,8,9, Lourdes Ibáñez10,11. 1. Endocrinology Department, Institut de Recerca Sant Joan de Déu, University of Barcelona, 08950 Esplugues, Barcelona, Spain. 2. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, 28029, Madrid, Spain. 3. Pediatric Endocrinology Research Group, Girona Institute for Biomedical Research (IDIBGI), Faculty of Medicine, University of Girona and Dr. Josep Trueta Hospital, 17007, Girona, Spain. 4. Biochemistry and Molecular Biomedicine, Institute of Biomedicine, University of Barcelona and Institut de Recerca Sant Joan de Déu, Barcelona, Spain. 5. Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), ISCIII, 28029, Madrid, Spain. 6. Leuven Research and Development, 3000, Leuven, Belgium. 7. Endocrinology Department, Institut de Recerca Sant Joan de Déu, University of Barcelona, 08950 Esplugues, Barcelona, Spain. fvillarroya@ub.edu. 8. Biochemistry and Molecular Biomedicine, Institute of Biomedicine, University of Barcelona and Institut de Recerca Sant Joan de Déu, Barcelona, Spain. fvillarroya@ub.edu. 9. Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), ISCIII, 28029, Madrid, Spain. fvillarroya@ub.edu. 10. Endocrinology Department, Institut de Recerca Sant Joan de Déu, University of Barcelona, 08950 Esplugues, Barcelona, Spain. lourdes.ibanez@sjd.es. 11. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, 28029, Madrid, Spain. lourdes.ibanez@sjd.es.
Abstract
BACKGROUND: Low birth weight (LBW) followed by a rapid postnatal catch-up in weight predisposes individuals to a central distribution of body fat, which is reverted by metformin. Growth-and-differentiation-factor-15 (GDF15) plays an important role in the regulation of energy homeostasis, reducing food intake and body weight. We assessed whether GDF15 concentrations are raised by long-term metformin treatment in LBW/catch-up girls with precocious pubarche (PP, pubic hair <8 years), and whether they relate to changes in endocrine-metabolic variables, body composition, and abdominal fat partitioning. METHODS: Circulating GDF15 was determined in 30 LBW/catch-up girls with PP randomly assigned to receive metformin for 4 years (n = 15; 425 mg/d for 2 years, then 850 mg/d for 2 years) or to remain untreated (n = 15). Endocrine-metabolic variables, body composition (by absorptiometry), and abdominal fat partitioning (by MRI) were assessed at the start and yearly during follow-up. RESULTS: Circulating GDF15 concentrations increased significantly in LBW-PP girls only after 3 and 4 years on metformin. GDF15 levels associated negatively with insulin, HOMA-IR, androgens, body fat, and visceral fat. CONCLUSION: Prepubertal intervention with metformin reduces central adiposity and insulin resistance in girls with reduced prenatal growth. GDF15 could be among the mediators of such effects, especially over the long term. IMPACT: Low birth weight followed by a rapid postnatal catch-up in weight predisposes individuals to a central distribution of body fat, which is reverted by metformin. Growth-and-differentiation-factor-15 (GDF15) is a peptide hormone that reduces food intake and lowers body weight; metformin is an exogenous GDF15 secretagogue. Serum GDF15 concentrations increase after 3 and 4 years on metformin and associate negatively with insulin, androgens, body fat, and visceral fat. Prepubertal intervention with metformin reduces central adiposity and insulin resistance in girls with low birth weight. GDF15 could mediate these effects, especially over the long term.
BACKGROUND: Low birth weight (LBW) followed by a rapid postnatal catch-up in weight predisposes individuals to a central distribution of body fat, which is reverted by metformin. Growth-and-differentiation-factor-15 (GDF15) plays an important role in the regulation of energy homeostasis, reducing food intake and body weight. We assessed whether GDF15 concentrations are raised by long-term metformin treatment in LBW/catch-up girls with precocious pubarche (PP, pubic hair <8 years), and whether they relate to changes in endocrine-metabolic variables, body composition, and abdominal fat partitioning. METHODS: Circulating GDF15 was determined in 30 LBW/catch-up girls with PP randomly assigned to receive metformin for 4 years (n = 15; 425 mg/d for 2 years, then 850 mg/d for 2 years) or to remain untreated (n = 15). Endocrine-metabolic variables, body composition (by absorptiometry), and abdominal fat partitioning (by MRI) were assessed at the start and yearly during follow-up. RESULTS: Circulating GDF15 concentrations increased significantly in LBW-PP girls only after 3 and 4 years on metformin. GDF15 levels associated negatively with insulin, HOMA-IR, androgens, body fat, and visceral fat. CONCLUSION: Prepubertal intervention with metformin reduces central adiposity and insulin resistance in girls with reduced prenatal growth. GDF15 could be among the mediators of such effects, especially over the long term. IMPACT: Low birth weight followed by a rapid postnatal catch-up in weight predisposes individuals to a central distribution of body fat, which is reverted by metformin. Growth-and-differentiation-factor-15 (GDF15) is a peptide hormone that reduces food intake and lowers body weight; metformin is an exogenous GDF15 secretagogue. Serum GDF15 concentrations increase after 3 and 4 years on metformin and associate negatively with insulin, androgens, body fat, and visceral fat. Prepubertal intervention with metformin reduces central adiposity and insulin resistance in girls with low birth weight. GDF15 could mediate these effects, especially over the long term.
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