Circulating growth-and-differentiation factor-15 in early life: relation to prenatal and postnatal growth and adiposity measurements

Díaz, Marta; Campderrós, Laura; Guimarães, Mariana P.; López‐Bermejo, Abel; Zegher, Francis de; Villarroya, Francesc; Ibáñez, Lourdes

doi:10.1038/s41390-019-0633-z

Cited by 22 publications

(25 citation statements)

References 38 publications

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“…This study provides additional information on body composition during childhood, based on a detailed evaluation with DXA, and confirms a predominant central fat distribution related to weight gain during childhood in an unselected cohort of children born SGA and at term. These findings are in line with those of previous studies that support reduced fat mass in short SGA children, mainly in the subcutaneous compartment [17,[31][32][33].…”

Section: Discussionsupporting

confidence: 93%

Catch-Up Growth in Children Born Small for Gestational Age Related to Body Composition and Metabolic Risk at Six Years of Age in the UK

et al. 2020

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Objectives: To determine differences in body composition and glucose metabolism according to childhood growth outcomes in a population-based sample of children born small for gestational age (SGA). Methods: A single-centre study of 259 children born SGA identified through hospital records and contacted when aged 4-7 years. Questionnaire data on pre/perinatal history and growth parameters during childhood was collected from the parents, and in a subgroup of 150 children face-to-face assessments were performed, including anthropometric parameters, lean and fat mass, blood pressure, fasting glucose, and C-peptide. Results: Based on the questionnaires, few children had formal clinic follow-up of growth, but 7% of the cohort showed a height and weight of <-2SDS during childhood, and only 2 children met the criteria for growth hormone therapy. Out of the 150 children assessed at a mean age of 6.1 ± 0.8 years, 122 (81%) showed a catch-up growth in weight. Compared to those without weight catch-up, these children had a higher fat mass index (3.13 ± 1.36 vs. 2.56 ± 0.91 kg/m 2 , p = 0.04), trunk-to-limb fat mass ratio (0.63 ± 0.14 vs. 0.56 ± 0.08, p = 0.002), systolic blood pressure SDS (0.09 ± 0.71 vs.-0.32 ± 0.63, p = 0.008), fasting glucose (4.5 ± 0.5 vs. 4.3 ± 0.5 mmol/L, p = 0.03), and C-peptide (306 ± 116 vs. 256 ± 112 pmol/L, p = 0.08). Among children with weight catch-up growth, those with less height gain had a lower limb lean mass index (4.25 ± 0.48 vs. 4.48 ± 0.56 kg/m 2 , p = 0.02) and fat mass index (1.57 ± 0.59 vs. 1.83 ± 0.77 kg/m 2 , p = 0.04). Conclusions: Within this population-based sample of SGA children, catch-up growth in weight was associated with higher abdominal fat mass, blood pressure and glycemia; furthermore, in these children, less height gain was associated with reduced limb lean and fat mass.

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Section: Discussionsupporting

confidence: 93%

Catch-Up Growth in Children Born Small for Gestational Age Related to Body Composition and Metabolic Risk at Six Years of Age in the UK

et al. 2020

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“…The normal range of circulating GDF15 is generally considered to be 0.2-1.2 ng/mL 18 , with higher levels in early life 16 and also in later life 17 . Thus, SPIOMET increased the GDF15 levels in adolescents with PCOS from low-normal (0.2-0.4 ng/mL) into high-normal range (0.8-1.2 ng/mL); it reduced liver steatosis, insulin resistance and low-grade inflammation, and raised adiponectinaemia, without causing anorexia or a loss of body weight.…”

Section: Discussionmentioning

confidence: 99%

“…Blood sampling was performed in the early morning, after an overnight fast, in the follicular phase of the menstrual cycle (day 3-7) or after two months of amenorrhea. GDF15 was measured in duplicate by ELISA (R&D Systems, Minneapolis, USA) with intra-and inter-assay coefficients of variation (CVs) below 6% 16 . CRP was measured with a highly sensitive method (Architect c8000; Abbott, Wiesbaden, Germany), and insulin by immunochemiluminiscence (Immulite 2000, Diagnostic Products, Los Angeles, USA).…”

Section: Methodsmentioning

confidence: 99%

Catch-up growth in juvenile rats, fat expansion, and dysregulation of visceral adipose tissue

et al. 2021

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A prime concern of young patients with Polycystic Ovary Syndrome (PCOS) is the control of body adiposity, given their tendency to gain weight and/or their difficulty to lose weight. Circulating growth-and-differentiation factor-15 (GDF15) facilitates the control of body weight via receptors in the brainstem. C-reactive protein (CRP) and insulin are endogenous GDF15 secretagogues. We hypothesised that PCOS in non-obese adolescents is characterised by low concentrations of circulating GDF15, when judged by the degree of CRP and insulin drive. GDF15 was added as a posthoc endpoint of two previously reported, randomised studies in non-obese adolescent girls with PCOS (N = 58; 60% normal weight; 40% overweight) who received either an oral oestroprogestogen contraceptive (OC), or a low-dose combination of spironolactone-pioglitazone-metformin (SPIOMET) for 1 year; subsequently, all girls remained untreated for 1 year. Adolescent girls with regular menses (N = 20) served as healthy controls. Circulating GDF15, CRP and fasting insulin were assessed prior to treatment, and halfway the on-and post-treatment years. Pre-treatment, the absolute GDF15 concentrations were normal in PCOS girls, but their relative levels were markedly low, in view of the augmented CRP and insulin drives. OC treatment was accompanied by a near-doubling of circulating GDF15 (on average, from 296 to 507 pg/mL) and CRP, so that the relative GDF15 levels remained low. SPIOMET treatment was accompanied by a 3.4-fold rise of circulating GDF15 (on average, from 308 to 1045 pg/mL) and by a concomitant lowering of CRP and insulin concentrations towards normal, so that the relative GDF15 levels became markedly abundant. Post-OC, the relatively low GDF15 levels persisted; post-SPIOMET, the circulating concentrations of GDF15, CRP and insulin were all normal. BMI remained stable in both treatment groups. Only SPIOMET was accompanied by a reduction of hepato-visceral fat (by MRI) towards normal. In conclusion, early PCOS was found to be characterised by a relative GDF15 deficit that may partly explain the difficulties that young patients experience to control their body adiposity. This relative GDF15 deficit persisted during and after OC treatment. In contrast, SPIOMET treatment was accompanied by an absolute and a relative abundance of GDF15, and followed by normal GDF15, CRP and insulin concentrations. The present findings strengthen the rationale to raise the concentrations of circulating GDF15 in early PCOS, for example with a SPIOMETlike intervention that attenuates low-grade inflammation, insulin resistance and ectopic adiposity, without necessarily lowering body weight. Clinical trial registries: ISRCTN29234515 and ISRCTN11062950.

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“…During fetal lung development, GDF15 expression seemed to be involved in the promotion of proliferation and differentiation and was androgen-responsive (19). The circulating levels of GDF15 in full-term newborns are 10-fold higher than adult levels, that soon after birth trend down to reach adult levels between 4 and 12 months (20). The circulatory levels of GDF15 in preterm infants across different gestational age windows have not been studied.…”

Section: Role Of Gdf15 In Chronic Lung Disease: Neonatal and Pediatricmentioning

confidence: 99%

“…Promotes proliferation and differentiation in fetal lung development (19) Maternal serum levels increase throughout during pregnancy (12) High serum levels in term neonates that decline postnatally (20) Upregulated in neonatal mice exposed to hyperoxia in vivo (21) Upregulated in pulmonary epithelial and endothelial cells exposed to hyperoxia (22) GDF15 loss leads to decreased cell viability and increased oxidative stress (23) Chronic Obstructive Pulmonary Disease (COPD) Higher serum levels are associated with increased morbidity and mortality (4,24) Mediates smoking-induced inflammation and cellular senescence (25)(26)(27) Promotes mucin production in ciliated epithelial cells (28) Exacerbates lung inflammation secondary to infection (29) Contributes to cachexia: GFRAL mediated signaling, induces lipolysis and promotes muscle wasting (30)(31)(32)(33) Pulmonary Hypertension (PH) Associated with prognosis and response to therapy (34)(35)(36) Levels increased in pediatric PH related to congenital heart disease (37) Associated with increase in right atrial and pulmonary capillary wedge pressure (34) Induces muscle atrophy that is reversed by TAK1 inhibitor (38) Promotes angiogenesis and hinders endothelial cell apoptosis (39,40) Lung Fibrosis Associated with disease severity (41) Associated with higher odds of interstitial lung abnormality (42) Activates fibroblasts and M2 macrophages (40) Prevents the activation of fibroblasts during lung remodeling (43) FIGURE 1 | Cellular senescence and lung disease across the lifespan: role of GDF15.…”

Section: Age/condition Role Of Gdf15 Referencesmentioning

confidence: 99%

Role of Growth Differentiation Factor 15 in Lung Disease and Senescence: Potential Role Across the Lifespan

et al. 2020

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Growth Differentiation Factor 15 (GDF15) is a divergent member of transforming growth factor-beta (TGF-β) superfamily and is ubiquitously expressed, under normal physiological conditions. GDF15 expression increases during many pathological states and serves a marker of cellular stress. GDF15 has multiple and even paradoxical roles within a pathological condition, as its effects can be dose- and time-dependent and vary based on the targeted tissues and downstream pathways. GDF15 has emerged as one of the most recognized proteins as part of the senescence associated secretory phenotype. Cellular senescence plays a major role in many lung diseases across the life-span from bronchopulmonary dysplasia in the premature neonate to COPD and idiopathic pulmonary fibrosis in aged adults. GDF15 levels have been reported to be as a useful biomarker in chronic obstructive pulmonary disease, lung fibrosis and pulmonary arterial hypertension and predict disease severity, decline in lung function and mortality. Glial-cell-line-derived neurotrophic factor family receptor alpha-like (GFRAL) in the brain stem has been identified as the only validated GDF15 receptor and mediates GDF15-mediated anorexia and wasting. The mechanisms and pathways by which GDF15 exerts its pulmonary effects are being elucidated. GDF15 may also have an impact on the lung based on the changes in circulating levels or through the central action of GDF15 activating peripheral metabolic changes. This review focuses on the role of GDF15 in different lung diseases across the lifespan and its role in cellular senescence.

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Circulating growth-and-differentiation factor-15 in early life: relation to prenatal and postnatal growth and adiposity measurements

Cited by 22 publications

References 38 publications

Catch-Up Growth in Children Born Small for Gestational Age Related to Body Composition and Metabolic Risk at Six Years of Age in the UK

Catch-Up Growth in Children Born Small for Gestational Age Related to Body Composition and Metabolic Risk at Six Years of Age in the UK

Catch-up growth in juvenile rats, fat expansion, and dysregulation of visceral adipose tissue

Role of Growth Differentiation Factor 15 in Lung Disease and Senescence: Potential Role Across the Lifespan

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