GDF15 mediates adiposity resistance through actions on GFRAL neurons in the hindbrain AP/NTS

Tsai, Vicky Wang-Wei; Zhang, Hong Ping; Manandhar, Rakesh; Schofield, Peter R.; Christ, Daniel; Lee-Ng, Ka Ki Michelle; Lebhar, Hélène; Marquis, Christopher; Husaini, Yasmin; Brown, David A.; Breit, Samuel N.

doi:10.1038/s41366-019-0365-5

Cited by 59 publications

(38 citation statements)

References 22 publications

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“…We found an inverse correlation between GDF15 increase during pregnancy and FM gain in NW but did not see a relationship between GDF15 and gestational weight gain. Increases in GDF15 mediate adiposity resistance 29 and are linked to reductions in body weight 9,30,31 and in FM 32 . The effect of GDF15 on weight loss is thought to be associated with appetite reduction regulated by binding to the GDNF family receptor α‐like (GFRAL) receptor in the hindbrain 29,33 .…”

Section: Discussionmentioning

confidence: 99%

Growth‐differentiation‐factor 15 levels in obese and healthy pregnancies: Relation to insulin resistance and insulin secretory function

Andersson‐Hall

Joelsson

Svedin

et al. 2021

Clinical Endocrinology

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Objective/Aim Growth‐differentiation‐factor 15 (GDF15) has been suggested to improve or protect beta cell function. During pregnancy, beta cell numbers and function increase to overcome the natural rise in insulin resistance during gestation. In this study, we longitudinally measured serum GDF15 levels during and after pregnancy in women of normal weight (NW) and in women with obesity (OB) and explored associations between GDF15 and changes in beta cell function by homeostatic model assessment (HOMA). Methods The cohort participants were 38 NW (BMI 22.3 ± 1.7) and 35 OB (BMI 35.8 ± 4.2). Blood was sampled and body composition measured at each trimester (T1, T2, and T3) and at 6, 12 and 18 months postpartum. Fasting glucose, insulin and GDF15 were measured, and HOMA for insulin resistance (HOMA‐IR) and beta cell function (HOMA‐B) determined. Results GDF15 levels increased significantly each trimester and were ~200‐fold higher at T3 than in the nonpregnant postpartum state. GDF15 was higher in NW than OB during pregnancy, but was reversed after pregnancy with a significant interaction effect. GDF15 correlated inversely with BMI and fat‐free mass at T3. Low GDF15 was associated with lower incidence of nausea and with carrying a male foetus. The pregnancy induced increase in GDF15 associated with increased HOMA‐B in OB and with reduced fasting glucose in all women. Conclusion Large gestational upregulation of GDF15 levels may help increase insulin secretory function to overcome pregnancy‐induced insulin resistance.

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Section: Discussionmentioning

confidence: 99%

Growth‐differentiation‐factor 15 levels in obese and healthy pregnancies: Relation to insulin resistance and insulin secretory function

Andersson‐Hall

Joelsson

Svedin

et al. 2021

Clinical Endocrinology

View full text Add to dashboard Cite

show abstract

“…We found an inverse correlation between GDF15 increase during pregnancy and FM gain in NW but did not see a relationship between GDF15 and gestational weight gain. Increases in GDF15 mediate adiposity resistance 32 and are linked to reductions in body weight 12,33,34 and in FM 35 . The effect of GDF15 on weight loss is thought to be associated with appetite reduction regulated by binding to the GDNF family receptor α-like (GFRAL) receptor in the hindbrain 32,36 .…”

Section: Discussionmentioning

confidence: 99%

“…Increases in GDF15 mediate adiposity resistance 32 and are linked to reductions in body weight 12,33,34 and in FM 35 . The effect of GDF15 on weight loss is thought to be associated with appetite reduction regulated by binding to the GDNF family receptor α-like (GFRAL) receptor in the hindbrain 32,36 . The effect of GDF15 on pregnancy-related weight gain has not previously been reported, but GDF15 has been linked to pregnancy-related nausea and hyperemesis gravidarum 20,21 .…”

Section: Discussionmentioning

confidence: 99%

Growth differentiation factor 15 levels in obese and healthy pregnancies and its relation to insulin resistance and insulin secretory function: a longitudinal study during and after pregnancy

Andersson‐Hall

Joelsson

Svedin

et al. 2020

Preprint

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Objective/aim Growth-differentiation-factor 15 (GDF15) has been suggested to improve or protect beta-cell function. During pregnancy, beta-cell numbers and function increase to overcome the natural rise in insulin resistance during gestation. In this study, we longitudinally measured serum GDF15 levels during and after pregnancy in women of normal weight (NW) and in women with obesity (OB) and explored associations between GDF15 and changes in beta-cell function by homeostatic model assessment (HOMA). Methods The cohort participants were 38 NW (BMI 22.3±1.7) and 35 OB (BMI 35.8±4.2). Blood was sampled and body composition measured at each trimester (T1, T2, and T3) and at 6, 12, and 18 months postpartum. Fasting glucose, insulin, and GDF15 were measured, and HOMA for insulin resistance (HOMA-IR) and beta cell function (HOMA-B) determined. Results GDF15 levels increased significantly each trimester and were˜200-fold higher at T3 than in the nonpregnant postpartum state. GDF15 was higher in NW than OB in T3, but was lower in NW at 18 months after pregnancy. GDF15 correlated inversely with BMI and fat-free mass at T3. Low GDF15 in T1 was associated with lower incidence of nausea and with carrying a male fetus. GDF15 at T2 and T3 and the increases between trimesters associated with increased HOMA-B over the course of pregnancy. Increases in GDF15 either early or late in pregnancy were associated with a reduction in blood glucose between T2 and T3. Conclusion Large gestational upregulation of GDF15 levels may help increase insulin secretory function to overcome pregnancy-induced insulin resistance. Abbreviations GDF15 Growth differentiation factor 15 HOMA-B Homeostatic model assessment for beta cell function HOMA-IR Homeostatic model assessment for insulin resistance NW Women of normal weight OB Women with obesity

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“…This protein has previously been implicated in diabetes incidence and the control of food intake 43,44 , acting via receptors in the hind brain. 28 GDF-15 has also been reported to serve as a useful biomarker for impaired fasting glucose 45 and diabetic kidney disease 46 as well as a number of conditions including cardiovascular disease 47,48 GDF15 is strongly elevated following metformin exposure, due to release from the gut. 49 Of note, we did not show any attenuation of the GDF15 signal with progression when adjusting for whether the patients were treated with metformin at the time of blood sampling.…”

Section: Proteins and Glycaemic Deteriorationmentioning

confidence: 99%

Novel biomarkers for glycaemic deterioration in type 2 diabetes: an IMI RHAPSODY study

López-Noriega

et al. 2021

Preprint

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We have deployed a multi-omics approach in large cohorts of patients with existing type 2 diabetes to identify biomarkers for disease progression across three molecular classes, metabolites, lipids and proteins. A Cox regression analysis for association with time to insulin requirement in 2,973 patients in the DCS, ANDIS and GoDARTS cohorts identified homocitrulline, isoleucine and 2-aminoadipic acid, as well as the bile acids glycocholic and taurocholic acids, as predictive of more rapid deterioration. Increased levels of eight triacylglycerol species, and lowered levels of the sphingomyelin SM 42:2;2 were also predictive of disease progression. Of ∼1,300 proteins examined in two cohorts, levels of GDF-15/MIC1, IL-18RA, CRELD1, NogoR, FAS, and ENPP7 were associated with faster progression, whilst SMAC/DIABLO, COTL1, SPOCK1 and HEMK2 predicted lower progression rates. Strikingly, identified proteins and lipids were also associated with diabetes incidence and prevalence in external replication cohorts. Implicating roles in disease compensation, NogoR/RTN4R improved glucose tolerance in high fat-fed mice and tended to improved insulin signalling in liver cells whilst IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. Conversely, high NogoR levels led to islet cell apoptosis. This comprehensive, multi-disciplinary approach thus identifies novel biomarkers with potential prognostic utility, provides evidence for new disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.

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GDF15 mediates adiposity resistance through actions on GFRAL neurons in the hindbrain AP/NTS

Cited by 59 publications

References 22 publications

Growth‐differentiation‐factor 15 levels in obese and healthy pregnancies: Relation to insulin resistance and insulin secretory function

Growth‐differentiation‐factor 15 levels in obese and healthy pregnancies: Relation to insulin resistance and insulin secretory function

Growth differentiation factor 15 levels in obese and healthy pregnancies and its relation to insulin resistance and insulin secretory function: a longitudinal study during and after pregnancy

Novel biomarkers for glycaemic deterioration in type 2 diabetes: an IMI RHAPSODY study

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