GDF15 mediates the metabolic effects of PPARβ/δ by activating AMPK

Aguilar-Recarte, David; Barroso, Emma; Gumà, Anna; Pizarro-Delgado, Javier; Peña, Lucía; Ruart, Maria; Palomer, Xavier; Wahli, Walter; Vázquez‐Carrera, Manuel

doi:10.1016/j.celrep.2021.109501

Cited by 60 publications

(33 citation statements)

References 58 publications

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“…Three-month-old C57BL/6 mice were treated with either vehicle or recombinant GDF15 (0.1 mg kg −1 , 8944-GD, R&D, the dose was selected based on previous reports on the efficiency of GDF15 neutralizing antibody [ 69 , 70 ]) (IP injection, every other day) for 12 days. On day 7, the GDF15-treated mice were divided into 2 groups ( n = 5 per group), receiving either GDF15 antibody (5 mg kg −1 ) or IgG control (IP injection, every other day).…”

Section: Methodsmentioning

confidence: 99%

Camptothecin effectively treats obesity in mice through GDF15 induction

Zhu

Xie

et al. 2022

PLoS Biol

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Elevated circulating levels of growth differentiation factor 15 (GDF15) have been shown to reduce food intake and lower body weight through activation of hindbrain receptor glial-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) in rodents and nonhuman primates, thus endogenous induction of this peptide holds promise for obesity treatment. Here, through in silico drug-screening methods, we found that small molecule Camptothecin (CPT), a previously identified drug with potential antitumor activity, is a GDF15 inducer. Oral CPT administration increases circulating GDF15 levels in diet-induced obese (DIO) mice and genetic ob/ob mice, with elevated Gdf15 expression predominantly in the liver through activation of integrated stress response. In line with GDF15’s anorectic effect, CPT suppresses food intake, thereby reducing body weight, blood glucose, and hepatic fat content in obese mice. Conversely, CPT loses these beneficial effects when Gdf15 is inhibited by a neutralizing antibody or AAV8-mediated liver-specific knockdown. Similarly, CPT failed to reduce food intake and body weight in GDF15’s specific receptor GFRAL-deficient mice despite high levels of GDF15. Together, these results indicate that CPT is a promising anti-obesity agent through activation of GDF15-GFRAL pathway.

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Section: Methodsmentioning

confidence: 99%

Camptothecin effectively treats obesity in mice through GDF15 induction

Zhu

Xie

et al. 2022

PLoS Biol

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“…Downstream signaling of GDF-15 has been studied in different models. In a mouse model, GDF-15 has been shown to activate the PPARβ/δ-AMPK-p53 pathway, enhancing the fatty acid oxidation and glucose uptake and reducing ER stress as well as inflammation ( 39 ). Interestingly, the antidiabetic effect of PPARβ/δ was independent of the central GDF-15/GFRAL receptor in the hindbrain ( 39 ).…”

Section: Cellular Mechanisms and Downstream Signaling Pathways Of Gdf-15mentioning

confidence: 99%

“…In a mouse model, GDF-15 has been shown to activate the PPARβ/δ-AMPK-p53 pathway, enhancing the fatty acid oxidation and glucose uptake and reducing ER stress as well as inflammation ( 39 ). Interestingly, the antidiabetic effect of PPARβ/δ was independent of the central GDF-15/GFRAL receptor in the hindbrain ( 39 ). Moreover, GDF-15 was reported to contribute to the increase in peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α and lipin-1, involved in fatty acid metabolism induced by PPARβ/δ activation ( 39 ).…”

Section: Cellular Mechanisms and Downstream Signaling Pathways Of Gdf-15mentioning

confidence: 99%

“…Interestingly, the antidiabetic effect of PPARβ/δ was independent of the central GDF-15/GFRAL receptor in the hindbrain ( 39 ). Moreover, GDF-15 was reported to contribute to the increase in peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α and lipin-1, involved in fatty acid metabolism induced by PPARβ/δ activation ( 39 ). In the same animal model, the expression of GDF-15 was induced in the skeletal muscles via PPARβ/δ agonist, mitigating inflammation and improving glucose tolerance ( 39 ).…”

Section: Cellular Mechanisms and Downstream Signaling Pathways Of Gdf-15mentioning

confidence: 99%

“…Moreover, GDF-15 was reported to contribute to the increase in peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α and lipin-1, involved in fatty acid metabolism induced by PPARβ/δ activation ( 39 ). In the same animal model, the expression of GDF-15 was induced in the skeletal muscles via PPARβ/δ agonist, mitigating inflammation and improving glucose tolerance ( 39 ). In another mouse model, GDF-15 induction through the PPARγ pathway plays a key role in tissue regeneration ( 40 ).…”

Section: Cellular Mechanisms and Downstream Signaling Pathways Of Gdf-15mentioning

confidence: 99%

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Coping With Stress: The Mitokine GDF-15 as a Biomarker of COVID-19 Severity

et al. 2022

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Growth differentiation factor 15 (GDF-15) is a transforming growth factor (TGF)-β superfamily cytokine that plays a central role in metabolism regulation. Produced in response to mitochondrial stress, tissue damage or hypoxia, this cytokine has emerged as one of the strongest predictors of disease severity during inflammatory conditions, cancers and infections. Reports suggest that GDF-15 plays a tissue protective role via sympathetic and metabolic adaptation in the context of mitochondrial damage, although the exact mechanisms involved remain uncertain. In this review, we discuss the emergence of GDF-15 as a distinctive marker of viral infection severity, especially in the context of COVID-19. We will critically review the role of GDF-15 as an inflammation-induced mediator of disease tolerance, through metabolic and immune reprogramming. Finally, we discuss potential mechanisms of GDF-15 elevation during COVID-19 cytokine storm and its limitations. Altogether, this cytokine seems to be involved in disease tolerance to viral infections including SARS-CoV-2, paving the way for novel therapeutic interventions.

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Growth differentiation factor‐15 and the effect of empagliflozin in heart failure: Findings from the EMPEROR program

Ferreira,

Packer,

Butler

et al. 2023

European J of Heart Fail

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BackgroundGrowth differentiation factor 15 (GDF‐15) is upregulated in part in response to cardiomyocyte stretch and stress, and it exerts a protective role that is mediated by its action to suppress signaling through insulin‐like growth factor (IGF) and enhance signaling through adenosine monophosphate‐activated protein kinase (AMPK). Sodium glucose co‐transporter 2 (SGLT2) inhibitors improve outcomes in heart failure, which has been experimentally linked to AMPK.AimsTo study the associations of GDF‐15 with baseline characteristics, the prognostic significance of GDF‐15, and the effect of empagliflozin on GDF‐15 in patients with heart failure with a reduced and preserved ejection fraction.MethodsGDF‐15 was determined in serum samples from the EMPEROR‐Reduced and EMPEROR‐Preserved trials. Cox regression and mixed models for repeated measures were used to study the association with outcomes and the effect of empagliflozin on GDF‐15, respectively.ResultsWe studied 1124 patients (560 placebo and 564 empagliflozin) with median GDF‐15 levels at baseline of 2442 (IQR 1603‐3780) pg/mL. Patients with higher GDF‐15 levels were typically older men with more severe symptoms, higher NT‐proBNP levels, worse kidney function and who were prescribed metformin. Baseline levels of GDF‐15 were well correlated with levels of insulin‐like binding protein 7 (IGFBP‐7; rho=0.64). Higher levels of GDF‐15 were independently associated with an increased risk of cardiovascular death, heart failure hospitalizations, and worse kidney outcomes. When considered as a continuous variable, for each doubling in GDF‐15, the adjusted hazard ratio for cardiovascular death or HF hospitalization was 1.40 (95%CI 1.15,1.71; P<0.001). The relative effect of empagliflozin on cardiovascular death and hospitalization for heart failure was most pronounced in patients with higher baseline levels of GDF‐15 (interaction P‐trend=0.031). At week 52, when compared with placebo, empagliflozin increased GDF‐15 by an additional 8% (P=0.020), an effect that was primarily seen in patients not receiving metformin, a known AMPK activator.ConclusionsGDF‐15 is a marker of worse heart failure severity, is an independent predictor of major heart failure outcomes and may be associated with more pronounced benefits of empagliflozin. GDF‐15 is increased among metformin users, and empagliflozin was associated with an increase in GDF‐15 levels, primarily in patients not receiving metformin.This article is protected by copyright. All rights reserved.

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GDF15 mediates the metabolic effects of PPARβ/δ by activating AMPK

Cited by 60 publications

References 58 publications

Camptothecin effectively treats obesity in mice through GDF15 induction

Camptothecin effectively treats obesity in mice through GDF15 induction

Coping With Stress: The Mitokine GDF-15 as a Biomarker of COVID-19 Severity

Growth differentiation factor‐15 and the effect of empagliflozin in heart failure: Findings from the EMPEROR program

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