Antibody-mediated inhibition of GDF15–GFRAL activity reverses cancer cachexia in mice

Suriben, Rowena; Chen, Michael; Higbee, Jared; Oeffinger, Julie; Ventura, Richard; Li, Betty; Mondal, Kalyani; Gao, Zhengyu; Ayupova, Dina A.; Taskar, Pranali; Li, Diana; Starck, Shelley R.; Chen, Hung-I Harry; McEntee, Michele; Katewa, Subhash D.; Trung, Phùng Văn; Wang, Marilyn; Kekatpure, Avantika; Lakshminarasimhan, Damodharan; White, André; Olland, Andrea; Haldankar, Raj; Solloway, Mark J.; Hsu, Jer-Yuan; Wang, Yan; Tang, Jie; Lindhout, Darrin A.; Allan, Bernard B.

doi:10.1038/s41591-020-0945-x

Cited by 193 publications

(196 citation statements)

References 30 publications

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“…In some cases, this presents as frank anorexia, whereas in other cases, a more subtle failure to appropriately increase feeding is observed. [101][102][103][104] The resistance to the effects of energy debt are most notable after substantial weight is lost, when the hypothalamic feeding rheostat would be under increased pressure to reestablish homeostasis. The disinterest in feeding during cachexia is in direct opposition to what is observed in simple starvation or protein malnutrition, each of which results in behaviours that attempt to restore macronutrient homeostasis.…”

Section: Ingestive Behavioursmentioning

confidence: 99%

“…99,120 Treatment of mice with GDF-15 or implantation with a GDF-15 overexpressing tumour is sufficient to induce cachexia, whereas treatment with a neutralizing antibody reversed cachexia in multiple murine cancer models. 104,121,122 Although there is some integration of these anorectic pathways, the existence of multiple disparate mediators represents a level of redundancy found in few biological systems, suggesting that suppression of food intake during illness is an essential response. Indeed, a provocative study by Wang and colleagues demonstrated that improvement in survival in mice with a Salmonella infection required fasting-induced ketogenesis.…”

Section: Ingestive Behavioursmentioning

confidence: 99%

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Diverging metabolic programmes and behaviours during states of starvation, protein malnutrition, and cachexia

Olson

Marks

Grossberg

2020

J cachexia sarcopenia muscle

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Background Our evolutionary history is defined, in part, by our ability to survive times of nutrient scarcity. The outcomes of the metabolic and behavioural adaptations during starvation are highly efficient macronutrient allocation, minimization of energy expenditure, and maximized odds of finding food. However, in different contexts, caloric deprivation is met with vastly different physiologic and behavioural responses, which challenge the primacy of energy homeostasis. Methods We conducted a literature review of scientific studies in humans, laboratory animals, and non-laboratory animals that evaluated the physiologic, metabolic, and behavioural responses to fasting, starvation, protein-deficient or essential amino acid-deficient diets, and cachexia. Studies that investigated the changes in ingestive behaviour, locomotor activity, resting metabolic rate, and tissue catabolism were selected as the focus of discussion. Results Whereas starvation responses prioritize energy balance, both protein malnutrition and cachexia present existential threats that induce unique adaptive programmes, which can exacerbate the caloric insufficiency of undernutrition. We compare and contrast the behavioural and metabolic responses and elucidate the mechanistic pathways that drive state-dependent alterations in energy seeking and partitioning. Conclusions The evolution of energetically inefficient metabolic and behavioural responses to protein malnutrition and cachexia reveal a hierarchy of metabolic priorities governed by discrete regulatory networks.

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Section: Ingestive Behavioursmentioning

confidence: 99%

Section: Ingestive Behavioursmentioning

confidence: 99%

Diverging metabolic programmes and behaviours during states of starvation, protein malnutrition, and cachexia

Olson

Marks

Grossberg

2020

J cachexia sarcopenia muscle

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“…[30,73] In August 2020, Suriben et al were the first to link the GDF15/GRFAL sympathetic pathway with the hepatic lipid oxidation in a cancer cachexia mouse model. [65] The injection of a monoclonal antibody antagonist that targets GFRAL and inhibit Ret proto-oncogene (RET) signaling complex in brainstem neurons (area postrema: AP; and nucleus of solitary tract: NTS) reversed excessive lipid oxidation in tumor-bearing mice and prevents cancer cachexia. [65] Furthermore, to unveil the mechanism of action of GDF15, the same group showed that activation of the GFRAL-RET pathway induces the expression of genes involved in lipid metabolism in adipose tissues.…”

Section: Gdf15 Induces Anorexia Lipid Oxidation and Muscle Atrophy mentioning

confidence: 99%

GDF15/GFRAL Pathway as a Metabolic Signature for Cachexia in Patients with Cancer

Ahmed¹,

Isnard²,

Lin³

et al. 2021

J. Cancer

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“…GDF15 may mediate its anorexia effects by acting on these receptors. However, the recent use of monoclonal antibodies inhibiting GFRAL signaling reversed the GDF15-induced cachexia even under calorie-restricted conditions, revealing that GDF15 may lead to decreased adipose and muscle mass and function independently of anorexia (31). This was mediated through its lipolytic effect in the adipose tissue via the sympathetic axis.…”

Section: Regulation Of Expression and Signalingmentioning

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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Antibody-mediated inhibition of GDF15–GFRAL activity reverses cancer cachexia in mice

Cited by 193 publications

References 30 publications

Diverging metabolic programmes and behaviours during states of starvation, protein malnutrition, and cachexia

Diverging metabolic programmes and behaviours during states of starvation, protein malnutrition, and cachexia

GDF15/GFRAL Pathway as a Metabolic Signature for Cachexia in Patients with Cancer

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

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