Supraphysiologic Administration of GDF11 Induces Cachexia in Part by Upregulating GDF15

Jones, Juli E.; Cadena, Samuel M.; Gong, Chenguang; Wang, Xiaomei; Chen, Zhiping; Wang, Sharon X.; Vickers, Chad; Chen, Hong; Lach-Trifilieff, Estelle; Hadcock, John R.; Glass, David J.

doi:10.1016/j.celrep.2018.01.044

Cited by 70 publications

(53 citation statements)

References 33 publications

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“…A recent report suggested that very high levels or supraphysiological overexpression of GDF11 promotes activin A mediated cachexia and directly invokes an increase in circulating levels of the TGFβ ligand, GDF15 14 , also known macrophage inhibitory cytokine-1 (MIC1). This study further suggested that elevated GDF15 acts as an appetite suppressant, resulting in weight loss 14 . As it is known that a reduction in body weight can have n = 9 mice/treatment) and aged (E, n = 6-8 mice/treatment; G, 9-10 mice/treatment) mice.…”

Section: Resultsmentioning

confidence: 99%

“…These observations thus raise the possibility that GDF11 may participate in appetite regulation. (2020) 10:4561 | https://doi.org/10.1038/s41598-020-61443-y www.nature.com/scientificreports www.nature.com/scientificreports/ A recent report suggested that GDF11 can stimulate the production of GDF15, which then acts as an appetite suppressant 14 . We tested the plasma of young and aged mice following the conclusion of the daily 0.5 mg/kg ligand dosing regimen, and we did not find any differences in circulating levels of GDF15 among the groups.…”

Section: Discussionmentioning

confidence: 99%

“…5E,F). Based on the stability of activity patterns www.nature.com/scientificreports www.nature.com/scientificreports/ in rGDF11-injected mice, we believe it is unlikely that their transient behavioral change was due to illness, although we cannot rule out the possibility that administration of rGDF11 induced nausea leading to reduced food intake 14 . Taken together, the data presented here suggest that supplementation with rGDF11 is potentially protective from HFD-induced fat mass accumulation in part by transiently reducing food intake in aging mice leading to the mice utilizing their adipose stores as fuel.…”

Section: Exogenous Rgdf11 But Not Rgdf8 Protects Against Hfd-inducementioning

confidence: 99%

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Exogenous GDF11, but not GDF8, reduces body weight and improves glucose homeostasis in mice

Walker

Barrandon

Poggioli

et al. 2020

Sci Rep

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Insulin resistance is associated with aging in mice and humans. We have previously shown that administration of recombinant GDF11 (rGDF11) to aged mice alters aging phenotypes in the brain, skeletal muscle, and heart. While the closely related protein GDF8 has a role in metabolism, limited data are available on the potential metabolic effects of GDF11 or GDF8 in aging. To determine the metabolic effects of these two ligands, we administered rGDF11 or rGDF8 protein to young or aged mice fed a standard chow diet, short-term high-fat diet (HFD), or long-term HFD. Under nearly all of these diet conditions, administration of exogenous rGDF11 reduced body weight by 3-17% and significantly improved glucose tolerance in aged mice fed a chow (~30% vs. saline) or HF (~50% vs. saline) diet and young mice fed a HFD (~30%). On the other hand, exogenous rGDF8 showed signifcantly lesser effect or no effect at all on glucose tolerance compared to rGDF11, consistent with data demonstrating that GFD11 is a more potent signaling ligand than GDF8. Collectively, our results show that administration of exogenous rGDF11, but not rGDF8, can reduce diet-induced weight gain and improve metabolic homeostasis. Aging is typically associated with impaired glucose tolerance, insulin resistance, and hepatosteatosis in both mice and humans. These metabolic disorders correlate with increased adiposity 1 , as well as an age-related decline in functional pancreatic β-cell mass (reviewed in 2). Identifying signals that modulate adipose tissue mass, glucose tolerance, insulin sensitivity, and/or functional β-cell mass in aging mammals could provide new targets for treatment of metabolic syndrome and diabetes. We previously showed that rGDF11 administration to aging mice results in a broad range of beneficial effects on brain 3,4 , skeletal muscle 5 , and cardiac tissues 6,7. GDF11 is a circulating blood factor which belongs to the larger transforming growth factor β (TGFβ) superfamily of extracellular ligands. New data published from multiple labs indicate that exogenous delivery of rGDF11 to rodent models of hyperglycemia (e.g. fed a high-fat diet HFD) reduced fasting blood glucose levels and improved glucose tolerance. The mechanism(s) behind these metabolic improvements may be due to a significant, yet transient, reduction in body mass 8-10. In fact, recent data suggests that rGDF11 stimulates secretion of adiponectin and a caloric restriction-like phenotype 10. On the other hand, others have shown that higher dosages of exogenous rGDF11 or viral overexpression of GDF11 via plasmid or viral vector caused cachexia, premature death, and anorexia 11-15. It is possible that these conflicting reports are due to drastically different doses and/or methodology used to artifically raise circulating GDF11 levels. Similarly, opposing results have also been reported regarding how GDF8, also known as myostatin, effects energy balance and metabolism 16-21. GDF8 is classically described as a potent negative regulator of skeletal muscle mass in addition to playin...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Exogenous Rgdf11 But Not Rgdf8 Protects Against Hfd-inducementioning

confidence: 99%

See 1 more Smart Citation

Exogenous GDF11, but not GDF8, reduces body weight and improves glucose homeostasis in mice

Walker

Barrandon

Poggioli

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…MIC-1/GDF15 mRNA expression and/or serum levels are elevated by drug classes such as cyclooxygenase inhibitors (Baek et al, 2001), many organic compounds isolated from natural products (Bottone et al, 2002;Baek et al, 2004a), the anti-diabetic drug metformin (Gerstein et al, 2017), anticancer therapies including chemotherapy and ionizing irradiation (Kis et al, 2006;Okazaki et al, 2006;Moritake et al, 2012;Tucker et al, 2014), the cytokine GDF11 (Jones et al, 2018), and tissue injury (Schober et al, 2001;Hsiao et al, 2000;Koniaris, 2003), strenuous exercise (Tchou et al, 2009;Galliera et al, 2014;Kleinert et al, 2018), cardiac (Kempf et al, 2007b;Stiermaier et al, 2014), and renal failure (Johnen et al, 2007;Breit et al, 2012;Ho et al, 2013), chronic liver disease (Liu et al, 2015;Lee et al, 2017), chronic inflammatory diseases like rheumatoid arthritis (Brown et al, 2007;Tanrıkulu et al, 2017), scleroderma (Yanaba et al, 2012;Gamal et al, 2017), and Behcet's syndrome (Sarıyıldız et al, 2016). Because MIC-1/GDF15 serum levels were elevated in a wide range of malignancies, studies of disease-associated expression of MIC-1/ GDF15 initially focused on the cancer area.…”

Section: Mic-1/gdf15 Expressionmentioning

confidence: 99%

The MIC-1/GDF15-GFRAL Pathway in Energy Homeostasis: Implications for Obesity, Cachexia, and Other Associated Diseases

et al. 2018

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MIC-1/GDF15 is a stress response cytokine and a distant member of the transforming growth factor beta (TGFb) superfamily, with no close relatives. It acts via a recently identified receptor called glial-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL), which is a distant orphan member of the GDNF receptor family that signals through the tyrosine kinase receptor Ret. MIC-1/GDF15 expression and serum levels rise in response to many stimuli that initiate cell stress and as part of a wide variety of disease processes, most prominently cancer and cardiovascular disease. The best documented actions of MIC-1/GDF15 are on regulation of energy homeostasis. When MIC-1/GDF15 serum levels are substantially elevated in diseases like cancer, it subverts a physiological pathway of appetite regulation to induce an anorexia/cachexia syndrome initiated by its actions on hindbrain neurons. These effects make it a potential target for the treatment of both obesity and anorexia/cachexia syndromes, disorders lacking any highly effective, readily accessible therapies.

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“…Etiologically, CAC is driven by various metabolic abnormalities besides anorexia, including elevated energy expenditure, excess catabolism and inflammation . Multifactorial pathogeneses of CAC necessitate combination therapies and the development of novel therapeutics to improve the quality of life of patients and their tolerance to cancer therapy . Studying the potential mechanisms of CAC could provide clues on novel therapeutics for CAC patients.…”

Section: Introductionmentioning

confidence: 99%

Cachexia‐related long noncoding RNA, CAAlnc1, suppresses adipogenesis by blocking the binding of HuR to adipogenic transcription factor mRNAs

Shen

Han

et al. 2019

Intl Journal of Cancer

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Cancer‐associated cachexia (CAC) is a devastating syndrome characterized by progressive losses of adipose tissue and skeletal muscle. CAC‐related adipose tissue loss (CAL) occurs early and is associated with a shorter survival time. To explore potential regulatory long noncoding RNAs (lncRNAs) of CAL, RNA microarrays were used to analyze the transcriptomes of white adipose tissue from CAC mice vs. control mice. A set of differentially expressed lncRNAs was identified, and among them was CAAlnc1, which suppressed adipogenesis of C3H10 cells as demonstrated by gain‐of‐function and loss‐of‐function experiments. RNA immunoprecipitation and pull‐down assays revealed Hu antigen R (HuR) was an important binding partner of CAAlnc1. The interaction between CAAlnc1 and HuR blocked the binding of HuR to adipogenic transcription factor mRNAs and further downregulated the expression of these transcription factors. This study generated a list of CAL‐related lncRNAs and provided details of a functional lncRNA which may play an important role in CAL.

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Supraphysiologic Administration of GDF11 Induces Cachexia in Part by Upregulating GDF15

Cited by 70 publications

References 33 publications

Exogenous GDF11, but not GDF8, reduces body weight and improves glucose homeostasis in mice

Exogenous GDF11, but not GDF8, reduces body weight and improves glucose homeostasis in mice

The MIC-1/GDF15-GFRAL Pathway in Energy Homeostasis: Implications for Obesity, Cachexia, and Other Associated Diseases

Cachexia‐related long noncoding RNA, CAAlnc1, suppresses adipogenesis by blocking the binding of HuR to adipogenic transcription factor mRNAs

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