GDF-15 Neutralization Alleviates Platinum-Based Chemotherapy-Induced Emesis, Anorexia, and Weight Loss in Mice and Nonhuman Primates

Breen, Danna M.; Kim, Hanna; Bennett, Donald; Calle, Roberto A.; Collins, Susie; Esquejo, Ryan M.; He, Tao; Joaquim, Stephanie; Joyce, Alison; Lambert, Matthew; Lin, Laura; Pettersen, Betty; Qiao, Shuxi; Rossulek, Michelle; Weber, Gregory L.; Wu, Zhidan; Zhang, Bei B.; Birnbaum, Morris J.

doi:10.1016/j.cmet.2020.10.023

Cited by 98 publications

(100 citation statements)

References 91 publications

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“…Previous studies have reported that cisplatin significantly increases circulating GDF15 levels in humans and in preclinical models (17,21,22) We first studied the effects of cisplatin on the HPA axis in Gdf15 −/− mice and wild-type littermates. Independent studies were undertaken at standard and thermoneutral housing temperatures.…”

Section: Resultsmentioning

confidence: 99%

“…GDF15 signals via a heterodimeric receptor, GDNF-family receptor α-like (GFRAL)-RET, localized specifically in the brainstem (14)(15)(16)(17). To date, reports of the central actions of GDF15 in mammals have largely focused on regulation of food intake anorexia, weight loss (18)(19)(20), emesis (21), pica (22), delayed gastric emptying (23,24), and conditioned aversion (25). Recent data indicate that GDF15 administration also reduces physical activity in mice (26).…”

mentioning

confidence: 99%

“…We undertook a set of experiments to examine whether GDF15 might be involved in the HPA response to stress; possibly synergizing with cytokines in the case of infections and/or playing a more prominent role in the response to chemical stressors (27). As examples of the latter, we chose the genotoxin, cisplatin, known to elevate circulating levels of both corticosterone (9, 10) and GDF15 (21,22) and the well-established inducer of endoplas mic reticulum (ER) stress, tunicamycin. ER stress is mechanistically distinct from genotoxicity and its effects to increase GDF15 expression and secretion are well established (20,28).…”

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confidence: 99%

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Activation of the hypothalamic–pituitary–adrenal axis by exogenous and endogenous GDF15

Cimino

Kim

Tung

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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An acute increase in the circulating concentration of glucocorticoid hormones is essential for the survival of severe somatic stresses. Circulating concentrations of GDF15, a hormone that acts in the brain to reduce food intake, are frequently elevated in stressful states. We now report that GDF15 potently activates the hypothalamic–pituitary–adrenal (HPA) axis in mice and rats. A blocking antibody to the GDNF-family receptor α-like receptor completely prevented the corticosterone response to GDF15 administration. In wild-type mice exposed to a range of stressful stimuli, circulating levels of both corticosterone and GDF15 rose acutely. In the case of Escherichia coli or lipopolysaccharide injections, the vigorous proinflammatory cytokine response elicited was sufficient to produce a near-maximal HPA response, regardless of the presence or absence of GDF15. In contrast, the activation of the HPA axis seen in wild-type mice in response to the administration of genotoxic or endoplasmic reticulum toxins, which do not provoke a marked rise in cytokines, was absent in Gdf15−/− mice. In conclusion, consistent with its proposed role as a sentinel hormone, endogenous GDF15 is required for the activation of the protective HPA response to toxins that do not induce a substantial cytokine response. In the context of efforts to develop GDF15 as an antiobesity therapeutic, these findings identify a biomarker of target engagement and a previously unrecognized pharmacodynamic effect, which will require monitoring in human studies.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Activation of the hypothalamic–pituitary–adrenal axis by exogenous and endogenous GDF15

Cimino

Kim

Tung

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…In fact, cisplatin induces emesis via release of multiple classic emetic neurotransmitters such as 5-HT, substance P, and dopamine from the enterochromaffin cells and/or sensory neurons of the gastrointestinal tract, as well as the central nervous system during both acute and delayed phases of CINV [151]. The less well investigated emetic mediators in CINV are prostaglandins [130,131], leukotrienes [17,152], peptide YY [153], GDF15 [117], and oxidative stress [154].…”

Section: Physiological Mechanisms Of Emesis and Clinical Uses Of Antiemetics 41 Chemotherapy-induced Nausea And Vomiting (Cinv)mentioning

confidence: 99%

“…Accumulating evidence support a direct role for GDF15 in the mediation of nausea and vomiting. In fact, GDF15 neutralization with monoclonal antibody attenuates cisplatin-induced emesis in nonhuman primates [ 117 ]. Elevated endogenous GDF15 has become a well-known marker associated with nausea and vomiting during pregnancy [ 118 , 119 , 120 , 121 , 122 , 123 ].…”

Section: Diverse Stimuli Evoke Vomiting Via Distinct Receptorsmentioning

confidence: 99%

Mechanisms of Nausea and Vomiting: Current Knowledge and Recent Advances in Intracellular Emetic Signaling Systems

Zhong

Shahbaz

Teskey

et al. 2021

IJMS

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Nausea and vomiting are common gastrointestinal complaints that can be triggered by diverse emetic stimuli through central and/or peripheral nervous systems. Both nausea and vomiting are considered as defense mechanisms when threatening toxins/drugs/bacteria/viruses/fungi enter the body either via the enteral (e.g., the gastrointestinal tract) or parenteral routes, including the blood, skin, and respiratory systems. While vomiting is the act of forceful removal of gastrointestinal contents, nausea is believed to be a subjective sensation that is more difficult to study in nonhuman species. In this review, the authors discuss the anatomical structures, neurotransmitters/mediators, and corresponding receptors, as well as intracellular emetic signaling pathways involved in the processes of nausea and vomiting in diverse animal models as well as humans. While blockade of emetic receptors in the prevention of vomiting is fairly well understood, the potential of new classes of antiemetics altering postreceptor signal transduction mechanisms is currently evolving, which is also reviewed. Finally, future directions within the field will be discussed in terms of important questions that remain to be resolved and advances in technology that may help provide potential answers.

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Early‐life behavioral features are associated with chronic emesis in rhesus macaques (Macaca mulatta)

Nakatani

Pomerantz

Stockinger

et al. 2023

American J Primatol

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Chronic emesis (CE) is a poorly understood condition in human and nonhuman primates that negatively impacts the quality of life. Early identification of risk factors for the development of CE is likely to improve the ability to manage CE cases successfully and is, therefore, desirable. Using a case‐control study, we reviewed the necropsy records of the California National Primate Research Center and identified 24 animals with recorded CE, defined as five or more incidents of emesis in 1 month. A group of 89 healthy rhesus macaques (Macaca mulatta), comparable in age and percent time housed indoors, was similarly identified. Next, we investigated the association between the occurrence of CE during later stages of life after infancy and the behavioral temperament scores attained in infancy, age, sex, birth location, rearing condition, history of self‐injurious behavior (SIB), and the number of lifetime sedation events. Our analysis revealed that CE was associated with degrees of temperament constructs obtained in infancy (data was available for n = 113), such as Confidence (odds ratio (OR) = 0.45, 95% CI: 0.18, 1.08, p = 0.07), Gentleness (OR = 0.47, 95% CI: 0.23, 0.96, p = 0.03), Nervousness (OR = 2.04, 95% CI: 0.98, 4.23, p = 0.05), and Vigilance (OR = 0.36, 95% CI: 015, 0.87, p = 0.02), suggesting that CE is linked to behavioral phenomenon measured in early life, long before it becomes a medical concern. Our data suggest that CE was positively correlated with a history of SIB (OR 4.26, 95% CI: 0.98, 18.47, p = 0.04). Accurate prediction of CE can then assist behavioral and colony management professionals in making informed decisions regarding the care of animals at risk of developing CE. Moreover, the novel information we reported here could have valuable implications in human medicine, where gastrointestinal distress is a common complaint affecting a person's quality of life.

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GDF-15 Neutralization Alleviates Platinum-Based Chemotherapy-Induced Emesis, Anorexia, and Weight Loss in Mice and Nonhuman Primates

Cited by 98 publications

References 91 publications

Activation of the hypothalamic–pituitary–adrenal axis by exogenous and endogenous GDF15

Activation of the hypothalamic–pituitary–adrenal axis by exogenous and endogenous GDF15

Mechanisms of Nausea and Vomiting: Current Knowledge and Recent Advances in Intracellular Emetic Signaling Systems

Early‐life behavioral features are associated with chronic emesis in rhesus macaques (Macaca mulatta)

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