GDF15 Induces an Aversive Visceral Malaise State that Drives Anorexia and Weight Loss

Borner, Tito; Wald, Hallie S.; Ghidewon, Misgana Y.; Zhang, Bei; Wu, Zhidan; Jonghe, Bart C. De; Breen, Danna M.; Grill, Harvey J.

doi:10.1016/j.celrep.2020.107543

Cited by 69 publications

(59 citation statements)

References 56 publications

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“…Together, these and recently published data ( Borner et al, 2020a ; Borner et al, 2020b ) suggest that GDF15 is probably not a natural satiety factor, but exerts a pathophysiological action to cause anorexia. This conclusion is supported by the findings that circulating GDF15 levels do not correlate with meal times in humans, ( Patel et al, 2019 ; Tsai et al, 2015 ) and that GDF15 knock out in mice does not result in significant changes in normal chow intake ( Tsai et al, 2013 ; Tran et al, 2018 ).…”

Section: Resultssupporting

confidence: 59%

The cytokine GDF15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signalling

Worth

Shoop

Tye

et al. 2020

eLife

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The cytokine, GDF15, is produced in pathological states which cause cellular stress, including cancer. When over expressed, it causes dramatic weight reduction, suggesting a role in disease-related anorexia. Here we demonstrate that the GDF15 receptor, GFRAL, is located in a subset of cholecystokinin neurons which span the area postrema and the nucleus of the tractus solitarius of the mouse. GDF15 activates GFRALAP/NTS neurons and supports conditioned taste and place aversions, while the anorexia it causes can be blocked by a monoclonal antibody directed at GFRAL or by disrupting CCK neuronal signalling. The cancer-therapeutic drug, cisplatin, induces the release of GDF15 and activates GFRALAP/NTS neurons, as well as causing significant reductions in food intake and body weight in mice. These metabolic effects of cisplatin are abolished by pre-treatment with the GFRAL monoclonal antibody. Our results suggest that GFRAL neutralising antibodies or antagonists may provide a co-treatment opportunity for patients undergoing chemotherapy.

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Section: Resultssupporting

confidence: 59%

The cytokine GDF15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signalling

Worth

Shoop

Tye

et al. 2020

eLife

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“…In fact, GDF-15 was previously observed to be related with inflammatory markers in gastrointestinal cancer patients but not with nutritional parameters, such as body weight loss, anthropometry, and only weakly with low dietary food intake [ 20 ]. On the other hand, the GDF-15 circulating levels were found higher in cancer patients with body weight loss with respect to those with a stable weight [ 10 ], observations that were also recently confirmed in experimental models [ 21 ]. These different results obtained by others, including patients suffering by a miscellaneous of cancer diseases (only male) [ 10 ], or by esophago-gastric cancer [ 20 ] and by our study—focused on lung and gastrointestinal cancer patients—may be in part related to the different populations enrolled and likely to a different stage of cancer disease.…”

Section: Discussionmentioning

confidence: 87%

Association between Growth Differentiation Factor-15 (GDF-15) Serum Levels, Anorexia and Low Muscle Mass among Cancer Patients

Molfino

Amabile

Imbimbo

et al. 2020

Cancers

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The pathophysiology of cancer anorexia is complex and serum biomarkers, including growth and differentiation factor(s) (GDF), may be modulated. We explored the association(s) between GDF-15 serum levels and anorexia and, secondarily, with low muscle mass and body weight loss in cancer patients. We considered gastrointestinal and lung cancer patients (CP) and healthy BMI-matched controls. The FAACT-questionnaire was administered to diagnose anorexia and we calculated the L3-SMI by CT scan to assess low muscularity, setting their cutoff values at the lowest tertile. GDF-15 serum levels were assessed by ELISA. We enrolled 59 CP and 30 controls; among CP, 25 were affected by gastrointestinal and 34 by lung cancer. Anorexia was present in 36% of CP. Gastrointestinal CP resulted more anorexic compared to lung CP (p = 0.0067). Low muscle mass was present in 33.9% of CP and L3-SMI was lower in gastrointestinal compared to lung CP (p = 0.049). The GDF-15 levels were higher in CP vs. controls (p = 0.00016), as well as in anorexic vs. non-anorexic CP (p = 0.005) and vs. controls (p < 0.0001). Gastrointestinal CP showed higher GDF-15 levels vs. lung CP (p = 0.0004). No difference was found in GDF-15 between CP with low muscle mass and those with moderate/high muscularity and between patients with body weight loss and those with stable weight. Our data support the involvement of GDF-15 in the pathogenesis of cancer anorexia. The mechanisms of action of GDF-15 in cancer should be further clarified also regarding the changes in muscularity.

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“…demonstrated that GDF15 showed short-term effects on reducing food intake and longer-term effects on conditioned food aversion [ 83 ]. When rats were administered GDF15 and then exposed to a food substance, they displayed avoidance and disgust toward the food, which lasted well after the anorectic effect of GDF15 had waned; the food aversion remained in the absence of effects on gastric emptying [ 83 ]. These findings suggest that a long-term taste aversion has been established, presumably through involvement of the CTZ as previously discussed.…”

Section: Recent Developments Of Gdf15mentioning

confidence: 99%

Growth differentiation factor 15 as a potential therapeutic for treating obesity

Hale

Véniant

2021

Molecular Metabolism

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Background Obesity is rapidly becoming one of the world's most critical health care concerns. Comorbidities accompanying excess weight include cardiovascular disease, diabetes, and certain cancers. These comorbidities result in greater hospitalization and other health care-related costs. Economic impacts are likely to be felt more acutely in developing countries, where obesity rates continue to rise and health care resources are already insufficient. Some of the more effective treatments are invasive and expensive surgeries, which some economies in the world cannot afford to offer to a broad population. Pharmacological therapies are needed to supplement treatment options for patients who cannot, or will not, undergo surgical treatment. However, the few drug therapies currently available have either limited efficacy or safety concerns. A possible exception has been glucagon-like peptide-1 analogs, although these have shown a number of adverse events. New drug therapies that are safe and produce robust weight loss are needed. Scope of review Herein, we review the role of growth differentiation factor 15 (GDF15) in feeding behavior and obesity, summarize some of the new and exciting biological discoveries around signaling pathways and tissue sites of action, and highlight initial efforts to develop GDF15-based therapies suitable for inducing weight loss in humans. Major conclusions Within the last several years, great strides have been made in understanding the biology of GDF15. Recent developments include identification of an endogenous receptor, biological localization of the receptor system, impact on energy homeostasis, and identification of molecules suitable for administration to humans as anti-obesity treatments. New and exciting research on GDF15 suggests that it holds promise as a novel obesity treatment as new molecules progress toward clinical development.

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GDF15 Induces an Aversive Visceral Malaise State that Drives Anorexia and Weight Loss

Cited by 69 publications

References 56 publications

The cytokine GDF15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signalling

The cytokine GDF15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signalling

Association between Growth Differentiation Factor-15 (GDF-15) Serum Levels, Anorexia and Low Muscle Mass among Cancer Patients

Growth differentiation factor 15 as a potential therapeutic for treating obesity

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