Growth differentiation factor 15 neutralization does not impact anorexia or survival in lipopolysaccharide-induced inflammation

Breen, Danna M.; Jagarlapudi, Srinath; Patel, Anita; Zou, Chang; Joaquim, Stephanie; Li, Xiangping; Kang, Liya; Pang, Jincheng; Hales, Katherine; Ziso-Qejvanaj, Enida; Vera, Nicholas B.; Bennett, Donald; He, Tao; Lambert, Matthew; Kelleher, Kerry; Wu, Zhidan; Zhang, Bei B.; Lin, Laura; Seeley, Randy J.; Bézy, Olivier

doi:10.1016/j.isci.2021.102554

Cited by 18 publications

(13 citation statements)

References 26 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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“…GDF15 mAb2 is a humanized monoclonal antibody that binds GDF15 and blocks its interaction with GFRAL. It was characterized previously [ 29 ]. MCT was purchased from Oakwood Chemical (Cat.no.…”

Section: Methodsmentioning

confidence: 99%

Neutralization of GDF15 Prevents Anorexia and Weight Loss in the Monocrotaline-Induced Cardiac Cachexia Rat Model

Albuquerque

Chen

Hirenallur-Shanthappa

et al. 2022

Cells

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Growth and differentiation factor 15 (GDF15) is a cytokine reported to cause anorexia and weight loss in animal models. Neutralization of GDF15 was efficacious in mitigating cachexia and improving survival in cachectic tumor models. Interestingly, elevated circulating GDF15 was reported in patients with pulmonary arterial hypertension and heart failure, but it is unclear whether GDF15 contributes to cachexia in these disease conditions. In this study, rats treated with monocrotaline (MCT) manifested a progressive decrease in body weight, food intake, and lean and fat mass concomitant with elevated circulating GDF15, as well as development of right-ventricular dysfunction. Cotreatment of GDF15 antibody mAb2 with MCT prevented MCT-induced anorexia and weight loss, as well as preserved lean and fat mass. These results indicate that elevated GDF15 by MCT is causal to anorexia and weight loss. GDF15 mAb2 is efficacious in mitigating MCT-induced cachexia in vivo. Furthermore, the results suggest GDF15 inhibition is a potential therapeutic approach to alleviate cardiac cachexia in patients.

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“…However, given the pleiotropic toxic nature of many potent GDF15 secretagogues, the direct contribution from elevated plasma GDF15 to the drug-induced anorectic response can be challenging to discern. For example, whereas weight loss following treatment with the chemotherapeutic drug, cisplatin, is ascribed to be partially driven by an increase in circulating GDF15 (Breen et al, 2020; Hsu et al, 2017), weight loss induced by endotoxin is not attenuated in GDF15-GFRAL loss-of-function mice, despite that endotoxin increases plasma GDF15 by a striking 20-50-fold in mice (Breen et al, 2021; Luan et al, 2019; Patel et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance

Klein

Nicolaisen

Johann

et al. 2022

Preprint

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Metformin is a blood glucose lowering medication with physiological effects that extend beyond its anti-diabetic indication. Recently, it was reported that metformin lowers body weight via induction of growth differentiation factor 15 (GDF15), which suppresses food intake by binding to the GDNF family receptor α-like (GFRAL) in the hindbrain. At the same time, we demonstrated that recombinant GDF15 suppresses voluntary exercise in a GFRAL-dependent fashion. Here, we corroborate that metformin increases circulating GDF15 in mice and humans, but that it does not reduce voluntary running activity in mice. Unexpectedly, we fail to confirm previous reports that the GDF15-GFRAL pathway is necessary for the weight-lowering effects of metformin. Instead, our studies in wild-type, GDF15 knockout and GFRAL knockout mice suggest that the GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance. The data presented here question whether metformin is a sufficiently strong stimulator of GDF15 to drive anorexia and weight loss and emphasize that additional work is needed to untangle the relationship among metformin, GDF15 and energy balance.

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Growth differentiation factor 15 neutralization does not impact anorexia or survival in lipopolysaccharide-induced inflammation

Cited by 18 publications

References 26 publications

Camptothecin effectively treats obesity in mice through GDF15 induction

Camptothecin effectively treats obesity in mice through GDF15 induction

Neutralization of GDF15 Prevents Anorexia and Weight Loss in the Monocrotaline-Induced Cardiac Cachexia Rat Model

The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance

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