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

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

doi:10.1016/j.isci.2021.102554

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

iScience. 2021 May 19;24(6):102554. doi: 10.1016/j.isci.2021.102554. eCollection 2021 Jun 25.

Authors

Danna M Breen¹, Srinath Jagarlapudi¹, Anita Patel², Chang Zou¹, Stephanie Joaquim¹, Xiangping Li¹, Liya Kang¹, Jincheng Pang¹, Katherine Hales¹, Enida Ziso-Qejvanaj¹, Nicholas B Vera¹, Donald Bennett³, Tao He⁴, Matthew Lambert⁴, Kerry Kelleher⁴, Zhidan Wu¹, Bei B Zhang¹, Laura Lin⁴, Randy J Seeley², Olivier Bezy¹

Affiliations

¹ Internal Medicine Research Unit, Pfizer Inc, 1 Portland St, Cambridge, MA 02139, USA.
² Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
³ Biostatistics, Early Clinical Development, Pfizer Inc, 1 Portland St, Cambridge, MA, USA.
⁴ Biomedicine Design, Pfizer Inc, 1 Portland St, Cambridge, MA, USA.

Abstract

Growth differentiation factor 15 (GDF15) causes anorexia and weight loss in animal models, and higher circulating levels are associated with cachexia and reduced survival in cancer and other chronic diseases such as sepsis. To investigate the role of sepsis-induced GDF15, we examined whether GDF15 neutralization via a validated and highly potent monoclonal antibody, mAB2, modulates lipopolysaccharide (LPS)-induced anorexia, weight loss, and mortality in rodents. LPS injection transiently increased circulating GDF15 in wild-type mice, decreased food intake and body weight, and increased illness behavior and mortality at a high dose. GDF15 neutralization with mAB2 did not prevent or exacerbate any of the effects of LPS. Similarly, in GDF15 knockout mice, the LPS effect on appetite and survival was comparable with that observed in wild-type controls. Therefore, effective inhibition of circulating active GDF15 via an antibody or via gene knockout demonstrated that survival in the LPS acute inflammation model was independent of GDF15.

Keywords: Cell Biology; Physiology.

Abstract

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