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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., Competing Interests: R.J.S. is a member of the advisory boards of Novo Nordisk, Scohia, Kintai Therapeutics, and Ionis. D.M.B., S.J., C.Z., S.J., X.L., L.K., J.P., K.H., E.Z.Q., D.B., M.L., K.K., Z.W., B.B.Z., and L.L. are employees and shareholders of Pfizer. N.B.V., T.H., and O.B. were employees of Pfizer during the conduct of the study and are current employees of Dicerna Pharmaceuticals, Inc., JOINN Biologics, and Cellarity, respectively. A.P. declares no conflict of interest., (© 2021 Elsevier Inc.)

Platinum-based cancer therapy is restricted by dose-limiting side effects and is associated with elevation of growth differentiation factor 15 (GDF-15). But whether this elevation contributes to such side effects has been unclear. Here, we explored the effects of GDF-15 blockade on platinum-based chemotherapy-induced emesis, anorexia, and weight loss in mice and/or nonhuman primate models. We found that circulating GDF-15 is higher in subjects with cancer receiving platinum-based chemotherapy and is positively associated with weight loss in colorectal cancer (NCT00609622). Further, chemotherapy agents associated with high clinical emetic score induce circulating GDF-15 and weight loss in mice. Platinum-based treatment-induced anorexia and weight loss are attenuated in GDF-15 knockout mice, while GDF-15 neutralization with the monoclonal antibody mAB1 improves survival. In nonhuman primates, mAB1 treatment attenuates anorexia and emesis. These results suggest that GDF-15 neutralization is a potential therapeutic approach to alleviate chemotherapy-induced side effects and improve the quality of life., Competing Interests: Declaration of Interests All authors are full-time employees of Pfizer Inc. D.B., M.J.B., R.A.C., B.P., and B.B.Z. are shareholders of Pfizer. M.R. has an immediate family member with management interests in Pfizer Inc. M.J.B. is a member of the Board of Directors of Cerevel. This manuscript relates to International Patent Application Publication No. WO2020/039321, which published February 27, 2020. Patent publication numbers US2020055930 and TW202021619 are both patent family members of the International Patent Application Publication No. WO2020/039321., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The fat-derived hormone leptin binds to its hypothalamic receptors to regulate glucose homeostasis. Leptin is also synthesized in the stomach and subsequently binds to its receptors expressed in the intestine, although the functional relevance of such activation remains largely unknown. We report here that intrajejunal leptin administration activates jejunal leptin receptors and signals through a phosphatidylinositol 3-kinase (PI3K)-dependent and signal transducer and activator of transcription 3 (STAT3)-independent signaling pathway to lower glucose production in healthy rodents. Jejunal leptin action is sufficient to lower glucose production in uncontrolled diabetic and high-fat-fed rodents and contributes to the early antidiabetic effect of duodenal-jejunal bypass surgery. These data unveil a glucoregulatory site of leptin action and suggest that enhancing leptin-PI3K signaling in the jejunum lowers plasma glucose concentrations in diabetes., (Copyright © 2014 Elsevier Inc. All rights reserved.)