Circulating total and intact GDF-15 levels are not altered in response to weight loss induced by liraglutide or lorcaserin treatment in humans with obesity

• Published in: Metabolism, clinical and experimental Vol. 133; p. 155237
• Main Authors: Valenzuela-Vallejo, Laura, Chrysafi, Pavlina, Bello-Ramos, Jenny, Bsata, Shahd, Mantzoros, Christos S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2022
• Subjects: Benzazepines - administration & dosage; Body Weight; Double-Blind Method; GDF15; GFRAL; GLP1; GLP1RA; Growth Differentiation Factor 15 - blood; Humans; lipidomics; Liraglutide; Liraglutide - administration & dosage; Lorcaserin; metabolism; metabolomics; obesity; Obesity - blood; Obesity - drug therapy; Receptor, Serotonin, 5-HT2C - metabolism; Serotonin 5-HT2 Receptor Agonists - administration & dosage; TGFB; Weight Loss; GLP-1; D; GDF15; GLP1; TGFB; H; GLP1RA; Lorcaserin; GDF-15; POMC; NMR; CV; metabolomics; CRC; GFRAL; metabolism; 5-HT; obesity; Liraglutide; lipidomics; ELISA
• ISSN: 0026-0495; 1532-8600; 1532-8600
• DOI: 10.1016/j.metabol.2022.155237

Growth differentiation factor 15 (GDF-15) is a stress-response cytokine proposed to be associated with body weight regulation. The primary aim was to investigate changes of circulating intact GDF-15 (wildtype, non-carrier of the rs1058587 polymorphism coding for the H2O2D mutation) and total GDF-15 (measured irrespective of the mutation) in response to liraglutide (GLP-1 receptor agonist) and lorcaserin (5-HT2C receptor agonist), two pharmacologic agents that induce food intake and weight reduction. In addition, we perform exploratory correlations of total and intact GDF-15 with clinical, hormonal and metabolo-lipidomic parameters in humans with obesity. We utilized two studies: 1) Study 1, a randomized, double-blinded, cross-over trial of liraglutide and placebo administration for 5 weeks in subjects with obesity (n = 20; BMI = 35.6 ± 5.9 kg/m2), in escalating doses starting at 0.6 mg/day on week 1 and increased every week, up to the highest dose of 3.0 mg/day during week 5. b) Study 2, a randomized, double-blinded trial of lorcaserin 10 mg twice daily, or placebo for 12-weeks in humans with obesity (n = 34 BMI = 37.4 ± 6.1 kg/m2). Total and intact GDF-15 levels were measured with novel enzyme-linked immunosorbent assays and the metabolomics and lipidomics analysis was performed with nuclear magnetic resonance spectroscopy. Total and intact GDF-15 were positively correlated with diabetes risk index and trimethylamine N-oxide and negatively with eGFR. Despite significant changes in body weight, total and intact GDF-15 were not altered in response to liraglutide or lorcaserin treatment in subjects with obesity. Total and intact GDF-15 levels are not altered in response to liraglutide or lorcaserin therapy and are thus not directly involved in the metabolic feedback loop pathways downstream of GLP1 or 5-HT2C receptor agonists. Since neither total nor intact GDF-15 levels were altered in response to weight loss, future studies are needed to elucidate the pathways activated by GDF-15 in humans and its role, if any, in body weight regulation and energy homeostasis. [Display omitted] •GDF-15 is a stress-response cytokine proposed to mediate food intake and weight regulation that has been gaining attention as a possible anti-obesity treatment.•Total and intact GDF-15 levels are not altered by weight loss or in response to liraglutide or lorcaserin treatment.•GDF-15 is not downstream of the GLP1 or 5-HT2C receptor pathways.