Long-acting MIC-1/GDF15 molecules to treat obesity: Evidence from mice to monkeys

Abstract

In search of metabolically regulated secreted proteins, we conducted a microarray study comparing gene expression in major metabolic tissues of fed and fasted ob/ob mice and C57BL/6 mice. The array used in this study included probes for ~4000 genes annotated as potential secreted proteins. Circulating macrophage inhibitory cytokine 1 (MIC-1)/growth differentiation factor 15 (GDF15) concentrations were increased in obese mice, rats, and humans in comparison to age-matched lean controls. Adeno-associated virus-mediated overexpression of GDF15 and recombinant GDF15 treatments reduced food intake and body weight and improved metabolic profiles in various metabolic disease models in mice, rats, and obese cynomolgus monkeys. Analysis of the GDF15 crystal structure suggested that the protein is not suitable for conventional Fc fusion at the carboxyl terminus of the protein. Thus, we used a structure-guided approach to design and successfully generate several Fc fusion molecules with extended half-life and potent efficacy. Furthermore, we discovered that GDF15 delayed gastric emptying, changed food preference, and activated area postrema neurons, confirming a role for GDF15 in the gut-brain axis responsible for the regulation of body energy intake. Our work provides evidence that GDF15 Fc fusion proteins could be potential therapeutic agents for the treatment of obesity and related comorbidities.

The evolving systemic biomarker milieu in obese ZSF1 rat model of human cardiometabolic syndrome: Characterization of the model and cardioprotective effect of GDF15

“…We also used echocardiography, invasive hemodynamic assessment, exercise capacity assessment, and LV gene expression analysis to complete the characterization of this animal model. Additionally, we investigated whether 12 weeks of treatment with Fc-GDF15 in 22-week-old obese ZSF1 males would result in decreased body weight and food intake and improvement in metabolic profile, similar to prior non-clinical studies [15, 18], and also whether a cardioprotective effect could be demonstrated by improving exercise capacity and circulating levels of cardiovascular protein biomarkers. Overall, our study suggests that obese ZSF1 male rats represent a preclinical model for human cardiometabolic syndrome with established HFpEF.…”

“…Thus, daily injections of GDF15 to mice for 14 days to 21 weeks resulted in significantly reduced body weight and food intake, increased energy expenditure, improved glucose tolerance, and reduced inflammatory cytokines [14]. Administration of human GDF15 to rodents via an adenovirus system and to obese monkeys via protein injections led to body weight loss and an improved metabolic profile [15]. Treatment of obese mice with a human GDF15-Fc fusion protein (Fc-GDF15) led to reduced appetite and body weight and a shift of metabolic parameters toward lipid oxidation [15–18].…”

“…Administration of human GDF15 to rodents via an adenovirus system and to obese monkeys via protein injections led to body weight loss and an improved metabolic profile [15]. Treatment of obese mice with a human GDF15-Fc fusion protein (Fc-GDF15) led to reduced appetite and body weight and a shift of metabolic parameters toward lipid oxidation [15–18]. Weekly administration of Fc-GDF15 to obese cynomolgus monkeys for 28–42 days resulted in significantly reduced body weight and food consumption, lower serum triglyceride levels, and improved serum insulin [15, 19].…”

“…Treatment of obese mice with a human GDF15-Fc fusion protein (Fc-GDF15) led to reduced appetite and body weight and a shift of metabolic parameters toward lipid oxidation [15–18]. Weekly administration of Fc-GDF15 to obese cynomolgus monkeys for 28–42 days resulted in significantly reduced body weight and food consumption, lower serum triglyceride levels, and improved serum insulin [15, 19]. To date, GDF15 is shown to have mediated aversive dietary response, influenced the governance of systemic energy balance, and prevented obesity through enhanced thermogenesis and oxidative metabolism [20, 21].…”

Prediction of Cardiovascular Clinical Outcomes with Novel Biomarker: the Focus on Growth Differentiation Factor 15

“…The HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) study was yielded that GDF-15 in plasma positively associated with severity of HF, peak concentration of NT-proBNP, all-cause death rate and inversely related to peak oxygen uptake on cardiopulmonary exercise testing [21]. Interestingly, the serum levels of GDF-15 in patients with HFpEF were similar to those in HFrEF, while it associated with the severity of HF symptoms, echocardiographic parameters of LV dysfunction, 6 minute walk test distance and SF-36 physical score [33,34].…”