Research ArticleObesity

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

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Science Translational Medicine  18 Oct 2017:
Vol. 9, Issue 412, eaan8732
DOI: 10.1126/scitranslmed.aan8732

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A bigger molecule to help slim down

Obesity is becoming increasingly common worldwide, and the available interventions do not fully address this problem. Surgery is currently the most effective intervention, especially for severe obesity, but it carries more risks than noninvasive treatments and produces permanent side effects. Xiong et al. searched for metabolically regulated proteins and identified the growth differentiation factor 15 (GDF15) pathway as a potential target for intervention. The loss of this protein in mice is associated with weight gain and worsened metabolic parameters. Conversely, the authors showed that treating with GDF15 improved metabolic health in mice, rats, and monkeys. They also designed a modified version of GDF15 (GDF15-Fc fusion) that has a longer half-life and would thus be a better candidate for clinical testing.

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.

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