Endogenous Gdf15 induction promotes obesity resistance by augmenting energy excretion

Growth differentiation factor 15 (GDF15) is a hormone-like factor that has emerged as a potential therapeutic treatment of obesity. Pharmacological studies have shown that high, supraphysiological doses of recombinant, mature human GDF15 decrease food intake in obese mice; yet, the metabolic impact of physiological elevations in endogenous GDF15 are unknown. Here, we delivered CRISPR activation (CRISPRa) via muscle-targeting viral vectors in mice to upregulate endogenous Gdf15 expression, resulting in a five- to eight-fold increase in circulating GDF15 levels, comparable to that seen after prolonged exercise or with aging. This physiological elevation in circulating GDF15 conferred resistance to diet-induced obesity by selectively preventing fat mass accumulation without detrimental impact on lean mass and in the absence of aversion-like behavior typically observed with high GDF15 levels. The anti-obesity effect was Gdf15 locus-specific, dependent on the GDF15-receptor, GFRAL, and occurred without changes in energy expenditure of mice. Instead, elevated circulating GDF15 was linked to a reduction in food intake coupled with increased fecal energy loss, a distinct clustering of gut microbiota composition associated with higher microbial diversity, and transcriptional reprogramming of the ileal epithelium towards higher barrier function and antimicrobial defense. In conclusion, we show that in an obesogenic environment, endogenous GDF15 selectively prevents fat accumulation, spares lean mass and regulates energy assimilation with clear consequences for the gut microbial milieu and whole-body energy balance.