Endogenous Gdf15 activation limits adiposity and increases fecal energy excretion in mice

Q: What is the clinical evidence from this study?

Population: Diet-induced obesity. Intervention: MyoAAV2a-delivered intein-split CRISPRa targeting endogenous Gdf15 (CRISPRa-Gdf15) vs. Vehicle (PBS), MyoAAV2a-GFP, or MyoAAV2a encoding CRISPRa without gRNAs / with scrambled gRNA (CRISPRa-Scr). Primary outcome: Body weight and fecal energy excretion.

Q: What does this research mean for the field?

Endogenous Gdf15 activation via muscle-targeted CRISPRa prevents diet-induced obesity and reduces adiposity in mice by increasing fecal energy excretion through GFRAL signaling. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Maximilian Kleinert; Sarah Engelbeen; Kornelia Johann; Casper M. Sigvardsen; Franziska Sörgel; Alina Blenninger; Christopher A. Bishop; Christian T. Voldstedlund; Soeren Ocvirk; Joan Pasano; Heike Vogel; Erik Arne Richter; Alberto Cebrian-Serrano

doi:10.21203/rs.3.rs-10982795/v1

October 15, 2026Open Access

Endogenous Gdf15 activation limits adiposity and increases fecal energy excretion in mice

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Key result

Muscle-targeted GDF15 CRISPRa cuts established obesity ~15% and increases fecal energy excretion.

Why the study?

Growth differentiation factor 15 is an emerging target for obesity, but the effects of sustained physiological increases in endogenous GDF15 remain unclear.

Does muscle-targeted CRISPRa-mediated elevation of endogenous Gdf15 prevent or reduce diet-induced obesity and increase fecal energy excretion in mice?

Key Points

To determine whether sustained physiological increases in endogenous Gdf15 expression limit adiposity and alter energy balance.
Engineered an intein-split CRISPR activation system delivered via muscle-tropic adeno-associated virus (MyoAAV2a) intravenously or intramuscularly to activate endogenous Gdf15 in mice.
Assessed body weight, fat and fat-free mass, food intake, energy expenditure, fecal energy excretion, and voluntary running in mice fed high-fat, high-sucrose diet across wild-type, Gfral-knockout, and Gdf15-knockout models.
MyoAAV2a delivery achieved a stable five- to eightfold increase in circulating GDF15, which prevented diet-induced weight gain (~10 g gain in controls vs. weight stability in treated mice) by restricting fat mass while preserving lean mass.
Gdf15 activation elevated fecal mass and fecal energy density alongside gut microbiota remodeling, reducing adiposity in established obesity even in the absence of reduced food intake.

Structured PICO

Does muscle-targeted CRISPRa-mediated elevation of endogenous Gdf15 prevent or reduce diet-induced obesity and increase fecal energy excretion in mice?

P

Population

Preclinical mouse models (C57BL/6J, Gfral KO, and Gdf15 KO mice aged 7-12 weeks) fed a high-fat, high-sucrose diet and followed for up to 14 weeks.

I

Intervention

Muscle-targeted intein-split CRISPR activation system targeting the short Gdf15 isoform promoter (CRISPRa-Gdf15 using gRNA pair 5+7) delivered via muscle-tropic AAV vector (MyoAAV2a) intravenously or intramuscularly into multiple muscles (bilateral gastrocnemius, tibialis anterior, quadriceps, and triceps)

C

Comparator

Control groups receiving vehicle, MyoAAV2a encoding GFP, MyoAAV2a encoding CRISPRa components lacking gRNAs, or CRISPRa-Scr (scrambled control)

O

Outcome

Body weight, fat mass, fat-free mass, and fecal energy excretionsurrogate

Sustained high-physiological elevation of endogenous GDF15 prevents and reduces diet-induced obesity in mice while preserving lean mass, identifying increased fecal energy excretion and gut microbiome remodeling as a novel GDF15-GFRAL-regulated component of energy balance beyond appetite suppression.

Limitations

Preclinical study performed in mice; unknown if sustained physiological elevation of endogenous GDF15 similarly alters intestinal energy handling in humans.
Measurements do not resolve the underlying mechanism of additional fecal energy loss (e.g., reduced nutrient absorption, altered gastrointestinal transit or secretion, or microbial metabolism).
Observed changes in the gut microbiome and ileal transcriptional programs are associative, and their causal contribution to increased fecal energy excretion remains unresolved.
Sex-specific effects were not systematically examined across experiments, limiting conclusions regarding potential differences between male and female mice.

Ask about this paper

Answers are grounded in this paper and cite their sources.

Implication

Muscle-targeted endogenous GDF15 elevation reduces adiposity in obese mice; extends GDF15 as therapeutic target but leaves human translation open.

Abstract

Growth differentiation factor 15 (GDF15) is an emerging target for obesity, but the effects of sustained physiological increases in endogenous GDF15 remain unclear. Here we use muscle-targeted CRISPR activation to elevate endogenous Gdf15 expression in mice. High-physiological circulating GDF15 prevents diet-induced obesity by limiting fat accumulation while preserving lean mass. This protection requires the endogenous Gdf15 locus and GFRAL signaling, without a detectable increase in energy expenditure. Alongside modest, inconsistent reductions in food intake, Gdf15 activation increases fecal energy excretion, accompanied by gut microbiota remodeling and altered ileal transcriptional programs. In mice with established obesity, Gdf15 activation reduces adiposity and increases fecal energy excretion without a detectable reduction in food intake. These findings identify fecal energy excretion as a GDF15-regulated component of energy balance and support a role for endogenous GDF15 beyond appetite regulation.

Discussion

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Cite This Study

Kleinert et al. (2026) studied Diet-induced obesity. MyoAAV2a-delivered intein-split CRISPRa targeting endogenous Gdf15 (CRISPRa-Gdf15) vs. Vehicle (PBS), MyoAAV2a-GFP, or MyoAAV2a encoding CRISPRa without gRNAs / with scrambled gRNA (CRISPRa-Scr) was evaluated on Body weight and fecal energy excretion. Muscle-targeted CRISPRa of endogenous Gdf15 elevated circulating GDF15 5- to 8-fold, preventing diet-induced obesity, increasing fecal energy excretion by ~50%, and reducing established obesity by ~15%.

synapsesocial.com/papers/6aee6b8671a7594806220972 https://doi.org/10.21203/rs.3.rs-10982795/v1

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Endogenous Gdf15 activation limits adiposity and increases fecal energy excretion in mice

Key Points

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Endogenous Gdf15 activation limits adiposity and increases fecal energy excretion in mice

Key Points

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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