# Gut-restricted FXR agonists fexaramine and fexaramine-3 cut appetite and weight in obese mice via leptin and secretin

- Published: 2026-11-13 13:10 UTC
- Section: Life & Health › Medicine
- Tags: intestinal FXR agonists, fexaramine-3, obesity in mice, leptin and secretin, appetite suppression, db/db mice, ob/ob mice, H3K4 methylation, EMBO Reports
- URL: https://realtech.media/news/rt-3456c4ab25df283764b11715_gut_restricted_fxr/

**In diet-induced obese and db/db mice, fexaramine and fexaramine-3 reduced food intake and fat mass, but barely worked in leptin-deficient ob/ob mice. The effect required leptin and secretin.**

![Gut-restricted FXR agonists fexaramine and fexaramine-3 cut appetite and weight in obese mice via leptin and secretin](https://realtech.media/media/2026/11/906486e452e91291.jpg)
*Oak Ridge National Laboratory, Wikimedia Commons, CC BY 2.0*

A study in EMBO Reports shows that intestinal-restricted agonists of the farnesoid X receptor (FXR) reduce body weight and fat in mouse models of obesity by suppressing appetite. The effect appeared in diet-induced obesity (DIO) mice and leptin receptor-deficient db/db mice, but not in leptin-deficient ob/ob mice [1]. The compounds, fexaramine and fexaramine-3, were given intragastrically at 10 mg/kg to male mice [1].

Systemic FXR agonists cause side effects, including raised LDL cholesterol and severe pruritus. Gut-restricted agonists were developed to stay in the intestine and avoid systemic circulation. Their anti-obesity mechanism had remained unclear.

## Weight, fat and liver in mice

DIO was established with fourteen weeks of a high-fat diet. In DIO and db/db mice, both agonists lowered absolute and relative body weight, and magnetic resonance imaging showed a decrease in total fat [1]. Inguinal, subcutaneous and bone marrow white fat depots became lighter, mean adipocyte size fell, and transcription of the pro-inflammatory cytokines TNF-alpha and IL-1 beta decreased. Fexaramine-3 also reduced liver lipid accumulation, liver weight and circulating alanine aminotransferase in DIO and db/db mice. In ob/ob mice, changes in body weight, fat mass and adipocyte size were marginal.

## Leptin, secretin and appetite

Metabolic cage measurements of oxygen consumption and carbon dioxide release showed no significant change in energy expenditure. Weight loss came from lower daily food intake, which fell in DIO and db/db mice but not in ob/ob mice [1]. Because db/db mice lack leptin receptor signaling but keep circulating leptin, the authors conclude that leptin itself is required, not the classical receptor cascade.

Adding 5 mg/kg leptin to the agonists in DIO mice strengthened the reduction in food intake and body mass. In ob/ob mice, a 0.1 mg/kg leptin dose that had no effect alone restored appetite suppression and lowered body weight when combined with the agonists [1].

In the hypothalamus, the agonists raised expression of the anorexigenic neuropeptide CART in DIO and db/db mice and lowered agouti-related protein mRNA in db/db mice. Ob/ob mice showed no such changes with the agonists alone. Fibroblast growth factor 15 mRNA rose in all groups, including ob/ob.

The authors report that intestinal FXR agonism raises secretin (SCT) expression in the presence of leptin. FXR agonism enhances histone H3K4 methylation at the Sct locus, while leptin suppresses DNA methylation at the same locus independently of the leptin receptor [1]. All data come from mice.

## Sources

1. [EMBO Reports](https://doi.org/10.1038/s44319-026-00938-7)
2. [bioengineer.org](https://bioengineer.org/intestinal-fxr-activation-teams-with-leptin-to-curb-appetite-via-secretin)

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Source: RealTech, realtech.media — https://realtech.media/news/rt-3456c4ab25df283764b11715_gut_restricted_fxr/