Command Palette

Search for a command to run...

Preprint WatchModerateSeptember 29th, 2026

Hypothalamic Farnesoid X Receptor deficiency alters energy balance by modulating hepatic glucose production and adipose tissue metabolism through central insulin signaling.

Blondel, C.; Bourouh, C.; Nicolas, E.; Vadel, A.; Dorchies, E.; Vallez, E.; Tailleux, A.; Lestavel, S.; Staels, B.; Bantubungi, K.

Deletion of the bile acid nuclear receptor FXR (NR1H4) in the mediobasal hypothalamus produces a positive energy balance, reduced energy expenditure and altered glucose metabolism through central insulin signalling.

Moderate contradiction

2 prior failures

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

This preprint assigns FXR (NR1H4) a central role in energy homeostasis, showing that hypothalamic FXR deletion in mice shifts energy balance and hepatic glucose production through central insulin signalling. Claidex holds two NR1H4 failures, both safety signals on the same agonist: obeticholic-acid-nr1h4-fxr-biliary-atresia-phase2-3-safety-hold and obeticholic-acid-bezafibrate-nr1h4-pbc-phase3-safety-withdrawal. Severity is MODERATE on count. The relevance is that this work locates functionally consequential FXR signalling in the brain, outside the liver and gut compartments that systemic FXR agonists are dosed to reach. If central FXR engagement contributes to the metabolic profile of systemic agonists, then tissue-restricted or non-brain-penetrant designs deserve evaluation before another systemic FXR agonist enters late-phase hepatology trials. The preprint is a mouse genetics study and makes no claim about human drug safety.

Abstract excerpt

Objectives: The bile acid nuclear receptor Farnesoid X Receptor (FXR, NR1H4) is a major regulator of metabolism and energy homeostasis in peripheral organs. It modulates bile acid, glucose, and lipid metabolism, as well as fat mass and body weight. However, FXR is also expressed in the brain, particularly in the hypothalamus, a key center for the regulation of energy homeostasis. Although one study has demonstrated a role for brain FXR activation in energy balance, its specific hypothalamic role is still unknown. Here, we examined the role of FXR in the mediobasal hypothalamus in the regulation of energy balance. Methods: We used a genetic approach combined with metabolic phenotyping to determine the effect of FXR invalidation in the mediobasal hypothalamus on metabolic parameters involved in the central regulation of energy homeostasis. Results: Our results demonstrate that hypothalamic FXR deficiency induces a positive energy balance, resulting in a reduction in energy expenditure due to alterations in glucose metabolism accompanied by structural changes in white adipose tissues. Conclusion: This study uncovers a previously unrecognized role for hypothalamic FXR in the central homeostatic control of energy balance, providing new insights into its contribution to peripheral glucose metabolism and adipose tissue structural remodeling.

Matching Claidex post-mortems

2 of 2 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.