Related Experiment Video

Updated: Mar 28, 2026

Optimized Analysis of In Vivo and In Vitro Hepatic Steatosis
08:58

Optimized Analysis of In Vivo and In Vitro Hepatic Steatosis

Published on: March 11, 2017

17.2K

Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction

Changtao Jiang1,2, Cen Xie1, Ying Lv2

  • 1Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

Nature Communications
|December 17, 2015
PubMed

Insights

Glycine-β-muricholic acid (Gly-MCA) selectively inhibits the farnesoid X receptor (FXR) in the intestine, improving obesity and insulin resistance in mice. This FXR inhibition reduces ceramides, enhancing beige fat function and offering a potential treatment for metabolic disorders.

Area of Science:

  • Metabolic disease research
  • Endocrinology
  • Pharmacology

Background:

  • The farnesoid X receptor (FXR) plays a crucial role in regulating bile acid, lipid, and glucose metabolism.
  • Dysregulation of FXR signaling is implicated in metabolic disorders such as obesity and insulin resistance.

Purpose of the Study:

  • To investigate the effects of glycine-β-muricholic acid (Gly-MCA) as a selective intestinal FXR inhibitor.
  • To evaluate the therapeutic potential of Gly-MCA in preclinical models of metabolic disease.

Main Methods:

  • Administration of Gly-MCA to mouse models of diet-induced and genetic obesity.
  • Assessment of metabolic parameters including body weight, insulin sensitivity, and hepatic steatosis.
  • Investigation of the molecular mechanisms involving ceramide biosynthesis and beige fat thermogenic function.
  • Utilized intestine-specific Fxr-null mice and FXR agonist GW4064 to confirm specificity.

Main Results:

  • Oral administration of Gly-MCA selectively inhibited intestinal FXR signaling.
  • Gly-MCA treatment prevented and reversed obesity, insulin resistance, and hepatic steatosis in mice.
  • Metabolic improvements were linked to reduced intestinal ceramide biosynthesis, preserving beige fat thermogenesis.
  • FXR signaling in human ileum biopsies positively correlated with body mass index.

Conclusions:

  • Gly-MCA acts as a selective intestinal FXR inhibitor with significant therapeutic potential.
  • Targeting intestinal FXR with Gly-MCA offers a novel strategy for treating metabolic disorders.
  • Reduced ceramide levels are a key mechanism underlying Gly-MCA's beneficial metabolic effects.

More Related Videos

Measurement of Basal and Forskolin-stimulated Lipolysis in Inguinal Adipose Fat Pads07:59

Measurement of Basal and Forskolin-stimulated Lipolysis in Inguinal Adipose Fat Pads

Published on: July 21, 2017

10.2K
Author Spotlight: Establishing MASLD Cell Models for Investigating Disease Mechanisms and the Lipid-Lowering Effects of Koumiss07:03

Author Spotlight: Establishing MASLD Cell Models for Investigating Disease Mechanisms and the Lipid-Lowering Effects of Koumiss

Published on: July 19, 2024

2.0K

Related Concept Videos

Pharmacokinetics in Obese Patients: Drug Metabolism and Excretion01:20

Pharmacokinetics in Obese Patients: Drug Metabolism and Excretion

Drug metabolism, a critical process in the liver, involves two primary phases: Phase I reactions and Phase II conjugation. Obesity introduces significant alterations in this metabolic process, primarily due to fatty infiltration of the liver, leading to conditions such as nonalcoholic fatty liver disease (NAFLD). This condition can modify the activities of both Phase I and II enzymes, impacting how drugs are metabolized in obese patients.Phase I metabolism sees variable effects across...
281
Transducer Mechanism: Nuclear Receptors01:31

Transducer Mechanism: Nuclear Receptors

Nuclear receptors, or NRs, are unique transcription factors that regulate gene transcription and affect the cellular pathways involved in reproduction, development, or metabolism. Their ability to be stimulated by small lipophilic ligands and control vital cellular processes makes them ideal drug targets. Nearly 10-15% of currently prescribed drugs target these receptors.
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
5.5K
Regulation of Food Intake01:30

Regulation of Food Intake

Short-term regulation of food intake primarily involves neural signals from the gastrointestinal (GI) tract, blood nutrient levels, and GI tract hormones. Communication between the gut and brain via vagal nerve fibers plays a significant role in evaluating the contents of the gut. Clinical studies have shown that protein ingestion produces a more prolonged response in these nerve fibers compared to an equivalent amount of glucose. Additionally, the activation of stretch receptors caused by GI...
3.1K
Pharmacokinetics in Obese Patients: Drug Absorption and Distribution01:25

Pharmacokinetics in Obese Patients: Drug Absorption and Distribution

Obesity significantly alters the pharmacokinetic processes of drug absorption and distribution, presenting unique challenges in medical treatment. The increased fat tissue and decreased lean muscle in obese individuals can significantly affect how drugs are absorbed into the body and distributed across different tissues. This alteration can lead to variances in the effectiveness and safety of medications, necessitating adjustments in dosing or drug selection for obese patients.One notable...
379