INT-767 prevents NASH and promotes visceral fat brown adipogenesis and mitochondrial function

Area of Science:

• Metabolic Syndrome Research
• Pharmacology
• Cell Biology

Background:

• Bile acid receptors, farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5), are key regulators of glucose and lipid metabolism.
• Metabolic syndrome, often induced by high-fat diets (HFD), is characterized by visceral adipose tissue accumulation, hypercholesterolemia, and nonalcoholic steatohepatitis.
• Insulin resistance is a central feature of metabolic syndrome, impacting various tissues including visceral adipose tissue (VAT).

Purpose of the Study:

• To investigate the therapeutic effects of the dual FXR/TGR5 agonist INT-767 on HFD-induced metabolic syndrome in a rabbit model.
• To elucidate the mechanisms by which INT-767 improves metabolic parameters and insulin sensitivity at the cellular and tissue levels.
• To assess the impact of INT-767 on preadipocyte differentiation and mitochondrial function.

Main Methods:

• A rabbit model of HFD-induced metabolic syndrome was established and treated long-term with INT-767.
• Visceral adipose tissue (VAT) and liver tissues were analyzed for metabolic markers, histological changes, and gene expression.
• VAT preadipocytes were isolated and treated with INT-767 *in vitro* to study cellular mechanisms, including mitochondrial function and insulin signaling.

Main Results:

• INT-767 treatment significantly reduced visceral adipose tissue, hypercholesterolemia, and nonalcoholic steatohepatitis in rabbits.
• The drug markedly improved insulin resistance hallmarks in VAT and induced mitochondrial and brown fat-specific markers.
• INT-767 treatment upregulated brown adipogenesis markers, improved mitochondrial ultrastructure and dynamics, reduced superoxide production, and enhanced insulin signaling and lipid handling in preadipocytes.
• INT-767 counteracted HFD-induced liver alterations, normalized pro-inflammatory genes, reduced fatty acid synthesis and fibrosis markers, and improved lipid handling and mitochondrial function.

Conclusions:

• INT-767 effectively counteracts HFD-induced liver and fat alterations, restoring insulin sensitivity.
• The compound promotes preadipocyte differentiation towards a metabolically healthy phenotype, partly via TGR5 activation and potentially FXR activation.
• INT-767 demonstrates significant therapeutic potential for managing metabolic syndrome and its associated complications.