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INT-767 prevents NASH and promotes visceral fat brown adipogenesis and mitochondrial function.
- Source :
-
The Journal of endocrinology [J Endocrinol] 2018 Aug; Vol. 238 (2), pp. 107-127. - Publication Year :
- 2018
-
Abstract
- The bile acid receptors, farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5), regulate multiple pathways, including glucose and lipid metabolism. In a rabbit model of high-fat diet (HFD)-induced metabolic syndrome, long-term treatment with the dual FXR/TGR5 agonist INT-767 reduces visceral adipose tissue accumulation, hypercholesterolemia and nonalcoholic steatohepatitis. INT-767 significantly improves the hallmarks of insulin resistance in visceral adipose tissue (VAT) and induces mitochondrial and brown fat-specific markers. VAT preadipocytes isolated from INT-767-treated rabbits, compared to preadipocytes from HFD, show increased mRNA expression of brown adipogenesis markers. In addition, INT-767 induces improved mitochondrial ultrastructure and dynamic, reduced superoxide production and improved insulin signaling and lipid handling in preadipocytes. Both in vivo and in vitro treatments with INT-767 counteract, in preadipocytes, the HFD-induced alterations by upregulating genes related to mitochondrial biogenesis and function. In preadipocytes, INT-767 behaves mainly as a TGR5 agonist, directly activating dose dependently the cAMP/PKA pathway. However, in vitro experiments also suggest that FXR activation by INT-767 contributes to the insulin signaling improvement. INT-767 treatment counteracts HFD-induced liver histological alterations and normalizes the increased pro-inflammatory genes. INT-767 also induces a significant reduction of fatty acid synthesis and fibrosis markers, while increasing lipid handling, insulin signaling and mitochondrial markers. In conclusion, INT-767 significantly counteracts HFD-induced liver and fat alterations, restoring insulin sensitivity and prompting preadipocytes differentiation toward a metabolically healthy phenotype.<br /> (© 2018 Society for Endocrinology.)
- Subjects :
- Adipocytes drug effects
Adipocytes physiology
Adipogenesis genetics
Adipose Tissue, Brown physiology
Adult
Aged
Animals
Bile Acids and Salts therapeutic use
Cell Differentiation genetics
Cells, Cultured
Disease Models, Animal
Humans
Intra-Abdominal Fat physiology
Liver drug effects
Liver metabolism
Male
Metabolic Syndrome genetics
Metabolic Syndrome metabolism
Metabolic Syndrome pathology
Metabolic Syndrome physiopathology
Middle Aged
Mitochondria metabolism
Non-alcoholic Fatty Liver Disease metabolism
Non-alcoholic Fatty Liver Disease pathology
Obesity metabolism
Obesity pathology
Rabbits
Receptors, Cytoplasmic and Nuclear genetics
Receptors, Cytoplasmic and Nuclear metabolism
Adipogenesis drug effects
Adipose Tissue, Brown drug effects
Bile Acids and Salts pharmacology
Cell Differentiation drug effects
Intra-Abdominal Fat drug effects
Mitochondria drug effects
Non-alcoholic Fatty Liver Disease prevention & control
Subjects
Details
- Language :
- English
- ISSN :
- 1479-6805
- Volume :
- 238
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- The Journal of endocrinology
- Publication Type :
- Academic Journal
- Accession number :
- 29945982
- Full Text :
- https://doi.org/10.1530/JOE-17-0557