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.

INT-767 prevents NASH and promotes visceral fat brown adipogenesis and mitochondrial function / Comeglio, Paolo; Cellai, Ilaria; Mello, Tommaso; Filippi, Sandra; Maneschi, Elena; Corcetto, Francesca; Corno, Chiara; Sarchielli, Erica; Morelli, Annamaria; Rapizzi, Elena; Bani, Daniele; Guasti, Daniele; Vannelli, Gabriella Barbara; Galli, Andrea; Adorini, Luciano; Maggi, Mario; Vignozzi, Linda. - In: JOURNAL OF ENDOCRINOLOGY. - ISSN 0022-0795. - STAMPA. - 238:(2018), pp. 107-127-127. [10.1530/JOE-17-0557]

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

Comeglio, Paolo;Cellai, Ilaria;Mello, Tommaso;Filippi, Sandra;Maneschi, Elena;Corcetto, Francesca;Corno, Chiara;Sarchielli, Erica;Morelli, Annamaria;Rapizzi, Elena;Bani, Daniele;Guasti, Daniele;Vannelli, Gabriella Barbara;Galli, Andrea;Maggi, Mario;Vignozzi, Linda
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.
2018
238
107-127
127
Goal 3: Good health and well-being for people
Comeglio, Paolo; Cellai, Ilaria; Mello, Tommaso; Filippi, Sandra; Maneschi, Elena; Corcetto, Francesca; Corno, Chiara; Sarchielli, Erica; Morelli, Ann...espandi
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1130758
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