Gpbar1 agonism promotes a Pgc-1α-dependent browning of white adipose tissue and energy expenditure and reverses diet-induced steatohepatitis in mice

Adriana Carino; Sabrina Cipriani; Silvia Marchianò; Michele Biagioli; Paolo Scarpelli; Angela Zampella; Maria Chiara Monti; Stefano Fiorucci

doi:10.1038/s41598-017-13102-y

Gpbar1 agonism promotes a Pgc-1α-dependent browning of white adipose tissue and energy expenditure and reverses diet-induced steatohepatitis in mice

Sci Rep. 2017 Oct 20;7(1):13689. doi: 10.1038/s41598-017-13102-y.

Authors

Adriana Carino¹, Sabrina Cipriani², Silvia Marchianò¹, Michele Biagioli¹, Paolo Scarpelli³, Angela Zampella⁴, Maria Chiara Monti⁵, Stefano Fiorucci⁶

Affiliations

¹ University of Perugia, Department Surgical and Biomedical Sciences, Perugia, Italy.
² University of Perugia, Department of Medicine, Perugia, Italy.
³ University of Perugia, Department of Experimental Medicine, Perugia, Italy.
⁴ University of Naples Federico II, Department of Pharmacy, Naples, Italy.
⁵ University of Salerno, Department of Pharmacy, Fisciano, Salerno, Italy.
⁶ University of Perugia, Department Surgical and Biomedical Sciences, Perugia, Italy. [email protected].

Abstract

Gpbar1 is a bile acid activated receptor for secondary bile acids. Here we have investigated the mechanistic role of Gpbar1 in the regulation of adipose tissues functionality in a murine model of steatohepatitis (NASH). Feeding wild type and Gpbar1^-/- mice with a high fat diet-fructose (HFD-F) lead to development of NASH-like features. Treating HFD-F mice with 6β-ethyl-3a,7b-dihydroxy-5b-cholan-24-ol (BAR501), a selective Gpbar1-ligand, reversed insulin resistance and histologic features of NASH, increased the weight of epWAT and BAT functionality and promoted energy expenditure and the browning of epWAT as assessed by measuring expression of Ucp1 and Pgc-1α. The beneficial effects of BAR501 were lost in Gpbar1^-/- mice. In vitro, BAR501 promoted the browning of 3T3-L1 cells a pre-adipocyte cell line and recruitment of CREB to the promoter of Pgc-1α. In conclusion, Gpbar1 agonism ameliorates liver histology in a rodent model of NASH and promotes the browning of white adipose tissue.

MeSH terms

3T3 Cells
Adipose Tissue, Brown / drug effects
Adipose Tissue, Brown / metabolism*
Adipose Tissue, Brown / pathology
Adipose Tissue, White / drug effects
Adipose Tissue, White / metabolism*
Adipose Tissue, White / pathology
Animals
Cholestanols / pharmacology
Cyclic AMP Response Element-Binding Protein / metabolism
Diet, High-Fat
Disease Models, Animal
Fatty Liver / drug therapy*
Fatty Liver / metabolism*
Fatty Liver / pathology
Fructose
Insulin Resistance / physiology
Liver / drug effects
Liver / metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism*
Promoter Regions, Genetic
Protective Agents / pharmacology
Random Allocation
Receptors, G-Protein-Coupled / agonists*
Receptors, G-Protein-Coupled / genetics
Receptors, G-Protein-Coupled / metabolism

Substances

6-ethyl-3,7-dihydroxycholan-24-ol
Cholestanols
Creb1 protein, mouse
Cyclic AMP Response Element-Binding Protein
Gpbar1 protein, mouse
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Ppargc1a protein, mouse
Protective Agents
Receptors, G-Protein-Coupled
Fructose