Expanding brown adipose tissue is a potential therapeutic strategy to counteract insulin resistance and metabolic syndrome (MetS). Farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) activation enhances insulin sensitivity, suggesting the capacity of FXR/TGR5 agonists to promote brown differentiation in adipose tissue. Treatment with increasing doses of the dual FXR/TGR5 agonist INT-767 (3, 10, 30 mg/Kg bw, daily for 5 days a week, by oral gavage, for 12 weeks) in a rabbit model of high fat diet (HFD)-induced MetS, characterized by insulin resistance, hypertension, dyslipidemia,visceral adipose tissue (VAT) accumulation, dose-dependently reduced VAT mass, as well as glycemia, insulin resistance, cholesterol levels while significantly increasing HDL levels. INT-767 also reduced HFD-induced hepatomegaly and ALT increase. Treatment with INT-767 decreased HFD-induced adipocyte hypertrophy and reduced GLUT4 translocation to the plasma membrane, both considered hallmarks of insulin resistance in VAT. Treatment with INT-767 also induced VAT expression of genes related to nitric oxide (NO)/cGMP/protein kinase G (PKG) signaling, mediating both mitochondriogenesis and brown adipocyte differentiation. Rabbit preadipocytes (rPADs), isolated from the different groups, were then investigated for their spontaneous adipogenic potential. The expression of genes specific for: i) brown fat ii) mitochondrial biogenesis, iii) membrane respiratory chain, iv) pro-fusion and pro-fission proteins of mitochondria, were all significantly increased in rPADs from INT-767-treated compared to HFD rabbits. Transmission electron microscopy demonstrated that INT-767 treatment normalized HFD-induced reduction of mitochondrial cristae. INT-767 treatment was also able to: i) improve mitochondrial architecture and dynamic, with the majority of mitochondria continuously moving and changing shape, as assessed by time lapse imaging with mitochondria-targeted fluorescent probe MitoTracker, ii) reduce superoxide production, assessed by measuring the time-dependent accumulation of dihydroethidium-derived fluorescence, iii) improve insulin sensitivity. In conclusion, the dual FXR/TGR5 agonist INT-767 ameliorates the metabolic profile and reduces visceral adiposity by improving insulin sensitivity and promoting brown differentiation in visceral adipose tissue.