The peak in circadian dopaminergic activity at the biological clock area, suprachiasmatic nucleus is diminished in insulin resistant states and daily co-administration of dopamine D1 and D2 receptor agonists to restore this circadian peak of hypothalamic dopaminergic activity reverses this insulin resistance (IR) in genetic animal models of MS. However, the impact of such dopamine D1D2 receptor agonist therapy on NAFLD in an obesogenic animal model of the disease has never been investigated and such was the focus of the present study. C57B6 mice were maintained on a 40% kcal fat and 29% kcal sucrose diet with 5% fructose in the drinking water for 12 weeks and then randomized to daily treatment with bromocriptine (BC, a D2 agonist) (10 mg/kg), SKF38393 (S, a D1 agonist) (10 mg/kg), BC + S, or vehicle (N=7-8/gr) for 3 weeks while maintained on the diet. At the end of treatment, animals were sacrificed for analyses of metabolic parameters and liver biochemistry. D1D2 but neither D1 nor D2 agonist therapy maximally improved IR, obesity, and NAFLD. The D1D2 improvement in NAFLD was associated with reduced hepatic expression of lipogenic, inflammatory, insulin resistance-inducing, and FFA oxidative genes while normalizing antioxidant gene expressions (Table). This study suggests that circadian-timed daily dopamine D1D2 agonist therapy may be a means of treating both type 2 diabetes and NAFLD.

M. Ezrokhi: Employee; Self; VeroScience LLC. S. Luo: Employee; Self; VeroScience LLC. N. Cominos: Employee; Self; VeroScience LLC. B. Raiche: Employee; Self; VeroScience LLC. M. Gustafson: Employee; Self; VeroScience LLC. A.H. Cincotta: Employee; Self; VeroScience LLC.

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