1823-P: Bromocriptine (BC) Normalizes Elevated Expression of Liver Genes Involved in Fatty Acid Oxidation, Lipogenesis, Inflammation, and Endoplasmic Reticulum (ER) Stress and Glucose Intolerance of High-Fat/Sucrose Diet-Fed Rats

Abstract

Consumption of the “westernized diet” (WD) of high fat and sucrose promotes the development of hepatic insulin resistance and metabolic syndrome (MS). This diet is well known to reduce brain dopamine activity and stimulate chronic over-activation of the sympathetic nervous system that potentiate liver insulin resistance by as yet unknown mechanisms. This study evaluated the effect of circadian-timed bromocriptine, a sympatholytic dopamine agonist, to reverse the adverse effects of the WD on glucose tolerance and liver expression of several genes involved in hepatic aspects of insulin sensitivity including lipid balance, inflammation and ER stress. Female Sprague-Dawley rats were maintained on a WD of high fat (40% by kcal/g) and sucrose (29% by kcal/g) for 4 weeks and then administered BC (7.5 mg/kg) or vehicle (N =10/group) at the onset of daily waking for an additional 10 weeks while maintained on WD to study end when a GTT (3g/kg glucose) was performed and 5 days later when animals were sacrificed for analyses of hepatic genes (via PCR) involved in insulin sensitivity. A regular chow fed group (N=10) served as positive control. BC treatment reduced the GTT glucose AUC by 39% vs. controls (P<0.001) without change in the insulin AUC and reduced body fat level by 35% (P= 0.01) without change in feeding vs. controls. BC also reduced hepatic gene transcripts for fatty acid oxidation - PPARa and CPT1A by 35 and 48%, respectively (P<0.03), for lipid synthesis - DGAT2 by 20% (P<0.04), and for inflammation and ER stress - monocyte chemoattractant protein 1 and C/EBP homologous protein by 40 and 47% (P<0.05), respectively, vs. controls, all to levels observed in regular chow fed rats. This study demonstrated that bromocriptine can reverse the adverse effects of WD on hepatic lipid, inflammation, and ER stress gene expression pathways that promote hepatic insulin resistance and MS. Disclosure Y. Zhang: Employee; Self; VeroScience LLC. M. Ezrokhi: Employee; Self; VeroScience LLC. N. Cominos: Employee; Self; VeroScience LLC. A.H. Cincotta: Employee; Self; VeroScience LLC.