Pathological activation of the renin-angiotensin system (RAS) and inflammation are associated with hypertension and the development of metabolic syndrome (MetS). The progression of MetS is also associated with the development of chronic kidney disease (CKD) and nonalcoholic fatty liver disease (NAFLD). However, the contributions of the angiotensin type 1 receptor (AT1) receptor activation and tumor necrosis factor (TNF)-α-mediated inflammation have on the development of insulin resistance and how they impact hepatorenal health is not well defined. The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is a well-characterized model of diet-induced obesity that progresses similarly to humans. Using this model and its lean strain counterpart, the Long Evans Tokushima Otsuka (LETO) the progression of the disease was observed in six groups of 16 week old rats with 6 weeks of treatment: 1) lean strain-control LETO; n=5, 2) obese OLETF; n=7, 3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg; n=8), 4) OLETF + TNF-α inhibitor (ETAN; 1.25mg etanercept/kgd; n=6), 5) OLETF + angiotensin receptor blocker + TNF-α inhibitor (ARB + ETAN; 10 mg olmesartan/kg + 1.25mg etanercept/kgd; n=6), and 6) OLETF + calcium channel blocker (CCB; 5 mg amlodipine/kg; n=7).

All treatments resulted in similar reductions in blood pressure; however the acute removal of etanercept resulted in an increase in blood pressure that was immediately reduced again once reintroduced. CCB treatment was not able to improve glucose tolerance or insulin resistance index, while ARB, ETAN, and ARB + ETAN were. Similarly, improvements in adiposity were observed with all treatment groups. Renal albumin excretion and glutathione peroxidase was recovered only with ETAN treatment. Renal 4-hydroxynonenal was reduced with ARB treatment. Hepatic non-esterified fatty acids were reduced with all treatments, however, there was a greater reduction found with ETAN and ARB + ETAN treatments. Despite relatively similar reductions in systolic blood pressure and adiposity, the calcium channel blocker did not improve glucose tolerance or calculated insulin resistance index, while the other treatments did, demonstrating that improper RAS activation and inflammation are larger factors contributing to the development of impaired glucose and lipid metabolism and regulation during metabolic syndrome, than hypertension. These results suggest that AT1 activation and TNF-α mediated inflammation are mechanistically important in the development of metabolic syndrome and that the associated increase in systolic blood pressure (SBP) may be a consequence of the condition. They also suggest that there are other factors contributing to impaired glucose tolerance and adiposity since none of the treatments completely ameliorated the derangement.