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High Fat Diet and Susceptibility to Obesity Increase the Effects of HIV Protease Inhibitors on Metabolism in Mice J. LENHARD*, D. CROOM, J. BINZ, E. FURFINE, D. REYNOLDS, A. SPALTENSTEIN, and J. WEIEL.
Glaxo Wellcome Inc., Res. Triangle Park, NC Objective: To determine if dietary fat or susceptibility to obesity influences the effects of HIV protease inhibitors (PIs) on metabolism in mice.
Methods: Obesity prone (AKR/J) and resistant (SWR/J) mice were fed high or low fat diets and treated with 2.9 mg/d of indinavir (IDV), nelfinavir (NFV), saquinavir (SQV) or amprenavir (APV) by sub-cutaneous infusion. After two weeks, metabolic and clinical toxicology markers were determined.
Results: Some metabolic effects of PIs were dependent on diet. For example, IDV and NFV lowered serum insulin (51%) and elevated serum glucose (10-15%) levels in AKR/J mice fed low (P<0.02) but not high fat diet. NFV, SQV, and IDV elevated serum triglycerides (25-60%) in AKR/J mice fed a high (P<0.02) but not low fat diet. Furthermore, IDV, SQV, or NFV increased fat mass only in AKR/J mice fed a low fat diet (P<0.03). High fat diet decreased the serum concentration of SQV by 2.5-fold (P=0.015), but did not affect the other PIs. Other effects were not dependent on diet. For example, IDV or NFV increased serum free fatty acids and alkaline phosphatase whereas IDV treatment increased serum bilirubin and pancreatic lipase in all AKR/J mice (P<0.05). In contrast to AKR/J mice, IDV or NFV treatment decreased serum glucose levels (13-15%) and NFV treatment decreased serum free fatty acid levels (23-27%) in SWR/J fed a low-fat diet (P<0.05). Moreover, NFV and IDV treatment had no effect on serum triglycerides, pancreatic lipase, or bilirubin levels in SWR/J mice fed a high-fat diet (P>0.4). APV lowered triglycerides (18%) in AKR/J mice fed a low fat diet (P=0.01), but otherwise had no significant affect on fat metabolism (P>0.05).
Conclusion: These observations indicate that dietary fat and obesity can influence an individual's susceptibility the effects of PIs on metabolism. Moreover, each PIs caused different effects on lipid metabolism, indicating the various Pis do not affect the same metabolic pathways.
Key Words: fat, metabolism, protease inhibitors
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