Alterations in hepatic macronutrient metabolism in response to short term high fat feeding in rats

Abstract

Insulin resistance (IR) is coupled to obesity or high fat feeding by ectopic lipid metabolism and accumulation of intermediates that disrupt insulin signaling. We recently reported that hepatic mitochondrial fat metabolism is dysfunctional in Zucker Diabetic Fatty (ZDF) rats. The objective of this study was to test whether similar effects on hepatic mitochondrial metabolism occur in lean (ZDF+/−) rats following a short term (7d) high fat (60% fat calories) challenge. Conscious, unrestrained rats were infused with stable isotope tracers followed by NMR or LC‐MS isotopomer analysis of plasma metabolites to determine hepatic fluxes. Fasting hepatic ketogenesis and fat oxidation is impaired in obese diabetic rats. In contrast, a short term high fat diet increased fasting ketone concentrations and did not affect TCA cycle flux or GNG. Ureagenesis, an energy intensive pathway that spans both cytosolic and mitochondrial compartments, was also lower in fat fed lean ZDF+/− rats compared to obese ZDF−/− rats. We conclude that short‐term high fat feeding elicits a physiological response in several hepatic mitochondrial and cytosolic pathways that facilitates whole body metabolism of lipid rich macronutrients, but that this adaptation is fundamentally different from the patho‐physiological features of hepatic fat metabolism in obese diabetic rats.