The current study was initially designed to (i) determine the effect of obesity on liver oxygen tension and HIF-1α and HIF-2α expression and (ii) define what role hepatocyte HIF-1α and HIF-2α play in obesity-associated changes in liver inflammation, steatosis, insulin resistance, and glucose intolerance. Initial results showed that, in HFD/obese states without massive liver damage and fibrosis, hepatocyte HIF-1α is not necessary for liver inflammation and insulin resistance but can reduce glucose-stimulated insulin secretion with decreased plasma active GLP-1 levels. The following studies were designed to (i) define what role hepatocytes HIF-1α and HIF-2α play in obesity-induced decreased incretin effects (glucose-stimulated insulin secretion) and plasma active GLP-1 degradation, (ii) define what role hepatocyte HIF-1α plays in obesity-induced liver microhemodynamics and portal blood pressure, and (iii) determine how obesity confers an isoform-selective induction of liver HIF-1α expression. For in vivo studies, age-matched Cre Hif1afl/fl or Hif2afl/fl littermates were caged together with Cre+ KO mice and were used as WT controls. Animal numbers for each study type were determined by the investigators on the basis of data from previous similar experiments or from pilot studies. Results were confirmed in at least two separate cohort mouse experiments. For in vitro studies, at least three biological replicates were used. For in vivo experiments and biochemical assays, mouse or sample identities were not blinded, but in most cases, the sequence of analyzed tubes and mice was randomized.

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