Tissue macrophage inflammatory pathways contribute to
obesity-associated
insulin resistance. Here, we have examined the efficacy and mechanisms of action of a novel anti-inflammatory compound (
HE3286) in vitro and in vivo. In primary murine macrophages,
HE3286 attenuates LPS- and
TNFalpha-stimulated
inflammation. In Zucker diabetic fatty rats, inflammatory
cytokine/
chemokine expression was downregulated in liver and adipose tissue by
HE3286 treatment, as was macrophage infiltration into adipose tissue. In line with reduced
inflammation,
HE3286 treatment normalized fasting and fed
glucose levels, improved
glucose tolerance, and enhanced skeletal muscle and liver
insulin sensitivity, as assessed by hyperinsulinemic euglycemic clamp studies. In phase 2 clinical trials,
HE3286 treatment led to an enhancement in
insulin sensitivity in humans. Gluconeogenic capacity was also reduced by
HE3286 treatment, as evidenced by a reduced glycemic response during
pyruvate tolerance tests and decreased basal hepatic
glucose production (HGP) rates. Since serum levels of gluconeogenic substrates were decreased by
HE3286, it indicates that the reduction of both intrinsic gluconeogenic capacity and substrate availability contributes to the decrease in HGP. Lipidomic analysis revealed that
HE3286 treatment reduced liver
cholesterol and
triglyceride content, leading to a feedback elevation of
LDL receptor and
HMG-CoA reductase expression. Accordingly,
HE3286 treatment markedly decreased total serum
cholesterol. In conclusion,
HE3286 is a novel anti-inflammatory compound, which displays both
glucose-lowering and
cholesterol-lowering effects.