Effect of tirzepatide, a GIPR and GLP1R dual agonist, on endothelial cell function and metabolism

Obesity is accompanied by systemic low-grade inflammation and several co-morbidities, including cardiovascular disease. A hallmark of obesity is endothelial cell dysfunction, one of the first steps leading to atherosclerosis. Tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon like peptide 1 (GLP-1) receptors is likely to become a cornerstone in obesity management therapy, thanks to its benefits on weight and glucose control and improvement of cardiometabolic risk factors. Both GIPR and GLP1R are expressed on endothelial cells, however the direct effect of tirzepatide on endothelial cells (ECs) is unclear.

We hypothesize that tirzepatide has beneficial effects on the vasodilatory function and metabolism of ECs exposed to low-grade inflammation.

Human Aortic Endothelial Cells (HAECs) were exposed to tirzepatide, GIP or GLP-1 (100 nM) for 24h with or without a pro-inflammatory cytokine cocktail (0,25ng/ml IL1β, 2,5ng/ml IL6, 1,25ng/ml TNFα and 1,25ng/ml IFNγ). Cell proliferation, endothelial function and metabolism were investigated using high content screening microscopy, Western blot, qPCR and Seahorse metabolic analyser. Statistical analysis was performed using GraphPad Prism software.

No significant effect on cell proliferation or basal nitric oxide production were observed in any conditions. Seahorse measurement showed that cytokine treatment increased basal glycolysis as well as compensatory glycolysis upon mitochondrial inhibition, compared to control. This was reverted with addition of tirzepatide. Likewise, the Mito Stress Test assay revealed increased basal, maximal and ATP-linked respiration in HAECs exposed to inflammation. Tirzepatide, however, reverted respiration to basal levels.

Tirzepatide treatment influenced the metabolism of ECs exposed to a pro-inflammatory stimulus by lowering increased glycolysis and mitochondrial respiration back to basal levels. Further experiments will be performed to investigate the effect of tirzepatide on glucose metabolism and mitochondrial function and morphology in detail.