MPO deficiency enhances energy consumption by altering metabolic activity and adipokine secretion of adipocytes, improving vascular function in obesity

Background: Obesity is a rapidly increasing epidemic, vastly contributing to cardiovascular disorders and mortality rates. Adipose tissues are involved in control of metabolism and energy expenditure, but also host a variety of immune cells, which disequilibrate in obesity. The role of Myeloperoxidase, a key enzyme of polymorph nuclear granuolcytes in this context is unknown.

Methods: Obese Leptin knock out mice were crossbred with Myeloperoxidase deficient mice (Lep^-/- Mpo^-/-). Metabolic characterization was performed by measuring HbA1c blood levels, insulin glucose tolerance testing and PhenoMaster cages. Visceral white (WAT), interscapular brown (BAT) and thoracic perivascular aortic adipose tissue (PVAT) were analysed by qPCR regarding expression of phenotypic and thermoregulartory genes and adipokines. Human white adipocytes were “beiged” by noradrenalin and cold exposure and were incubated with MPO. Subsequently, effects on cell phenotype and adipokine expression was analysed. Organbath experiments were performed on aortic sections of Mpo^-/- mice that were incubated with supernatant from Adiponektin (APN) PVAT vice versa. 

Results: HbA1c levels of Lep^-/- Mpo^-/- mice were significantly lower compared to Lep^-/- mice, likewise, blood glucose levels were significantly higher in insulin tolerance test. O2 consumption and CO2 production was elevated in obese mice, when MPO was knocked out. Analysis of phenotypic adipocyte markers in visceral adipose tissue showed a significant increase in gene expression of P2RX5, a characteristic marker of adipocyte beiging, whereas ASC-1, a white adipocyte marker was downregulated in Lep^-/- Mpo^-/- mice. In vitro experiments confirmed these findings, with reduced expression of UCP-1, P2RX5 and CITED-1 upon stimulation of beiged human white adipocytes with MPO. Likewise, WAT-marker ASC-1 was increased and APN expression was dampened when cells were treated with MPO. In PVAT, release of APN was induced when MPO was knocked out, ultimately leading to an improved endothelial function as measured in organ bath experiments.

Conclusion: In obesity, MPO deficiency improves energy dissipation by a phenotypic shift of adipocytes in different adipose tissues and enhances vasoprotective adipokine secretion, thereby improving vascular function.