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Myeloperoxidase deletion prevents high-fat diet-induced obesity and insulin resistance
Qilong Wang1, Zhonglin Xie1, Wencheng Zhang1
1Section of Molecular Medicine, Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
Abstract:
Activation of myeloperoxidase (MPO), a heme protein primarily expressed in granules of neutrophils, is associated with the development of obesity. However, whether MPO mediates high-fat diet (HFD)-induced obesity and obesity-associated insulin resistance remains to be determined. Here, we found that consumption of an HFD resulted in neutrophil infiltration and enhanced MPO expression and activity in epididymal white adipose tissue, with an increase in body weight gain and impaired insulin signaling. MPO knockout (MPO(-/-)) mice were protected from HFD-enhanced body weight gain and insulin resistance. The MPO inhibitor 4-aminobenzoic acid hydrazide reduced peroxidase activity of neutrophils and prevented HFD-enhanced insulin resistance. MPO deficiency caused high body temperature via upregulation of uncoupling protein-1 and mitochondrial oxygen consumption in brown adipose tissue. Lack of MPO also attenuated HFD-induced macrophage infiltration and expression of proinflammatory cytokines. We conclude that activation of MPO in adipose tissue contributes to the development of obesity and obesity-associated insulin resistance. Inhibition of MPO may be a potential strategy for prevention and treatment of obesity and insulin resistance.
Insights
Myeloperoxidase (MPO) activation drives high-fat diet obesity and insulin resistance. Inhibiting MPO offers a potential therapeutic strategy for metabolic disorders.
Area of Science:
- Biochemistry
- Immunology
- Metabolic Diseases
Background:
- Myeloperoxidase (MPO) is a neutrophil-associated heme protein linked to obesity development.
- The specific role of MPO in high-fat diet (HFD)-induced obesity and insulin resistance is not fully understood.
Purpose of the Study:
- To investigate whether MPO mediates HFD-induced obesity and associated insulin resistance.
- To explore MPO's role in metabolic regulation and inflammation in adipose tissue.
Main Methods:
- Utilized MPO knockout (MPO(-/-)) mice and an MPO inhibitor (4-aminobenzoic acid hydrazide).
- Administered a high-fat diet (HFD) to assess effects on body weight, insulin signaling, and adipose tissue parameters.
- Analyzed neutrophil and macrophage infiltration, pro-inflammatory cytokine expression, and brown adipose tissue activity (uncoupling protein-1, mitochondrial oxygen consumption).
Main Results:
- HFD consumption led to increased neutrophil infiltration, MPO expression/activity in epididymal white adipose tissue, body weight gain, and impaired insulin signaling.
- MPO(-/-) mice were protected against HFD-induced weight gain and insulin resistance.
- MPO inhibition reduced neutrophil peroxidase activity and prevented HFD-induced insulin resistance.
- MPO deficiency elevated body temperature via UCP-1 and mitochondrial respiration in brown adipose tissue.
- Lack of MPO attenuated HFD-induced macrophage infiltration and pro-inflammatory cytokine expression.
Conclusions:
- MPO activation in adipose tissue contributes significantly to HFD-induced obesity and insulin resistance.
- Targeting MPO presents a promising therapeutic avenue for managing obesity and related metabolic dysfunction.
- MPO plays a role in regulating energy expenditure and inflammation in metabolic tissues.
