Mitochondrial Dysfunction in Adipocytes as a Primary Cause of Adipose Tissue Inflammation

Figures

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  Fig. 1. Hypothesis: mitochondrial dysfunction in adipocytes may be a primary cause of adipose tissue inflammation. Hypertrophic adipocytes in obesity or cellular aging are associated with increased expression levels of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), and these cells show reduced mitochondrial respiration and increased glycolysis. Mitochondrial dysfunction may trigger necroptosis in adipocytes or increase monocyte chemoattractant protein-1 (MCP-1) production, which initiates adipose tissue inflammation by attracting macrophages into adipose tissue. In addition, mitochondrial dysfunction in adipocytes decreases synthesis of adiponectin, a well-known AMP-activated protein kinase (AMPK) activator. Reduced AMPK activation in macrophages may increase M1/M2 macrophage polarization. Therefore, mitochondrial dysfunction in adipocytes may increase adipose tissue inflammation with increased M1/M2 polarization through a decrease in adiponectin synthesis.

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  Fig. 2. Proinflammatory response of macrophages may exacerbate mitochondrial dysfunction in adipocytes. In addition to the primary mitochondrial dysfunction resulting from possible intrinsic defect in mitochondrial quality control in adipocytes, nitric oxide (NO) produced by inducible nitric oxide synthase in activated macrophages may exacerbate mitochondrial dysfunction in preadipocytes. Mitochondrial dysfunction in preadipocytes increases pseudohypoxic response, which leads to a defective differentiation of preadipocytes to mature adipocytes, and adipose tissue fibrosis. PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1α.

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  Fig. 3. Comparison of our hypothesis and “adipose tissue hypoxia” theory. The hypothesis of “adipose tissue hypoxia” explains that hypoxia occurs in enlarged adipocytes distant from the vasculature and that this local adipose tissue hypoxia decreases the production of adiponectin. On the other hand, we hypothesize that mitochondrial dysfunction in adipocytes is a primary cause of adipocyte enlargement, adipose tissue inflammation, and insulin resistance. Defective mitochondrial function and fatty acid oxidation (FAO) in adipocytes would increase triglyceride accumulation to cause adipocyte enlargement. Further, mitochondrial dysfunction in adipocytes may induce pseudo-hypoxia to increase accumulation of hypoxia-inducible factor 1α (HIF-1α), which promotes adipose tissue inflammation and fibrosis. Even though adipose tissue hypoxia has been commonly observed in mouse obesity, human data reported increased adipose tissue oxygen tension and mitochondrial dysfunction in adipose tissue. TG, triglyceride.