ANT2 drives proinflammatory macrophage activation in obesity
Jae-Su Moon, … , Chanond A. Nasamran, Yun Sok Lee
Jae-Su Moon, … , Chanond A. Nasamran, Yun Sok Lee
Published October 22, 2021
Citation Information: JCI Insight. 2021;6(20):e147033. https://doi.org/10.1172/jci.insight.147033.
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Research Article Endocrinology Metabolism

ANT2 drives proinflammatory macrophage activation in obesity

Abstract

Macrophage proinflammatory activation is an important etiologic component of the development of insulin resistance and metabolic dysfunction in obesity. However, the underlying mechanisms are not clearly understood. Here, we demonstrate that a mitochondrial inner membrane protein, adenine nucleotide translocase 2 (ANT2), mediates proinflammatory activation of adipose tissue macrophages (ATMs) in obesity. Ant2 expression was increased in ATMs of obese mice compared with lean mice. Myeloid-specific ANT2-knockout (ANT2-MKO) mice showed decreased adipose tissue inflammation and improved insulin sensitivity and glucose tolerance in HFD/obesity. At the molecular level, we found that ANT2 mediates free fatty acid–induced mitochondrial permeability transition, leading to increased mitochondrial reactive oxygen species production and damage. In turn, this increased HIF-1α expression and NF-κB activation, leading to proinflammatory macrophage activation. Our results provide a previously unknown mechanism for how obesity induces proinflammatory activation of macrophages with propagation of low-grade chronic inflammation (metaflammation).

Authors

Jae-Su Moon, Flavia Franco da Cunha, Jin Young Huh, Alexander Yu Andreyev, Jihyung Lee, Sushil K. Mahata, Felipe C.G. Reis, Chanond A. Nasamran, Yun Sok Lee

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Figure 6

ANT2 depletion preserves mitochondrial respiratory capacity during proinflammatory macrophage activation.

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ANT2 depletion preserves mitochondrial respiratory capacity during proin...
(A and B) Basal and chemical uncoupler–induced maximal OCRs were measured in the presence or absence of inhibitors of glucose (Glc) (UK5099), FA (etomoxir), and/or amino acid (AA) (BPTES) transport into mitochondria in WT and ANT2-MKO BMDMs treated without (A) or with (B) LPS for 24 hours (n = 6 wells/group). MΦ, macrophage. (C) Relative OCR in WT and ANT2-MKO BMDMs treated with or without LPS for 24 hours (n = 10 wells/group). DNP, 2,4-dinitrophenol. (D) CS activity in WT and ANT2-MKO BMDMs treated with or without LPS for 24 hours (n = 4 wells/group). (E) mtDNA content in WT and ANT2-MKO BMDMs treated with or without PA or LPS for 24 hours (n = 4 wells/group). (F–I) Transmission electron microscopy analysis of WT and ANT2-MKO BMDMs treated with or without PA or LPS for 24 hours. Representative pictures are shown in F (damaged mitochondria in the boxed areas are shown in higher magnitude on the right). The number of damaged and healthy-looking mitochondria was counted in a given cellular area and used to calculate mitochondrial density (G) and the ratio between damaged and intact mitochondria (H). Cristae density was measured in intact mitochondria in WT and ANT2-MKO BMDMs (I) (n = 1–2 mitochondria in 18–20 cells/group). In all panels, all values are mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001. Statistical analysis was performed by 2-way ANOVA with Tukey’s multiple comparison test.