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 1

Myeloid-specific ANT2 depletion improves insulin sensitivity and glucose tolerance in obesity.

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Myeloid-specific ANT2 depletion improves insulin sensitivity and glucose...
(A) Body weight of HFD-fed WT and ANT2-MKO mice (n = 6 mice per group). (B) Liver mass of HFD-fed mice (n = 6 mice per group). (C) eWAT mass of HFD-fed mice (n = 6 mice per group). (D) Hematoxylin and eosin (H&E) staining (left) of eWAT sections of HFD-fed WT and ANT2-MKO mice (n = 6 mice per group). Microscopic images were taken under ×20 magnification. The distribution of adipocyte sizes (middle) and average adipocyte size (right) were plotted. (E) Oral glucose tolerance tests (OGTTs) in HFD-fed mice (n = 8 WT and 9 ANT2-MKO mice). (F) Fasting (6 hours) plasma insulin levels (n = 8 WT and 14 ANT2-MKO mice). (G) HOMA-IR in (E) mice. (H) Intraperitoneal insulin tolerance test (IPITT) in HFD-fed mice (n = 8 WT and 14 ANT2-MKO mice). (I) Insulin-stimulated Akt phosphorylation (p-AKT) in liver of HFD mice. t-AKT, total AKT. (J) Insulin-stimulated Akt phosphorylation in skeletal muscle (quadriceps) of HFD-fed mice. (K) Insulin-stimulated Akt phosphorylation in eWAT of HFD-fed mice. (L) Insulin-stimulated Akt phosphorylation in skeletal muscle, liver, and eWAT of HFD-fed WT and ANT2-MKO mice (n = 6 [skeletal muscle and eWAT] and 7 [liver]mice per group). (M) mRNA expression of Glut4 and Adipoq in eWAT of HFD-fed mice (n = 6 WT and 6 ANT2-MKO mice). In all panels, values are mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. Statistical analysis was performed by 2-tailed, unpaired t test (C and D, right; E, right; F and G; H, right; and M) or 2-way ANOVA (E, left; H, left; and L) with Tukey’s multiple comparison test.