Obesity is known to induce adipose tissue hypoxia, leading to an increase in levels of adipocyte hypoxia-inducible factor 1α (HIF1α). This increase in HIF1α is proposed to trigger adipose tissue inflammation and insulin resistance. New research suggests that the mitochondrial protein adenine nucleotide translocase 2 (ANT2) might have a role in this sequence of events.

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Previously, increased free fatty acid levels have been shown to stimulate an ANT2-dependent increase in uncoupled mitochondrial respiration. “In the present study, we set out to test whether adipocyte ANT2 is necessary for obesity-induced increased adipocyte oxygen consumption and relative hypoxia,” say Yun Sok Lee and Jerrold Olefsky, corresponding authors.

To address their hypothesis, the researchers generated adipocyte-specific ANT2-knockout (ANT2 AKO) mice using the Cre–loxP system. Changes in adipocyte mitochondrial number, mass and activity were then assessed, along with adipocyte oxygen demand and HIF1α expression levels. Knockdown of ANT2 was found to reduce adipocyte oxygen consumption and improve hypoxia (without effects on mitochondrial number or mass). In turn, HIF1α expression levels were reduced.

Macrophage infiltration and proliferation in adipose tissue was measured, along with adipokine expression levels, showing that ANT2 AKO mice were protected from adipose inflammation and fibrosis. ANT2 AKO mice also had improved glucose tolerance and insulin sensitivity.

The role of ANT2 in established glucose intolerance and insulin resistance was also investigated using an inducible ANT2 AKO mouse strain. “[We] showed that ANT2 activation is important not only for the initiation of obesity-induced adipose tissue hypoxia, but also for the maintenance of obesity-induced metabolic dysfunction,” say Lee and Olefsky.

ANT2 warrants further investigation as a target for antidiabetic therapies

The researchers conclude that ANT2 warrants further investigation as a target for antidiabetic therapies. Furthermore, several features of high-fat diet fed ANT2 AKO mice resemble those of metabolically healthy obese individuals, raising the possibility that adipocyte ANT2 activity might be associated with metabolic health (or lack thereof) in obesity.