A major cause of type 2 diabetes is obesity, in which fat cells expand rapidly, in both size and number, and their oxygen demand outstrips supply. This low-oxygen state, known as hypoxia, leads to upregulation of the anti-hypoxic protein HIF-1α, which in turn causes tissue inflammation and prevents fat cells (adipocytes) from responding normally to insulin1,2. Hypoxia in expanding fat is often thought of mainly as a problem of supply, caused by the inability of blood vessels that deliver oxygen to grow as fast as the surrounding tissue3,4. Writing in Nature Metabolism, Seo et al.5 highlight a pathway by which excessive oxygen consumption in adipocytes can also contribute to hypoxia in expanding fat tissue. This pathway involves the enhanced activity of the enzyme adenine nucleotide translocase 2 (ANT2) in energy-generating organelles called mitochondria.
During normal mitochondrial respiration, electrons are transferred between a series of molecules, and this transfer is coupled to the removal of hydrogen ions (H+, also known as protons) from the central matrix of the mitochondrion into the space between its outer and inner membranes. This process creates a proton gradient that drives the production of energy-carrying ATP molecules in mitochondria by the enzyme ATP synthase. But the process can become uncoupled if protons leak across the inner mitochondrial membrane. Uncoupled respiration results in inefficient ATP production, and thereby increases the intracellular demand for oxygen for further respiration.
High levels of uncoupled respiration can alter cellular physiology, and inhibiting uncoupled respiration with various compounds increases cellular oxygen levels, decreasing hypoxia and so reducing HIF-1α levels6. Any manipulation that leads to a decrease in cellular HIF-1α activity in fat is metabolically beneficial1. Thus, a better understanding of uncoupled respiration and how to manipulate it is desirable.
Previous work7 by the group that carried out the current study has shown that the rate of oxygen consumption in the white adipocytes of mice increases if the animals eat a high-fat diet. The group proposed that increased levels of circulating free fatty acids in the blood of obese animals led to activation of ANT2. Excessive ANT2 activity results in an increased proton leak back into the mitochondrion8, leading to elevated levels of uncoupled mitochondrial respiration.
