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Understanding obesity-induced insulin resistance

Findings about HIF-1 are significant not only for their possible application to fighting insulin resistance and diabetes, but also cancer

Researchers at the University of California, San Diego School of Medicine have, for the first time, described the sequence of early cellular responses to a high-fat diet, one that can result in obesity-induced insulin resistance and diabetes. The findings, 'Increased Adipocyte O2 Consumption Triggers HIF-1α, Causing Inflammation and Insulin Resistance in Obesity' published in Cell, also suggest potential molecular targets for preventing or reversing the process.

Jerrold M Olefsky

"We've described the etiology of obesity-related diabetes. We've pinpointed the steps, the way the whole thing happens," said Dr Jerrold M Olefsky, associate dean for Scientific Affairs and Distinguished Professor of Medicine at UC San Diego. "The research is in mice, but the evidence suggests that the processes are comparable in humans and these findings are important to not just understanding how diabetes begins, but how better to treat and prevent it."

Previous research by Olefsky and others has shown that obesity is characterised by low-grade inflammation in adipose and that this inflammatory state can become chronic and result in systemic insulin resistance and diabetes. In this latest paper, they describe the earliest stages of the process, which begins even before obesity becomes manifest.

In the study, the researchers fed mice genetically engineered mice that lack the hypoxia inducible factor-1 (HIF-1 alpha) protein within the animals' adipocytes, a high-fat diet. They report that the abundant saturated fatty acids in the diet activated adenine nucleotide translocase 2 (ANT2), a mitochondrial protein in fat cell membranes that is involved in cellular energy metabolism. Activation of ANT2 caused increased oxygen consumption, which meant less was available for the rest of the cell.

Cells in the body normally consume oxygen to produce energy. But if oxygen levels decrease, for example during strenuous exercise or at high altitudes, cells enter a condition called hypoxia, or low oxygen. With oxygen in short supply, cells switch their metabolism. Instead of energy, the cells produce reactive oxygen species, which are molecules that can damage or kill cells. To help mitigate the damage, hypoxic cells activate HIF-1 alpha, which in turn shuts down the production of reactive oxygen species and signals inflammatory cells to migrate to the hypoxic areas.

Jung-whan Kim

"There is clearly a greater chance among the obese human population to develop insulin resistance and diabetes. We still don't know the exact mechanism, but now we know that HIF-1 alpha is very active in the pathogenesis of these diseases from obesity," said co-lead author of the study, Dr Jung-whan Kim from the University of California, San Diego. "Organisms need to be able to temporarily adapt to the stress of hypoxic conditions until the situation changes, so when inflammatory cells see this kind of signal, they come to the hypoxic area to do their normal job, which is to basically eat damaged cells.

Kim said the findings about HIF-1 are significant not only for their possible application to fighting insulin resistance and diabetes, but also cancer.

"If you look at adipose, or fat tissue, in the obese, there is massive and chronic inflammation," he explained. "It's a defence mechanism. The inflammatory cells are really good guys, but as obesity persists, inflammation becomes chronic. HIF-1 alpha is important for hypoxia adaptation, but it's constantly activated in the obese, and that's where it turns bad. In the obese, HIF-1 is aberrantly and chronically elevated and is the master regulator of ominous chronic inflammation."

Kim said several pharmaceutical companies are developing HIF-1 alpha inhibitors to block the protein from functioning, which might one day result in medications to treat type 2 diabetes and insulin resistance in obese people. But the primary reason the pharmaceutical industry is already investigating HIF-1 alpha inhibitors is cancer.

"Tumour cells grow really fast, but the blood vessels that feed them oxygen cannot grow fast enough, so tumour cells become hypoxic," he added. "The tumour cells have to develop some sort of mechanism to survive under hypoxic stress, and that's HIF-1 alpha. If you can inhibit HIF-1 alpha in a tumour cell, you can kill the cell, and that's why pharmaceutical companies are interested in HIF-1 inhibitors."

The research was funded by the National Institutes of Health, the American Diabetes Association and the Wellcome Trust.

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