Scientist Finds Clearer Obesity, Diabetes Link
Cell Discoveries in New Study Also May Help Explain Connection to Cancer
New findings about the biological links between obesity and insulin resistance and Type 2 diabetes may also shed light on the connection between obesity and cancer, says a scientist at The University of Texas at Dallas.
In a study published in the journal Cell, UT Dallas’ Dr. Jung-whan Kim and colleagues at the University of California, San Diego found that a protein called HIF-1 alpha plays a key role in the development of insulin resistance and Type 2 diabetes in obese mice.
“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.
In obesity, however, fat cells are in a chronic state of hypoxia.
“If you look at adipose, or fat tissue, in the obese, there is massive and chronic inflammation,” he said. “It’s a defense 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,” Kim said. “In the obese, HIF-1 is aberrantly and chronically elevated and is the master regulator of ominous chronic inflammation.”
To study the effect HIF-1 alpha might have on the development of insulin resistance and diabetes, Kim and his colleagues used genetic engineering techniques to completely remove, or “knock out,” HIF-1 alpha from adipose tissue in obese mice.
“Once we knocked out HIF-1, everything got better,” he said. “The fat cells survived and the mice remained obese, but we saw less inflammation in the fat tissue. These mice responded better to insulin than their normal counterparts, which means insulin sensitivity was improved and glucose tolerance was improved.”
Kim said several pharmaceutical companies are developing HIF-1 alpha inhibitors, which might one day result in medications to treat Type 2 diabetes and insulin resistance in obese people. But the primary reason behind the push for HIF-1 alpha inhibitors is cancer.
“Tumor cells grow really fast, but the blood vessels that feed them oxygen cannot grow fast enough, so tumor cells become hypoxic,” Kim said. “The tumor 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 tumor cell, you can kill the cell, and that’s why pharmaceutical companies are interested in HIF-1 inhibitors.”
Kim said one reason for the study was to gain a better understanding of the links between obesity and cancer.
“There is a clear correlation between the two, but it’s not clear why obese people have a greater chance of developing certain cancers,” he said. “If you look at breast cancer, the glands that produce milk are completely surrounded by fat cells.
“Tumor tissue is hypoxic. Obese tissue is hypoxic. HIF-1 alpha is important in both conditions. I’m very motivated to study the interaction between breast cancer cells and fat cells.”
The research was funded by the National Institutes of Health, the American Diabetes Association and the Wellcome Trust.
“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.
In obesity, however, fat cells are in a chronic state of hypoxia.
“If you look at adipose, or fat tissue, in the obese, there is massive and chronic inflammation,” he said. “It’s a defense 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,” Kim said. “In the obese, HIF-1 is aberrantly and chronically elevated and is the master regulator of ominous chronic inflammation.”
To study the effect HIF-1 alpha might have on the development of insulin resistance and diabetes, Kim and his colleagues used genetic engineering techniques to completely remove, or “knock out,” HIF-1 alpha from adipose tissue in obese mice.
“Once we knocked out HIF-1, everything got better,” he said. “The fat cells survived and the mice remained obese, but we saw less inflammation in the fat tissue. These mice responded better to insulin than their normal counterparts, which means insulin sensitivity was improved and glucose tolerance was improved.”
Kim said several pharmaceutical companies are developing HIF-1 alpha inhibitors, which might one day result in medications to treat Type 2 diabetes and insulin resistance in obese people. But the primary reason behind the push for HIF-1 alpha inhibitors is cancer.
“Tumor cells grow really fast, but the blood vessels that feed them oxygen cannot grow fast enough, so tumor cells become hypoxic,” Kim said. “The tumor 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 tumor cell, you can kill the cell, and that’s why pharmaceutical companies are interested in HIF-1 inhibitors.”
Kim said one reason for the study was to gain a better understanding of the links between obesity and cancer.
“There is a clear correlation between the two, but it’s not clear why obese people have a greater chance of developing certain cancers,” he said. “If you look at breast cancer, the glands that produce milk are completely surrounded by fat cells.
“Tumor tissue is hypoxic. Obese tissue is hypoxic. HIF-1 alpha is important in both conditions. I’m very motivated to study the interaction between breast cancer cells and fat cells.”
The research was funded by the National Institutes of Health, the American Diabetes Association and the Wellcome Trust.
Media Contact: Amanda Siegfried, UT Dallas, (972) 883-4335,
amanda.siegfried@utdallas.edu
or the Office of Media Relations, UT Dallas, (972) 883-2155, newscenter@utdallas.edu
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