Obesity impairs the body's ability to use vitamin A appropriately and leads to deficiencies of the vitamin in major organs, according to new research conducted at Weill Cornell Medicine.

Vitamin A is critical to the proper functioning of many systems in the body, including vision, fetal development, reproduction, immune responses, and wound healing. Vitamin A deficiency impairs these functions, and is also implicated in increased risk of respiratory infections, diabetes, infertility, and delayed growth and bone development. Because of these wide-ranging health effects, people are advised to get adequate amounts of the vitamin either through diet (eggs, milk, meat, and some fruits and vegetables are sources) or supplementation. But the study, published Nov. 2 in Scientific Reports, shows that obesity interferes with the body's ability to use vitamin A, even with adequate intake.

"Our research shows that, even if an obese animal consumes normal amounts of vitamin A, they have deficiencies of the vitamin A in major organs," said first author Dr. Steven Trasino, a postdoctoral fellow in pharmacology at Weill Cornell Medicine. "Obesity is categorized as a state of malnutrition, typically associated with consumption of too many calories and poor intake of essential nutrients. Our data expand on that definition by showing that obesity plays a role in the body's ability to use this essential nutrient properly."

Dr. Lorraine Gudas

The researchers fed mice a diet that had normal vitamin A levels, similar to the recommendations for human vitamin A intake.

"We found that normal-weight mice are healthy on that diet, but obese mice show severe vitamin A deficiencies in their livers, kidneys and pancreas," said senior author Dr. Lorraine Gudas, chair of the Department of Pharmacology and the Revlon Pharmaceutical Professor of Pharmacology and Toxicology at Weill Cornell Medicine.

When the obese mice lost weight, their vitamin A levels returned to normal. "Something about the state of obesity is impairing the body's ability to use vitamin A correctly," Dr. Gudas said.

What was particularly remarkable to the research team, which also included Dr. Xiao-Han Tang, an assistant research professor in pharmacology, and Dr. Jose Jessurun, a professor in pathology, was that the blood levels of vitamin A in all of the mice, including the obese mice, were normal. The deficiency was only noted when the researchers took tissue samples from various organs in the mice. "We call this ‘silent vitamin A deficiency' because it would not be picked up by a standard blood test for the vitamin," Dr. Trasino said.

The new findings suggest that obesity in humans is also associated with low vitamin A levels in many organs. Such deficiencies would have corresponding health effects.

"We know that obesity is associated with many illnesses, such as poor immune response and diabetes," Dr. Gudas said. "What we don't know is why. This gives us more information for understanding how the two go together, but many puzzles remain to be solved before we fully understand why obesity leads to less vitamin A in major organs of the body."

Investigators have long sought the answer to a vexing question: What are the biological mechanisms involved in the development of type 2 diabetes? A recent study from Weill Cornell Medical College researchers suggests that the culprit may be a lack of vitamin A, which helps give rise to the cells, called beta cells, in the pancreas that produce the blood sugar-regulating hormone insulin.

The researchers found in mice models that a lack of vitamin A spurred the death of beta cells, stunting the production of insulin, which is tasked with metabolizing sugars that come from food. These findings, published Dec. 1 in The Journal of Biological Chemistry, may offer new clues into the cause of type 2 diabetes, which is characterized by insulin-resistance, and in advanced cases, inadequate numbers of insulin-producing beta cells.

When the investigators removed vitamin A from the rodents’ diet, they found that the mice began to experience massive losses of beta cells, which resulted in drops in insulin and a big increase in blood glucose. The researchers then reintroduced vitamin A into the animals’ diet and found that the number of beta cells stabilized, insulin production was higher and that blood glucose returned to normal levels.

Because patients with type 1 diabetes and those with advanced type 2 diabetes experience a loss of beta cells, there is a strong interest in developing new treatments that either preserve or replenish them. “From a therapeutic point of view, our research is a very important contribution because there are no drugs available to do this,” said first author Dr. Steven Trasino, a postdoctoral associate in the Department of Pharmacology.

Scientists have understood that vitamin A is essential for the production of insulin-producing cells during fetal development, but whether that role continued into adulthood was not known. The researchers sought to answer that question by using both normal mice and mice that had a genetically impaired ability to store vitamin A.

"While there are thousands of publications on diabetes, there hasn’t been much research on the effects of removing vitamin A from the diets of animals, acting as a model for human disease," said senior author Dr. Lorraine Gudas, chairman of the Department of Pharmacology and the Revlon Pharmaceutical Professor of Pharmacology and Toxicology at Weill Cornell. "How the removal of vitamin A causes the death of the beta cells that make insulin in the pancreas is an important question we want to answer. These beta cells in the pancreas are exquisitely sensitive to the dietary removal of vitamin A. No one has found that before."

These early-stage findings raise the question of whether vitamin A deficiency is involved in humans and animals with type 2 diabetes, either through inadequate diet or through a metabolic defect. They also spark questions about whether a synthetic analog of vitamin A could reverse the disease’s effects.

"Our study sets the platform to take these studies further into pre-clinical and clinical settings," Dr. Trasino said.

Researchers at Weill Cornell Medical College have discovered what they believe may be the first effective drug therapy to prevent tongue cancer, one of the world’s most common cancers. The finding is reported in the June 2 issue of PNAS.

Currently, tongue cancer is treated with radiation and surgery, which can be very disfiguring. Because the cancer is often discovered at later stages — such as when a patient has difficulty swallowing — the five-year survival rates are less than 50 percent.

"Clearly, we need a treatment that can work to help prevent development of the cancer in people at risk, reducing the need for radical surgery," said Dr. Lorraine Gudas, chair of the Department of Pharmacology at Weill Cornell.

"The two drugs we tested showed remarkable benefit in our animal studies and our animal model mirrors development of human tongue cancer. While we have much research yet to do, this is a very exciting discovery," she says.

One of the drugs, Bexarotene, is approved by the FDA to treat T-cell lymphoma. The other, CD1530, is a synthetic derivative of vitamin A, similar to a cousin vitamin A derivative that is currently used as part of a combination chemotherapy for a blood cancer, acute promyelocytic leukemia.

"This is the first time this combination of agents has been used in a solid cancer, and given the impressive results we have seen in this preclinical study, we plan to test this combination in other solid tumors," Dr. Gudas says.

In the study, mice were given a carcinogen that causes the development of tongue cancer. Mice treated with the two drugs developed 75 percent fewer tumors on average than did untreated mice. "We have never seen such a dramatic reduction in cancer that was destined to develop," Dr. Gudas says.

If clinical studies prove successful, individuals at risk for developing tongue cancer — those who smoke and drink alcohol heavily, have a family history of the disease, or develop white "leukoplakia" lesions in the mouth that can signal future development of the cancer — could be treated preventatively, Dr. Gudas says.

She says that there may be a link between the blood cancers treated by vitamin A derivatives and the tongue cancer she has been studying. In both cases their growth likely depends on cancer stem cells — and Bexarotene and CD1530 may modify specific properties of these stem cells.

"This synergistic inhibition may also work on some of the solid cancers in which cancer stem cells play a pivotal role. If the drugs work to prevent tongue cancer, they may also work to treat cancer that has already developed," she adds, "and we are currently doing those studies.

"For the first time, we may be able to develop ways not just to treat, but to prevent, tongue cancer, and that is a remarkable development in this disease."

Other authors on the study are Drs. Xiao-Han Tang, Alison M. Urvalek, Kwame Osei-Sarfo, Tuo Zhang, and Theresa Scognamiglio, all from Weill Cornell. The research was supported by the National Institute of Dental and Craniofacial Research and the National Institute on Alcohol Abuse and Alcoholism.