Novel role for protein linked to obesity and development of type 2 diabetes identified

Dec. 17, 2012 — Researchers at UT Southwestern Medical Center have taken another step toward better understanding the metabolic functions of obesity and its connection to type 2 diabetes.

Dr. Philipp Scherer, Director of the Touchstone Center for Diabetes Research at UT Southwestern, led a group of researchers in a recent multicenter study published in Nature Medicine that successfully identified ways to manipulate the protein mitoNEET. This is the first time the protein has been effectively altered to expand fat tissue in a way that allows subjects -- in this case, mice -- to remain metabolically healthy.

MitoNEET is a key component of a cell's mitochondrion, which serves as the cell's energy powerhouse. When the levels of MitoNEET protein were elevated inside the fat cells of rodents, more fat was stored in the adipose tissue, thereby keeping toxic lipids away from other types of cells. This sequestration resulted in extremely obese yet metabolically healthy mice that displayed no signs of type 2 diabetes. In contrast, when MitoNEET levels were decreased, the mice became lean but unhealthy, and developed pre-diabetic conditions such as failure to metabolize glucose properly.

"The manipulation of mitochondrial activity in fat tissue is a very powerful approach to control how much excess energy we store in our bodies and where we store it. We have heretofore underestimated the importance of mitochondrial pathways in our fat cells and their influence on how we manage our weight," said Dr. Scherer, senior author of the three-year study and Professor of Internal Medicine and Cell Biology at UTSW.

The body stores fat in the white adipose tissue, and, ideally, individuals burn any excess calories through exercise and a healthy diet. The current research findings suggest that manipulating components of mitochondria in fat cells can be an effective way to funnel excess calories into "good" locations. This storage then thwarts their negative effect on other internal organs like the liver in which excess fat accumulation is toxic.

The obese mice in this study weighed 120 to 130 grams (4.23 to 4.58 ounces), whereas a normal adult mouse weighs 25 to 30 grams (.88 to 1.06 ounces). This difference is the equivalent of a 150-pound person increasing his or her weight to 700 pounds.

The researchers were careful to clarify that the findings were not meant to encourage obesity, even though the obese mice were considered metabolically healthy. The study instead provides a clearer understanding of the mitochondrion's importance to the metabolic dysfunction -- that is characteristic of obese patients and those with type 2 diabetes.

"These results taught us a great deal about how fat cells sense, store, and burn energy," said Dr. Christine Kusminski, a postdoctoral researcher in Internal Medicine who served as the study's first author. "By learning more about the underlying mechanisms, we hope to develop ways to target these pathways for future drug development."

The researchers now hope to translate these findings into a clinical setting. The staff of the Touchstone Center is devoted to the study of cells and tissues that either contribute to or are affected by diabetes and related diseases, including the physiology of adipose tissue.

Other UT Southwestern researchers involved in the study were Dr. William L. Holland, Instructor in Internal Medicine; Dr. Kai Sun, Assistant Instructor in Internal Medicine; Dr. Jiyoung Park, Assistant Instructor in Internal Medicine; and Stephen B. Spurgin, a medical student. Scientists from the Albert Einstein College of Medicine, the University of Utah School of Medicine, and Merck Research Laboratories also contributed.

The investigation was funded by support from the National Institutes of Health, the American Heart Association, and fellowships from the Juvenile Diabetes Research Foundation and the Department of Defense.

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Christine M Kusminski, William L Holland, Kai Sun, Jiyoung Park, Stephen B Spurgin, Ying Lin, G Roger Askew, Judith A Simcox, Don A McClain, Cai Li, Philipp E Scherer. MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity. Nature Medicine, 2012; 18 (10): 1539 DOI: 10.1038/nm.2899

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Muscle-loss study sheds new light on ways to prevent muscle loss, obesity and diabetes

Dec. 19, 2012 — A research study from Nanyang Technological University (NTU) has yielded important breakthroughs on how the body loses muscle, paving the way for new treatments for aging, obesity and diabetes.

The study found that by inhibiting a particular molecule produced naturally in the body, muscle loss due to aging or illnesses can be prevented. Blocking the same molecule will also trigger the body to go into a 'fat-burning mode' which will fight obesity and also treat the common form of diabetes.

The exciting discoveries have led NTU scientists to embark on joint clinical research with local hospitals to further validate their findings which were previously carried out on animals.

Their research on how humans lose muscle during extreme conditions such as chronic diseases or starvation was published last month in Cell Metabolism.

Associate Professor Ravi Kambadur and his team from the NTU School of Biological Sciences found that a protein called Myostatin, which controls muscle cell growth, is responsible for initiating muscle loss.

When excess levels of Myostatin is bound to a muscle cell, it induces heavy loss of mitochondria (the part of the cell responsible for energy production that keeps a cell alive), which in turn causes the muscle cell to waste or lose muscle tissue (atrophy) due to the 'lack of energy'.

Under normal healthy conditions, small loss of Mitochondria is needed for the regeneration of new cells, but when a patient is suffering from chronic diseases or is bedridden (and muscles are not used often), this process is disrupted due to high levels of myostatin which results in increased mitochondrial loss and muscle atrophy.

Prof Kambadur said recent studies have shown that extreme muscle wasting can lead to death.

"For example, about 30 per cent of cancer patients die not because of cancer, but because of muscle loss also known as cachexia," said Prof Kambadur.

"When someone is suffering from a chronic disease and doesn't eat enough, the body starts to generate energy by breaking down muscle proteins and that is the reason we see a lot of muscle wasting under chronic disease conditions."

"Over the years, our research has revealed that this type of muscle wasting is initiated by excess levels of myostatin in the body. If we block myostatin from binding to cells, then muscles won't waste away and we can then mitigate the effects of aging and chronic diseases."

Apart from regulating the growth and loss of muscle, myostatin also regulates whether the body will burn fat or carbohydrates during fasting and meal times.

Blocking myostatin keeps the body in "fat-burning mode" and promotes muscle growth at the same time -- which could potentially make obesity a thing of the past.

Because obesity is one of the main causes of the most common form of diabetes, Type 2 diabetes, blocking myostatin could also treat diabetes. In the US, 90 to 95 per cent of diabetes cases are Type 2, as reported by the Centers for Disease Control and Prevention.

According to Singapore's Health Promotion Board, diabetes is among the top ten causes of death locally. In 2010, it was reported by Ministry of Health that 11.3 per cent of the Singaporean adults aged 18 to 69 years are affected by diabetes while 10.8 percent were obese.

"In near future, myostatin blockers could increase fat utilisation in the body and give you the benefits of exercise, without actually doing intense physical activity," Prof Kambadur explained.

"This would be a good alternative treatment for people who are unable to exercise, such as those who are bed-ridden or are in cancer treatment, who are most at risk of massive muscle loss."

Prof Kambadur added that while blocking myostatin sounds like a good idea, there is a need to study the long term effects, as the molecule is needed to regulate cell growth for normal body operation.

Other studies on myostatin conducted by Prof Kambadur's group have also yielded interesting results.

For instance, people who exercise regularly have been found to have lower levels of myostatin as compared to those who do not. Studies have also found that older people have more myostatin and this can explain why when one ages, muscles become weaker.

Prof Kambadur's research projects on myostatin are funded by Ministry of Education, Biomedical Research Council and the National Research Foundation's (NRF) Competitive Research Programme (CRP). The research on myostatin is conducted in collaboration with Associate Professor Mridula Sharma from the National University of Singapore. The husband-and-wife team have collaborated on various research projects in the area of skeletal muscle for many years.

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Sudarsanareddy Lokireddy, Isuru W. Wijesoma, Serena Teng, Sabeera Bonala, Peter D. Gluckman, Craig McFarlane, Mridula Sharma, Ravi Kambadur. The Ubiquitin Ligase Mul1 Induces Mitophagy in Skeletal Muscle in Response to Muscle-Wasting Stimuli. Cell Metabolism, 2012; 16 (5): 613 DOI: 10.1016/j.cmet.2012.10.005

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Medical schools fall short on teaching students about obesity, study finds

Oct. 31, 2012 — It’s no secret that obesity is a major problem in America. More than one-third of adults and one-sixth of children are obese and it is one of the leading causes of preventable death. The costs associated with obesity are estimated at $99 million annually, comparable to the economic toll of cigarette smoking.

Despite all this, few U.S. medical schools are providing adequate, effective training on how to address weight issues in obese patients, according to researchers at Wake Forest Baptist Medical Center.

“Medical students are surrounded by the same environment that everyone is in this country, a culture of idealized images of physical attractiveness in which thin is good and fat is bad,” said Mara Vitolins, Dr.P.H., R.D., professor of public health sciences at Wake Forest Baptist and lead author of the study that was published in the July issue of the journal Teaching and Learning in Medicine. “We just aren’t doing a good enough job of teaching our students evidence-based methods of intervention and care for our obese patients.”

The purpose of the study was to provide a systematic review of the literature examining obesity-related educational programs. In an effort to gauge the amount and effectiveness of medical school training related to obesity, the researchers reviewed literature from the National Institutes of Health’s PubMed database from 1966 through 2010.

Of the 208 articles found, only five addressed ways to increase medical students’ knowledge, attitudes and skills regarding overweight and obesity treatment. Only two of those five addressed medical student bias toward obese patients, and just one dealt with attempting to change this bias.

The lack of published studies in this area is consistent with physicians’ reports of inadequate training in managing their patients’ weight, the researchers reported.
“Our study shows clear gaps in medical education regarding obesity,” Vitolins said. “Providing medical students with skills to address obesity is necessary to impact the national epidemic of obesity to decrease mortality and morbidity from chronic diseases related to excess weight.

“Our findings also highlight the need for medical school curricula to mitigate negative attitudes toward these patients, attitudes that may affect the care delivered.”

In addition, the researchers did not find any study that included obesity education over all four years of medical school, including the basic science and clinical years. Although some medical schools require their students to teach prevention, including nutrition and weight management in community clinics, this approach still doesn’t cover the full range of obesity counseling knowledge available.

“Utilizing multiple types of intervention approaches – lectures, standardized patient encounters and hands-on training – during multiple time points in the medical school curriculum is needed,” Vitolins added. “Such training should be based on tried and true educational approaches and include education in bias and stereotyping, as well as specifically addressing obesity bias.”

To help address the lack of obesity-related education in medical schools, the Wake Forest Baptist team has recently published a downloadable teaching and learning program for nutrition, exercise and weight management in MedEdPortal. According to Vitolins, the research team was committed to sharing their educational modules with others to improve nationwide efforts to reduce obesity.

Co-authors of the study are Sonia Crandall, Ph.D., David Miller, M.D., Eddie Ip, Ph.D., Gail Marion, Ph.D., and John Spangler, M.D., of Wake Forest Baptist.
The study was supported by the National Cancer Institute grant R25CA117887-01.

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Mara Z. Vitolins, Sonia Crandall, David Miller, Eddie Ip, Gail Marion, John G. Spangler. Obesity Educational Interventions in U.S. Medical Schools: A Systematic Review and Identified Gaps. Teaching and Learning in Medicine, 2012; 24 (3): 267 DOI: 10.1080/10401334.2012.692286

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