Top Stories - Metabolic Signaling & Disease

Loss of orexin impairs brown fat function and promotes obesity in mice. The leaner mouse with functional brown fat (left) dissipates considerable amounts of energy as heat. The orexin-deficient mouse (right) lacks fat fuel and active mitochondria, thus storing energy as fat instead of burning it. (Image by Peter Allen, UCSB)
Fighting fat with fat

The fat we typically think of as body fat is called white fat. But there’s another type—known as...

New report shows the percent of the population considered obese has increased over the past two decades.
Why are we so fat?

A new report released by the Trust for America’s Health and the Robert Wood Johnson Foundation...

This calorimetry suite will be an important tool in the new Translational Research Institute facility, opening January 2012 (rendering by Flad Architects)
A different kind of dorm room

When the Florida Hospital/Sanford-Burnham Translational Research Institute for Metabolism and...

Dr. Steven Smith and Dr. Stephen Gardell leave their marks on the new TRI building.
Building translational...

The  Translational Research Institute for Metabolism and Diabetes (TRI), a collaboration between...

A “twisted” grand opening ceremony

by on March 29, 2012 at 3:35 pm | 0 Comments
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TRI grand opening speakers (from left to right): John Reed, Terry Owen, Dan Kelly, Steve Smith, Lars Houmann, Des Cummings, Don Jernigan

TRI grand opening speakers (from left to right): John Reed, Terry Owen, Dan Kelly, Steve Smith, Lars Houmann, Des Cummings, Don Jernigan

“My goal is to cure diabetes,” Steven Smith, M.D., scientific director of the Florida Hospital – Sanford-Burnham Translational Research Institute for Metabolism and Diabetes (TRI), said boldly at the opening ceremony of the TRI’s new state-of-the-art facility in downtown Orlando on March 27. “We believe that personalized medicine is our best shot at discovering cures for our most serious health problems like diabetes.”

The ceremony’s highlight was the unveiling of a spectacular nine-foot double-helix DNA structure that will be placed at the main entrance of the building, symbolizing the fundamental research being conducted at the TRI, as well as the synergies and collaborations the TRI represents. Selected board members and presenters each added one illuminated “bar,” representing a nucleotide, to the double helix.

“This is one of those rare times when the reality far exceeds the dream,” said John Reed, M.D., Ph.D., CEO of Sanford-Burnham. “The TRI is a wonderful opportunity for our organization, which will bring more and more to life our slogan From Research, the Power to Cure. We’re very excited about this opportunity to take our relationship with Florida Hospital to the next level.”

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Tasting fructose with the pancreas

by on February 6, 2012 at 12:01 pm | 1 comment
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Taste receptors (green) in pancreatic insulin-producing beta cells (red). Nuclei are shown in blue.

Taste receptors (green) in pancreatic insulin-producing beta cells (red). Nuclei are shown in blue.

Taste receptors on the tongue help us distinguish between safe food and food that’s spoiled or toxic. But taste receptors are now being found in other organs, too. In a study published online February 6 by the Proceedings of the National Academy of Sciences, Sanford-Burnham researchers discovered that beta cells in the pancreas use taste receptors to sense fructose, a type of sugar. According to the study, the beta cells respond to fructose by secreting insulin, a hormone that regulates the body’s response to dietary sugar.

“Before this study, fructose’s effect on insulin release was not appreciated. Fructose, and especially high-fructose corn syrup, is found in everything from sodas to cereals, but it remains to be seen whether dietary fructose is good or bad for beta cells and human metabolism,” said Björn Tyrberg, Ph.D., adjunct assistant professor in the Diabetes and Obesity Research Center at Sanford-Burnham’s Lake Nona campus in Orlando and senior author of the study.

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Sanford-Burnham experts talk about why Americans are fat

by on January 6, 2012 at 10:11 am | 0 Comments
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Fireworks over the Sydney Opera House

Fireworks over the Sydney Opera House

New Year’s resolutions and dieting seem to go hand-in-hand. Setting a personal goal to lose weight and exercise more may jump-start the New Year but “February frustration” can derail even the most determined. Scientists in Sanford-Burnham’s Diabetes and Obesity Research Center recently shared their expertise on the causes of weight gain and the metabolic challenges that make it so hard to keep off the extra pounds. Their insights on genetics, diet, metabolism and lifestyle were included in a four-part series called “What’s making Americans so fat?” that ran in the Orlando Sentinel beginning January 1. Medical reporter Marni Jameson spoke with national obesity experts to compile a list of 40 reasons for why 60 percent of U.S. adults are obese or overweight.

“It’s not gluttony, and it’s not lack of willpower,” says Dr. Steven Smith, scientific director of the Florida Hospital – Sanford-Burnham Translational Research Institute for Metabolism and Diabetes. “No scientist in the field will say the problem is strictly one of willpower,” he says. “It’s a result of the way our genes are interacting with an environment that is stacked against them.”

Here’s an excerpt of how the experts weighed in:

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All weight gain is not the same

by on January 4, 2012 at 2:09 pm | 0 Comments
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Steven R. Smith, M.D.

Steven R. Smith, M.D.

Malnutrition in its many forms remains a world-wide epidemic. In the United States, more than 60 percent of adults are classified as overweight or obese, whereas third-world nations are struggling with under-nutrition and insufficient food supplies. A new study provides scientific insight that may benefit development of public health policy to influence healthy weight gain.

The study, published January 4 in the Journal of the American Medical Association (JAMA), examines the impact of diets containing varying amounts of protein on weight gain, body composition, and energy expenditure. The research, led by Sanford-Burnham’s Steven R. Smith, M.D. and George Bray, M.D., Pennington Biomedical Research Center, found that total calories account for increases in body fat, while increasing the percent of dietary protein during overfeeding led to more lean body mass storage. This work appears to be the first to analyze the impact of dietary protein during overfeeding and provides guidance on dietary composition for healthy weight gain.

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How a few extra mice prompted a diabetes collaboration

by on December 5, 2011 at 8:59 am | 1 comment
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insulin-producing beta-cells in a mouse pancreas (Image courtesy of Edward Monosov)

insulin-producing beta-cells in a mouse pancreas (Image courtesy of Edward Monosov)

Dr. Barbara Ranscht and her lab are working to better understand how T-cadherin—a protein found on the surface of neurons, muscle, and other cells—regulates communication between cells during development and disease. The best way to go about this is to see what happens when the protein is missing. To do this, her lab developed a mouse model that lacks the protein altogether. Using these animals, Dr. Ranscht’s group has revealed that T-cadherin protects the stressed heart and is necessary for new blood vessel growth in injury models.

One day, Dr. Ranscht found herself discussing possible roles for T-cadherin in metabolism with Sanford-Burnham colleagues Dr. Björn Tyrberg and Dr. Fred Levine. The researchers especially wondered about T-cadherin’s role in the pancreas (Drs. Tyrberg’s and Levine’s organ of expertise).

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Obesity is not one condition: an interview with Dr. Steven Smith

by on October 21, 2011 at 9:28 am | 0 Comments
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Dr. Steven Smith, scientific director of the Translational Research Institute for Metabolism and Diabetes

Dr. Steven Smith, scientific director of the Translational Research Institute for Metabolism and Diabetes

Dr. Steven Smith is the scientific director of the Translational Research Institute for Metabolism and Diabetes, a collaboration between Sanford-Burnham and Florida Hospital. In a special presentation at Obesity 2011: The Obesity Society 29th Annual Scientific Meeting, held October 1-5 in Orlando, Fla., Dr. Smith discussed some up-and-coming anti-obesity agents, how they work, and how physicians might be able to put them to use. In his talk, he emphasized the importance of better understanding the fundamental cellular mechanisms that fuel obesity. With a greater appreciation for human metabolism, Dr. Smith explained, scientists will be able to develop new medications that focus less on appetite suppression (the target of most current weight loss drugs) and more on peripheral targets such as muscle or fat.

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Fighting fat with fat

by on October 4, 2011 at 9:00 am | 0 Comments
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Loss of orexin impairs brown fat function and promotes obesity in mice. The leaner mouse with functional brown fat (left) dissipates considerable amounts of energy as heat. The orexin-deficient mouse (right) lacks fat fuel and active mitochondria, thus storing energy as fat instead of burning it. (Image by Peter Allen, UCSB)

Loss of orexin impairs brown fat function and promotes obesity in mice. The leaner mouse with functional brown fat (left) dissipates considerable amounts of energy as heat. The orexin-deficient mouse (right) lacks fat fuel and active mitochondria, thus storing energy as fat instead of burning it. (Image by Peter Allen, UCSB)

The fat we typically think of as body fat is called white fat. But there’s another type—known as brown fat—that does more than just store fat. It burns fat. Scientists used to think that brown fat disappeared after infancy, but recent advances in imaging technology led to its rediscovery in adult humans. Because brown fat is so full of blood vessels and mitochondria—that’s what makes it brown—it’s very good at converting calories into energy, a process that malfunctions in obesity.

In a study published October 5 in Cell Metabolism, Sanford-Burnham researchers discovered that orexin, a hormone produced in the brain, activates calorie-burning brown fat in mice. Orexin deficiency is associated with obesity, suggesting that orexin supplementation could provide a new therapeutic approach for the treatment of obesity and other metabolic disorders. Most current weight loss drugs are aimed at reducing a person’s appetite. An orexin-based therapy would represent a new class of fat-fighting drugs—one that focuses on peripheral fat-burning tissue rather than the brain’s appetite control center.

“Our study provides a possible reason why some people are overweight or obese despite the fact that they don’t overeat—they might lack the orexin necessary to activate brown fat and increase energy expenditure,” explains Dr. Devanjan Sikder, senior author of the study and assistant professor in Sanford-Burnham’s Diabetes and Obesity Research Center, located in Orlando’s Medical City at Lake Nona.

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Glucose uptake relies on newly identified protein

by on September 7, 2011 at 10:50 am | 0 Comments
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Dr. Zhen Jiang

Dr. Zhen Jiang

All cells need glucose (sugar) to produce the energy they need to survive. High glucose levels in the bloodstream (such as occur after a meal), trigger the pancreas to produce insulin. In turn, muscle and fat cells respond to insulin by moving GLUT4, a glucose transporter, from intracellular storage out to the cell surface. There, GLUT4 can take up the glucose the cell needs from the bloodstream.

A team led by Dr. Zhen Jiang recently identified the protein—called CDP138—responsible for ensuring that GLUT4 is properly inserted in the cellular membrane. This finding provides a new understanding of glucose metabolism—an important finding considering that impaired insulin action and glucose metabolism contribute to the development of type 2 diabetes.

“This is a newly identified protein that’s involved in an important step in glucose uptake,” said Dr. Jiang, assistant professor in Sanford-Burnham’s Diabetes and Obesity Research Center, located in Orlando’s Medical City at Lake Nona.

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Taste receptors…in the gut?

by on August 1, 2011 at 5:58 am | 0 Comments
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Dr. Tae-Il Jeon

Let’s suppose your summer backpacking trip takes a disastrous turn and you’re lost, out of food, and desperate. You think those berries look OK so you swallow them down—even though they’re as bitter as anything you’ve eaten before. It’s not long before you regret ignoring your taste buds and suspect you’ve eaten something poisonous.

Unless you’re a molecular biologist, you’re probably not thinking at that moment about the biochemistry churning in your gut. But a cacophony of cellular signals is actually assembling a second line of defense to keep your digestive system from absorbing toxins into your bloodstream.

Of course, your body doesn’t always win. But Dr. Timothy Osborne’s lab at Sanford-Burnham’s Lake Nona campus has outlined how bitter taste-sensing receptors on enteroendocrine cells in the gut, called T2Rs, automatically kick into gear when confronted with bitter-tasting substances. You might disregard the taste buds in your mouth, but your digestive system knows better and tries to make up for your recklessness.

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Why are we so fat?

by on July 11, 2011 at 2:33 pm | 0 Comments
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New report shows the percent of the population considered obese has increased over the past two decades.

New report shows the percent of the population considered obese has increased over the past two decades.

A new report released by the Trust for America’s Health and the Robert Wood Johnson Foundation held dire news about the state of America’s obesity epidemic. The report, aptly named “F as in Fat: How Obesity Threatens America’s Future 2011,” revealed several eye-opening statistics. Here are a few:

• Twenty years ago, no state had an obesity rate above 15 percent. Now every state does.
• Today, 12 states have obesity rates over 30 percent. Four years ago, only one did.
•  Since 1995, diabetes rates (long associated with obesity) have doubled in eight states. Then, only four states had diabetes rates above six percent.  Now, 43 states have diabetes rates over seven percent, and 32 have rates above eight percent.

To understand why the nation’s weight problem has ballooned over the past two decades, obesity researchers are increasingly looking to our environment. The Orlando Sentinel interviewed obesity expert Dr. Steven R. Smith, Sanford-Burnham professor and scientific director of the Translational Research Institute for Metabolism and Diabetes (TRI), a collaboration between Florida Hospital and Sanford-Burnham. He said:

“Our genes haven’t changed that much in thousands of years, but we have seen a rapid change in the environment, and that has interacted with our genetic propensity toward obesity.”

Read more in How fat is America? New report gives nation an F.

Building translational research

by on May 26, 2011 at 3:25 pm | 1 comment
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Dr. Steven Smith and Dr. Stephen Gardell leave their marks on the new TRI building.

Dr. Steven Smith and Dr. Stephen Gardell sign the new TRI building.

The  Translational Research Institute for Metabolism and Diabetes (TRI), a collaboration between Sanford-Burnham and Florida Hospital, is one step closer to opening its research facility. The 54,000 square-foot building recently reached its final height, and a special ceremony was held during which researchers gathered to sign one of the interior columns. Construction to enclose the building will now begin.The TRI, which studies diabetes, obesity and the metabolic origins of cardiovascular disease, will  help bridge the gap between the scientist’s laboratory and the patient’s bedside. The TRI will unite scientists, clinicians and advanced technologies to spur translational research and rapidly create new, more effective treatments.

“We are witnessing an epidemic of obesity and diabetes in the United States,” said Dr. Steven R. Smith, scientific director of the TRI. “The main goal of the TRI is to generate new knowledge to improve lives through innovative research. By ‘topping out’ the TRI, we are one step closer towards developing Orlando as a medical destination.”

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A different kind of dorm room

by on May 19, 2011 at 5:00 am | 3 Comments
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This calorimetry suite will be an important tool in the new Translational Research Institute facility, opening January 2012 (rendering by Flad Architects)

Calorimetry suite in the new Translational Research Institute facility, due to open January 2012 (artist's rendering by Flad Architects)

Obesity negatively affects the entire body – no organ system is left untouched. It increases a person’s risk of type 2 diabetes, high blood pressure, depression, certain cancers and many other conditions. If the current trend of expanding waistlines continues, the U.S. Centers for Disease Control and Prevention estimates that at least one in five Americans will be diabetic by the year 2050.

The goal of the Translational Research Institute for Metabolism and Diabetes (TRI), a collaboration between Florida Hospital and Sanford-Burnham, is to alter this course by translating basic scientific discoveries in the laboratory to usable information and products that improve the diagnosis and treatment of human diseases – especially obesity and diabetes.

“At the moment, there is a big gap between what we know and what we want to know about human metabolism, obesity and diabetes. Our ultimate goal in translational research is to bridge that gap,” says Dr. Steven R. Smith, TRI’s scientific director and professor at Sanford-Burnham. “As basic researchers continue to unravel the molecular underpinnings of these diseases, TRI will be conducting proof-of-concept experiments to validate new drug targets and test new therapies for safety and efficacy.”

When it opens in January 2012, the TRI’s new three-story facility in Orlando, Florida will contain a research clinic, imaging technology, a biorepository for sample collection and storage, and several other resources for metabolic studies. But the facility’s highlight will be the calorimeter rooms – small dormitory-style rooms outfitted with a bed, treadmill and toilet. These whole-room calorimeters will allow the TRI staff to measure fat and carbohydrate oxidation and energy expenditure as a person goes about his or her normal life – sleeping, eating, walking, etc. As the patient exercises on the treadmill, scientists will be able to measure his or her oxygen consumption and calories burned without using invasive tubing or sensors. This approach will provide superior comfort – and therefore generate more accurate data – during exercise.

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Fat to the rescue

by on May 12, 2011 at 8:59 am | 0 Comments
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Timothy Osborne, Ph.D., professor and program director in Sanford-Burnham's Diabetes and Obesity Center, was recently appointed to the NIH’s Molecular and Cellular Endocrinology Study Section.

Dr. Timothy Osborne

When pathogenic invaders – bacteria, viruses, parasites – are detected by the body, things begin to happen in a hurry. Macrophages, a type of immune cell, are among the first to respond as the body starts mobilizing its defense. These are phagocytic cells, meaning they engulf microorganisms – digesting them, clearing them away and using them to prod other immune cells into action. Scientists have studied these processes for a long time. And yet there are still surprises.Dr. Timothy Osborne is interested in lipid (fat) metabolism – specifically the role of sterol regulatory element-binding proteins (SREBP). Members of this protein family sense changes in the environment and trigger the genes needed to adjust cellular fat and cholesterol levels. But it turns out that SREBPs do more than just respond to nutrient levels. Dr. Osborne’s group and their collaborators recently determined that one SREBP, called SREBP-1a, directs macrophage lipid metabolism in a way that helps these immune cells fight infection.

“When macrophages engage their prey, they proliferate to generate more macrophages and they expand and contract their membranes as they engulf the invading microbes. Both of these responses require new lipids to generate and renew cellular membranes,” explains Dr. Osborne, professor and director of the Metabolic Signaling and Disease Program in Lake Nona, Orlando.

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Science, will power and weight loss

by on April 15, 2011 at 2:36 pm | 0 Comments
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Dr. Sheila Collins

Dr. Sheila Collins

Dr. Sheila Collins studies fat. Specifically, as a professor at Sanford-Burnham’s Lake Nona campus she studies fat metabolism and other biochemical mechanisms that regulate body weight. However, prior to becoming a scientist, Dr. Collins was a fitness trainer.

On April 13, Dr. Collins combined her scientific and fitness expertise to answer questions about dieting, exercise and weight loss for a syndicated web chat sponsored by the Orlando Sentinel.

Dr. Collins offered some practical advice for maintaining motivation, including setting realistic goals and working out with a buddy.  Another tip was mixing up workouts to avoid boredom and stress new muscle groups. Maintaining a balance between calories consumed and fuel expenditure is a challenge rooted in our genetic history.

“The body is WIRED to store energy. We evolved in the cave days with little to eat – fruit maybe, an occasional successful hunt for meat or fish,” said Dr. Collins. “So when food was available, you had better well store it because it’s infrequent. Not able to gain weight or retain it…your genes are gone from the gene-pool. All the biochemistry of appetite and body fat metabolism and muscle tell us that this is true.”

Visit Can’t stick with your exercise program? to read the complete transcript.

Cellular feast or famine

by on April 5, 2011 at 9:38 am | 0 Comments
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Fat droplets (green) meet the autophagosome (red) and its arsenal of enzymes. (Image courtesy of the Osborne lab)

Autophagosome colocalization

Not all cholesterol is bad. Every cell requires it for growth – they either have to get cholesterol somewhere or they die. A sensor called sterol regulatory element-binding protein 2 (SREBP-2) monitors cellular cholesterol levels and responds to low levels by switching on genes that allow the cell to either 1) take up more from the bloodstream or 2) manufacture more from cholesterol building blocks inside the cell. Now, in a study published in the April 6 issue of the journal Cell Metabolism, Sanford-Burnham researchers and their collaborators uncover a third cholesterol source also controlled by SREBP-2: fat droplets stored inside the cell itself.

“We were searching the mouse liver cell genome to find DNA sequences specifically bound by SREBP-2,” explains Dr. Timothy Osborne, director of Sanford-Burnham’s Metabolic Signaling and Disease Program in Lake Nona, Orlando, and senior author of the study. “First we were surprised that SREBP-2 binds very close to the genes it regulates – that’s not typical. Second, we were surprised to find that in addition to genes related to fat metabolism and cholesterol balance, SREBP-2 also binds and activates genes responsible for autophagy.”

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