TAG: "Obesity"

Researchers find novel signaling pathway involved in appetite control


Study could lead to new treatments for obesity.

By Tim Stephens, UC Santa Cruz

A new study has revealed important details of a molecular signaling system in the brain that is involved in the control of body weight and metabolism. The study, published today (Jan. 19) in Nature, provides a new understanding of the melanocortin pathway and could lead to new treatments for obesity.

Co-author Glenn Millhauser, a distinguished professor of chemistry and biochemistry at UC Santa Cruz, said the findings are very exciting and have broad biomedical implications. “We are getting to the real molecular features of what’s controlling this important signaling system in the brain,” Millhauser said.

The study, led by researchers at Vanderbilt University, focused on a receptor embedded in the membranes of nerve cells called the melanocortin-4 receptor, or MC4R. It belongs to a class of receptors known as G-protein coupled receptors (GPCRs), which typically act like on-off switches, signaling over short time frames, according to Roger Cone, who led the study at Vanderbilt.

“This finding identifies a molecular mechanism for converting an on-off switch into a rheostat,” Cone said. “This could help explain slow, sustained biological processes that also are mediated by GPCRs, such as tanning or weight regain after dieting.”

Millhauser’s lab has done extensive research on proteins that bind to the MC4R receptor, such as agouti-related protein (AgRP). AgRP is a potent appetite stimulant. Its role in regulating energy balance is to suppress metabolism and increase feeding when the body needs to put on weight and store energy, Millhauser said. His lab has developed modified versions of the AgRP protein that alter its activity. In the new study, the modified proteins from Millhauser’s lab helped researchers identify a previously unsuspected effect of AgRP.

Millhauser’s previous studies have shown that a single dose of AgRP given to laboratory animals can stimulate daily food intake for up to 10 days. This observation didn’t fit with the traditional “on-off” signaling model for the receptor it binds to, MC4R. G-protein coupled receptors can only take so much stimulation before they shut down, and this phenomenon, called desensitization, often happens rapidly.

Cone’s lab discovered a companion protein — a potassium channel in the membrane called Kir7.1 — that couples to the MC4R receptor and acts independently from G-protein signaling. The researchers found that AgRP induces MC4R to open the potassium channel, which “hyperpolarizes” and inhibits neurons that are involved in blocking appetite.

“Moreover, with modifications to AgRP discovered previously by our lab, we can increase or decrease this coupling of the receptor to the potassium channel,” Millhauser said. “These concepts could ultimately lead to new generations of therapeutics for treating metabolic disorders, including obesity, anorexia, and cachexia, the wasting condition that often occurs in cancer treatment.”

Co-author Rafael Palomino, a graduate student and NIH Fellow in Millhauser’s lab, did the protein synthesis and purification work for the study. The first author is Masoud Ghamari-Langroudi at Vanderbilt. Other contributors include Jerod Denton and Robert Matthews at Vanderbilt and Helen Cox at King’s College, London. This research was supported by the National Institutes of Health.

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Cooler temperatures may trigger body’s energy-burning brown fat


Study sheds light on type of fat that has drawn increased attention from researchers.

By Sarah Yang, UC Berkeley

Those who overindulged during the holidays may want to get a shot of cold air to kick-start some extra fat-burning activity for the new year.

Researchers at UC Berkeley found that exposure to cold temperatures increases levels of a newly discovered protein that is critical for the formation of brown fat, the type of fat in our bodies that generates heat. With extended exposure to chilly air, the protein, called transcription factor Zfp516, also helps the more abundant white fat in our bodies – the kind that stores excess energy – become more similar to brown fat in its ability to burn energy.

The researchers found that mice with boosted levels of the Zfp516 protein gained 30 percent less weight than control mice when both groups were fed a high-fat diet.

The new findings, published online today in the journal Molecular Cell, shed light on a type of fat that has drawn increased attention from researchers in the past five years.

“Knowing which proteins regulate brown fat is significant because brown fat is not only important for thermogenesis, but there is evidence that brown fat may also affect metabolism and insulin resistance,” said principal investigator Hei Sook Sul, UC Berkeley professor of nutritional science and toxicology. “If you can somehow increase levels of this protein through drugs, you could have more brown fat, and could possibly lose more weight even if eating the same amount of food.”

White fat, brown fat, good fat, bad fat

Unlike white fat, which stores excess energy, brown fat burns energy to keep us warm. Brown fat gets its hue from relatively high levels of mitochondria, the cell’s power station. In humans, brown fat was thought to be present only in infants, but stores of it were recently discovered in adults around such vital areas as the heart, brain, neck and spinal cord.

The study authors said that because we generally live our lives in controlled, ambient temperatures, our need for brown fat has decreased over time.

“It has been noted that outdoor workers in northern Finland who are exposed to cold temperature have a significant amount of brown fat when compared to same-aged indoor workers, but overall, the percentage of brown fat in adults is small compared to white fat,” said Sul. “We also know that obese people have lower levels of brown fat.”

The UC Berkeley team discovered that the Zfp516 protein activates uncoupling protein 1 (UCP1), found only in the mitochondria of brown fat and involved in the generation of heat.

“The amount of UCP1 produced by brown-like fat cells will be lower than that of classical brown fat, but since 90 percent of the fat in our bodies consists of white fat, finding a way to make that tissue more brown-like could have a significant impact,” said Sul.

Making white fat into brown-like fat

When the researchers disabled the gene for Zfp516 in mouse embryos, the embryos did not develop any brown fat. In another experiment, researchers found that mice with higher levels of Zfp516 protein were able to convert more white fat tissue into brown-like fat when exposed to cold air. After four hours in a room kept at 4 degrees Celsius (39.2 degrees Fahrenheit), the body temperature of the mice with the overexpressed Zfp516 protein was, on average, 1 degree Celsius (1.8 degrees Fahrenheit) higher than a control group of mice with normal levels of the protein.

“That difference in body temperature is huge for the mice,” said study co-lead author Jon Dempersmier, a Ph.D. student in nutritional science and toxicology. “The brown-like fat, the kind converted from white fat tissue, is inducible by cold. Classical brown fat, the kind in babies and prevalent in rodents, always has a ton of UCP1 and mitochondria in order to perform thermogenesis.”

The mice with overexpressed Zfp516 protein also gained less weight than their unaltered littermates after both groups ate a high-fat diet for four weeks.

“This suggests that the transgenic mice were protected from diet-induced obesity,” said Sul. “This protein could become an important target for research into the treatment and prevention of obesity and obesity-related diseases.”

The study authors noted that there’s an active area of research in the relationship between brown fat and diabetes. Higher levels of brown fat are associated with greater sensitivity to insulin. Resistance to insulin leads to Type 2 diabetes.

The researchers noted that there are many steps between discovering the protein in mice and determining whether it can be useful in humans, but they said that having a clear target is an important development.

“Brown fat is active, using up calories to keep the body warm,” said Dempersmier. “It’ll burn fat, it’ll burn glucose. So the idea is that if we can harness this, we can try to use this in therapy for weight loss and for diabetes.”

The National Institutes of Health helped support this research.

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Immune cells in brain respond to fat in diet, causing mice to eat


UCSF study indicates that microglia may play key role in shaping the brain’s response to diet.

By Jeffrey Norris, UC San Francisco

Immune cells perform a previously unsuspected role in the brain that may contribute to obesity, according to a new study by UC San Francisco researchers.

When the researchers fed mice a diet high in saturated milk fats, microglia, a type of immune cell, underwent a population explosion in the brain region called the hypothalamus, which is responsible for feeding behavior.

The researchers used an experimental drug and, alternatively, a genetic approach to knock out these microglia, and both strategies resulted in a complete loss of microglia-driven inflammation in the hypothalamus. Remarkably, doing so also resulted in the mice eating less food each day than did their untreated counterparts, without any apparent ill effects.

Furthermore, removing microglia from mice only reduced food intake when the content of saturated fat from milk in their diets was high. It had no effect on mice fed a low-fat diet or a diet high in other types of fat, including olive oil or coconut oil.

UCSF postdoctoral fellow Martin Valdearcos Contreras, Ph.D., first author on the paper, published in the Dec. 11 issue of Cell Reports, discovered that when mice consumed large amounts of saturated fats, the fat entered their brains and accumulated in the hypothalamus.

According to the senior scientist for the study, Suneil Koliwad, M.D., Ph.D., an assistant professor of medicine at the UCSF Diabetes Center, the microglia sense the saturated fat and send instructions to brain circuits in the hypothalamus. These instructions are important drivers of food intake, he said.

Microglia are primarily known for causing inflammation in the brain in response to infection or injury, but the new study indicates that they also play a key role in shaping the brain’s response to diet, according to Koliwad.

Outside the brain — in fat tissue, the liver, and muscles — other immune cells, called macrophages, trigger inflammation in response to “diet-induced obesity,” Koliwad said. This inflammation is implicated in triggering insulin resistance, a late stage event on the road to type 2 diabetes.

However, overeating causes microglia to accumulate much more quickly in the hypothalamus than macrophages accumulate in peripheral tissues, Koliwad said. But until now, the effects of this microglial build-up were unknown.

“As opposed to classically defined inflammation, in which immune cells build up in tissues where environmental insults have created disarray, microglial activation in the brain may be a part of a normal physiological process to remodel brain function in response to changes in the composition of food intake,” Koliwad said.

“When the intake of saturated fats is chronically high, this microglial sensory network may be hijacked, and this has the potential to mediate increased food consumption and promote more rapid weight gain.

“Targeting microglia may therefore be a novel way to control food intake in the face of consumption of a fat-rich diet, something that is quite common in today’s world,” he said.

The research was funded by the National Institutes of Health and by the UCSF Diabetes Family Fund.

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Obese children’s brains are more responsive to sugar


UC San Diego study detects brain differences in children as young as 8.

By Christina Johnson, UC San Diego

A new study led by researchers at the UC San Diego School of Medicine finds that the brains of obese children literally light up differently when tasting sugar.

Published online in International Journal of Obesity, the study does not show a causal relationship between sugar hypersensitivity and overeating, but it does support the idea that the growing number of America’s obese youth may have a heightened psychological reward response to food.

This elevated sense of “food reward” – which involves being motivated by food and deriving a good feeling from it – could mean some children have brain circuitries that predispose them to crave more sugar throughout life.

“The take-home message is that obese children, compared to healthy weight children, have enhanced responses in their brain to sugar,” said first author Kerri Boutelle, Ph.D., professor in the Department of Psychiatry and founder of the university’s Center for Healthy Eating and Activity Research (CHEAR).

“That we can detect these brain differences in children as young as 8 years old is the most remarkable and clinically significant part of the study,” she said.

For the study, the UC San Diego team scanned the brains of 23 children, ranging in age from 8 to 12, while they tasted one-fifth of a teaspoon of water mixed with sucrose (table sugar). The children were directed to swirl the sugar-water mix in the mouth with their eyes closed, while focusing on its taste.

Ten of the children were obese and 13 had healthy weights, as classified by their body mass indices. All had been pre-screened for factors that could confound the results. For example, they were all right-handed and none suffered from psychiatric disorders, such as anxiety or ADHD. They also all liked the taste of sucrose.

The brain images showed that obese children had heightened activity in the insular cortex and amygdala, regions of the brain involved in perception, emotion, awareness, taste, motivation and reward.

Notably, the obese children did not show any heightened neuronal activity in a third area of the brain – the striatum – that is also part of the response-reward circuitry and whose activity has, in other studies, been associated with obesity in adults.

The striatum, however, does not develop fully until adolescence. The researchers said one of the interesting aspects of the study is that the brain scans may be documenting, for the first time, the early development of the food reward circuitry in pre-adolescents.

“Any obesity expert will tell you that losing weight is hard and that the battle has to be won on the prevention side,” said Boutelle, who is also a clinical psychologist. “The study is a wake-up call that prevention has to start very early because some children may be born with a hypersensitivity to food rewards or they may be able to learn a relationship between food and feeling better faster than other children.”

According to studies, children who are obese have an 80 to 90 percent chance of growing up to become obese adults. Currently about one in three children in the U.S. is overweight or obese.

To learn more CHEAR and its weight management programs for children, call (855) 827-3498 or email chear@ucsd.edu.

Co-authors include Christina Wierenga, UC San Diego and Veterans Affairs San Diego Healthcare System; Amanda Bischoff-Grethe, Andrew James Melrose and Emily Grenesko-Stevens, UC San Diego; and Martin Paulus, Laureate Institute for Brain Research, Tulsa, Oklahoma.

Funding for the study was provided, in part, by National Institutes of Health (grants R01DK094475, R01 DK075861, K02HL112042, MH046001, MH042984, MH066122, MH001894 and MH092793).

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UCSF sugar science initiative launched

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Cloudy water, even if it is safe, affects rural immigrants’ health


UC Davis researchers examine connection between water quality, childhood obesity.

Cloudy tap water may have a greater effect for California’s rural immigrants than merely leaving behind a bad taste, according to a new policy brief released by the Center for Poverty Research at the University of California, Davis.

Researchers looked at the connection between water quality and childhood obesity in two poor immigrant communities in California’s Central Valley — San Joaquin and Firebaugh. Poor-quality tap water, or even a perception that the water is bad, combined with environmental factors such as lack of access to healthy foods and nutrition education, likely contribute to health disparities in these communities, the study finds.

“If the tap water that comes out looks dirty or has a poor taste, they’re not going to have a lot more confidence in the drinking system here,” said Lucia Kaiser, a UC Cooperative Extension specialist in the Department of Nutrition at UC Davis and the study’s co-principal investigator. “The immigrant populations in these communities come from Mexico, where they may have experienced unsafe drinking water in rural areas,” she said.

Kaiser interviewed 27 mothers from these communities after giving a class on the health effects of sugar-sweetened beverages. Most of the women reported relying on purchased and, to a lesser extent, home-filtered water for drinking and cooking. Kaiser said that the additional cost represents an extra burden on these low-income families.

“In these communities, more than a third can’t afford to put enough food on their table, and now they have to buy drinking water, too. Every expense really matters,” said Kaiser.

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Making an ‘IMPACT’ on childhood obesity


UC San Diego, San Diego Unified School District partner to get kids active.

UC San Diego student-athlete Kyra Scott shares the pull-up bar with a student from Toler Elementary. (Photo by Erika Johnson, UC San Diego)

By Jade Griffin and Gabriella Clark, UC San Diego

“I like to get out here and sweat,” said Dalton, an elementary student at Toler Elementary, as he began a series of stretches and exercises led by UC San Diego student-athletes volunteering their time at his elementary school in Clairemont.

Dalton and his classmates are benefiting from a program called IMPACT (Increasing Movement and Physical Activity in Class Time), which is designed to keep local elementary students moving despite the lack of recess and physical education classes in some schools, particularly in underserved areas of San Diego.

IMPACT was established by the San Diego Unified School District in partnership with UC San Diego Athletics and the UC San Diego School of Medicine Center for Community Health to promote healthy activity and battle the growing national epidemic of obesity among children. According to the Centers for Disease Control and Prevention, in 2012, more than one third of children and adolescents in the U.S. were overweight or obese.

Each week as part of IMPACT, UC San Diego student-athletes set up a series of circuits, including jump ropes, hula-hoops, monkey bars, stretching and more. The student-athletes assist and cheer on the students as they rotate through the stations for approximately 20 minutes. Each of the activities are designed to be fun for the students, while getting them moving and raising their heart rates — a key intention of the program.

“The IMPACT program was created to help students reach fitness standards at schools that otherwise would not have funding to maintain certain physical education programs,” said Kate McDevitt, senior manager of School Wellness Programs at UC San Diego’s Center for Community Health.

Many of the UC San Diego student-athletes who participate are members of the Triton Athletes’ Council (TAC), an organization of students from the university’s 23 intercollegiate teams who initiate campus and community service efforts. The IMPACT program was an ideal match for Triton Athletes’ because of the group’s focus on making a positive impact on the community.

Scott Acton, a member of the Triton Athletes’ Council who is also on the track and field and cross country teams, has helped coordinate UC San Diego Athletics’ role in the program this year. “It is great to see the elementary students get out and be active,” said Acton, a structural engineering major. “Word is spreading among student-athletes about what a great program this is, so more and more from UC San Diego are getting involved.”

“Having educated and physically fit athletes attend these sessions shows the children that with hard work and dedication, they can reach any goal they wish to attain in athletics, but the first step is being physically active,” said Lynn Barnes-Wallace, physical education resource teacher at San Diego Unified School District and creator of IMPACT. “The students from UC San Diego really get involved with the program and motivate the kids even more.”

IMPACT began at Edison Elementary in City Heights last spring. The program was such a success—as evidenced by the smiles and squeals of delight from the students—that it was expanded to Toler and will likely be implemented at other elementary schools in the future.

According to Peggy Lewis, principal of Toler Elementary, the program is a hit with her young students. “The kids love it,” said Lewis. “They need activity during the day. We have already seen improved student focus and concentration as a result of the program.”

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Obese kids burdened by more than weight


UC San Diego study finds higher risk for liver disease, high blood pressure, heart problems.

High blood pressure and nonalcoholic fatty liver disease (NAFLD) are two emerging health problems related to the epidemic of childhood obesity. In a recent study, researchers at the UC San Diego School of Medicine sought to determine the prevalence of high blood pressure in children with NAFLD, which places them at risk for premature cardiovascular disease.

The study, published in today’s (Nov. 24) edition of PLOS ONE, found that children with NAFLD are at substantial risk for high blood pressure, which is commonly undiagnosed.

“As a result of our study, we recommend that blood pressure evaluation, control and monitoring should be included as an integral component of the clinical management of children with NAFLD, especially because this patient population is at greater risk for heart attacks and strokes,” said Jeffrey Schwimmer, M.D., in the Department of Pediatrics at UC San Diego School of Medicine and principal investigator of the study. “Hypertension is a main cause of preventable death and disability in the United States in adults, but much of the origin occurs in childhood.”

NAFLD – the inappropriate storage of fat droplets inside liver cells – is the most common cause of chronic liver disease in the United States and affects nearly 10 percent of all children. Although children with chronic liver disease often have no symptoms, some children with NAFLD will have fatigue and/or abdominal pain. The initial evaluation for NAFLD is via a blood test and diagnosis is ultimately based upon a liver biopsy. The disease is most common in children and teenagers who are overweight and can develop in conjunction with other health problems, such as diabetes.

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UCSF sugar science initiative launched


Researchers highlight strong links between sugar and chronic disease.

By Kristen Bole, UC San Francisco

Researchers at UC San Francisco have launched SugarScience, a groundbreaking research and education initiative designed to highlight the most authoritative scientific findings on added sugar and its impact on health.

The national initiative is launching in partnership with outreach programs in health departments across the country, including the National Association of City and County Health Organizations and cities nationwide.

Developed by a team of UCSF health scientists in collaboration with scientists at UC Davis and Emory University School of Medicine, the initiative reflects an exhaustive review of more than 8,000 scientific papers that have been published to date on the health effects of added sugar.

The research shows strong evidence of links between the overconsumption of added sugar and chronic diseases, including Type 2 diabetes, heart disease and liver disease. It also reveals evidence linking sugar to Alzheimer’s disease and cancer, although the team assessed that more research is needed before those links can be considered conclusive.

Laura Schmidt, UC San Francisco

“The average American consumes nearly three times the recommended amount of added sugar every day, which is taking a tremendous toll on our nation’s health,” said Laura Schmidt, Ph.D., a UCSF professor in the Philip R. Lee Institute for Health Policy Studies and the lead investigator on the project. “This is the definitive science that establishes the causative link between sugar and chronic disease across the population.”

The initiative aims to bring scientific research out of medical journals and into the public domain by showcasing key findings that can help individuals and communities make informed decisions about their health. For example, SugarScience.org cites research showing that drinking just one can of soda per day can increase a person’s risk of dying from heart disease by nearly one-third, and can raise the risk of getting Type 2 diabetes by one-quarter.

More than 27 million Americans have been diagnosed with heart disease, which is the nation’s leading cause of death. Another 25.8 million Americans have Type 2 diabetes, caused by the body’s resistance to the hormone insulin coupled with the inability to produce enough insulin to regulate blood sugar levels. Of greatest concern is the rising number of children suffering from these chronic diseases.

Kristen Bibbins-Domingo, UC San Francisco

“Twenty years ago, Type 2 diabetes was unheard of among children, but now, more than 13,000 children are diagnosed with it each year,” said Kirsten Bibbins-Domingo, M.D., Ph.D., a UCSF professor of medicine, epidemiology and biostatistics, and director of the UCSF Center for Vulnerable Populations at San Francisco General Hospital and Trauma Center. “Diabetes is a devastating disease and we know that it is directly related to the added sugar we consume in food and beverages.”

Another rising concern is the impact of added sugar on Non-Alcoholic Fatty Liver Disease (NAFLD), which affects 31 percent of adults and 13 percent of children, and can lead to cirrhosis and liver failure.

“As pediatricians, we had evidence of the connection between sugar and diabetes, heart disease, and liver disease for years, but we haven’t had this level of definitive scientific evidence to back up our concerns,” said Robert Lustig, M.D., M.S.L., a pediatric endocrinologist at UCSF Benioff Children’s Hospital San Francisco and a member of the SugarScience team. “Our goal is to make that science digestible to the American public, and take the first step toward a national conversation based on the real scientific evidence.”

Robert Lustig, UC San Francisco

While there are no federal recommended daily values for added sugar, the American Heart Association recommends consuming less than 6 tsp. (25 g) for women and 9 tsp. (38 g) for men. Guidelines for children depend on caloric intake, but range between 3-6 tsp (12-25 g) per day. Americans currently consume 19.5 tsp. of added sugar, on average, every day.

Added sugar is defined as any caloric sweetener that is added in food preparation, at the table, in the kitchen or in a processing plant. It can be difficult for people to know how much sugar they are consuming, since roughly 74 percent of processed foods contain added sugar, which is listed under at least 60 different names on food labels.

The 12-member SugarScience team will continue to monitor scientific research about added sugar and will track findings at SugarScience.org. The initiative harnesses the power of UCSF’s extensive health sciences enterprise, which ranges from basic laboratory research to clinical, population and policy sciences, with an emphasis on translating science into public benefit. All four of UCSF’s graduate schools – dentistry, medicine, nursing and pharmacy – lead their fields in research funding from the National Institutes of Health, reflecting the caliber of their research. It also is aligned with the UC Global Food Initiative, which seeks to harness UC resources to address global food needs.

SugarScience is made possible by an independent grant from the Laura and John Arnold Foundation. It is supported by the Clinical and Translational Science Institute and the Philip R. Lee Institute for Health Policy Studies at UCSF.

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UC Merced, community programs join to prevent obesity in families


Effort will focus on reducing obesity in young children.

In an effort to combat the increasing rates of obesity among Latino residents, UC Merced and the Merced County Central California Regional Obesity Prevention Program will join forces.

Funded by a three-year, $90,000 grant from National Institutes of Health’s Eunice Kennedy Shriver National Institute of Child Health and Human Development, the campus and nonprofit will look at efforts in other areas that have scientifically proven successful in reducing obesity, particularly in young children.

They also will develop partnerships with community groups and hold public meetings to learn what obesity-related issues are of particular concern in the community. Forty-three percent of fifth-, seventh- and ninth-grade Merced County students were overweight or obese, according to the 2011 study A Patchwork of Progress.

“This is a powerful partnership that stands to benefit an underserved population within the San Joaquin Valley,” said psychology professor Jan Wallander, who co-authored the grant proposal. “By connecting talented researchers with community partners and members, we hope to help reduce the number of children who are plagued by this serious problem.”

The research project is an example of how the UC Merced Health Sciences Research Institute matches community needs with its multidisciplinary faculty affiliates. The research team will include Wallander, public health professor A. Susana Ramirez, sociology professor Zulema Valdez, anthropology professor Robin DeLugan and Blum Center interim Director Steve Roussos.

There are multiple challenges in helping people adopt healthy diets, said Claudia G. Corchado, program manager for the Central California Regional Obesity Prevention Program and lead community partner in the project. For example, some people believe chubby children are healthy children, she said, and others don’t fully understand the health impacts of high-sugar beverages.

“If we don’t understand what a calorie is, how can we understand and learn to control portion sizes?” Corchado said. “How can we know that a 20-ounce bottle of soda has 100 more calories than a can if we don’t know how to read and understand a nutritional label and what exactly that means to our overall health?”

In addition to education, Corchado said, some families need more access to fresh fruit and vegetables. Without nearby grocery stores, they must shop at corner stores that generally stock foods higher in fat, sodium and sugar, which cost less than healthier options.

“We’re living in a world of intervention, but we need to go back to a world of prevention,” she said. “We can teach Latino families to avoid obesity and diabetes through healthy eating and drinking habits.”

Corchado and Wallander hope the quarterly community forums are strongly attended. They’ll also organize an annual conference to share information and findings. With input from community groups and members, Wallander said, UC Merced researchers would likely have many projects they could pursue.

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Immunotherapy for cancer can be toxic with obesity


UC Davis researchers link increased body fat and lethal drug reactions in mice.

Annie Mirsoian, UC Davis

Immunotherapy that can be effective against tumors in young, thin mice can be lethal to obese ones, a new study by UC Davis researchers has found. The findings, published online today (Nov. 3) in The Journal of Experimental Medicine, suggest a possible link between body fat and the risk of toxicity from some types of immunotherapy.

The study comes at a time of great excitement about immunotherapy drugs, which are being developed and used increasingly against cancer, particularly in melanoma and kidney and prostate cancers. Immunotherapies use immune components, such as antibodies or cytokines, to stimulate or suppress the immune system to help the body recognize, fight and kill tumors.

Immunotherapies fall into many classes, including systemic stimulatory regimens, inhibitors of checkpoint blockade and cell-mediated vaccines. Despite the progress made in their development in the last decade, many of these agents induce severe, often limiting toxicities in patients, hindering their use. UC Davis researchers have been working with mouse models to determine if there is a subset of patients for whom certain types of immunotherapies are especially toxic.

“Cancer is primarily considered a disease of the aged, and yet preclinical studies generally use young, lean animal models that may not be reflective of the ‘typical’ cancer patient,” said study lead author Annie Mirsoian. “Aging is a dynamic process that is characterized by increases in inflammatory factors, as well as a shift in body composition, where there is a gradual loss of lean muscle mass and an increase in fat accumulation, which effect how the immune system functions.”

Mirsoian, part of the immunology graduate group in the UC Davis Department of Dermatology, said the study sought to determine if by adjusting the mouse model to more closely reflect the cancer patient phenotype (advanced age and  overweight), researchers could better understand the discrepancies between animal study outcomes and those in patients in the clinic. Their studies examined aged mice on standard diets and compared those to aged mice that were calorie-restricted throughout life.

The researchers found that calorie restriction plays a protective role against toxicity. When laboratory aged mice ate their standard diet freely throughout life, they became obese and ultimately experienced lethal adverse reactions after receiving a systemic immunotherapy regimen.

“We know that people who are obese in general are at higher risk for complications from surgery, radiation and chemotherapy,” said study co-author Arta Monjazeb, assistant professor in the UC Davis Department of Radiation Oncology. “We know that obese people have higher levels of inflammatory markers in their blood, but there is a lack of data examining the effects of obesity on cancer treatment outcomes.”

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UC Irvine pediatric exercise research expert to speak at White House summit


The summit will focus on improving health and fitness for Americans with disabilities.

Dan Cooper, UC Irvine (Photo by Steve Zylius, UC Irvine)

A White House summit next week focused on improving health and fitness for Americans with disabilities will include the voice of a UC Irvine pediatrician nationally renowned for childhood exercise research.

Dr. Dan Cooper, founding director of UCI’s Pediatric Exercise and Genomics Research Center and chair of the Department of Pediatrics, has been invited to discuss the benefits of clinically tested exercise regimens for children with chronic diseases and disabilities at the White House Summit & Research Forum on Improved Health & Fitness for Americans with Disabilities. The event will take place Oct. 6-7 in Washington, D.C., in the Great Hall of the Hubert H. Humphrey Building.

Speaking on a panel for exercise physiology on Oct. 7, Cooper will outline the work accomplished by PERC researchers, focusing on the positive effects of exercise – stimulating the growth of many tissues, strengthening the immune system and curbing obesity. He will also stress the need to pursue rigorous translational and clinical studies to understand how to properly “prescribe” exercise to maximize its benefits in children. Cooper said that the number of children and adults with long-term diseases and disabilities, ranging from cerebral palsy to cystic fibrosis, is increasing. Typically, these individuals are simply unable to exercise with the same intensity, frequency and duration as their peers, and more often than not, they live completely sedentary lifestyles.

“We simply do not yet know how to provide these children and adults with the necessary and powerful ‘medicine’ of exercise to advance health across the lifespan. The clinical and research communities must work together to build a robust biological basis for the ‘exercise prescription’ in children with chronic diseases and disabilities,” said Cooper, who also directs UCI’s Institute for Clinical & Translational Science, which supports PERC efforts.

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Bariatric center accreditation linked to improved patient outcomes


UC Irvine’s Ninh Nguyen co-leads study of surgery center performance.

Ninh Nguyen, UC Irvine

Patients who underwent weight loss operations in recent years, when most bariatric surgical centers were accredited, had fewer postoperative complications and were 2.3 times less likely to die in the hospital than patients who had bariatric procedures performed before a national movement toward facility accreditation occurred, according to a study published in the September issue of the Journal of the American College of Surgeons.

Study authors said the findings suggest that accreditation of bariatric surgery centers contributes to improved safety for patients who undergo weight loss operations and saves lives. “The patient’s most important concern is, am I going to survive this operation?” said study co-investigator Ninh T. Nguyen, M.D., professor of surgery and chief of gastrointestinal Surgery, at UC Irvine Medical Center in Orange.  “We found that death is very uncommon when the operation takes place at an accredited facility, meaning it has met rigorous standards for high-quality surgical care.”

A surgical approach is now widely considered a very effective treatment for severe obesity.  Potential benefits of bariatric operations include substantial long-term weight loss, an improvement or reversal of Type 2 diabetes, and improved risk factors for heart disease, according to the American Society for Metabolic and Bariatric Surgery (ASMBS).  Common bariatric procedures include the Roux-en-Y gastric bypass, gastric banding, and sleeve gastrectomy.

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