Author: Susan Thomas

Researchers at UCLA say it’s not just what you eat that makes those pants tighter — it’s also genetics. In a new study, scientists discovered that body-fat responses to a typical fast-food diet are determined in large part by genetic factors, and they have identified several genes they say may control those responses.

 

The study is the first of its kind to detail metabolic responses to a high-fat, high-sugar diet in a large and diverse mouse population under defined environmental conditions, modeling closely what is likely to occur in human populations. The researchers found that the amount of food consumed contributed only modestly to the degree of obesity.

 

The findings are published Jan. 8 in the online edition of the journal Cell Metabolism and will appear Jan. 9 in the print version.

 

“Our research demonstrates that body-fat responses to high-fat, high-sugar diets have a very strong genetic component, and we have identified several genetic factors potentially regulating these responses,” said first author Dr. Brian Parks, a postdoctoral researcher at the David Geffen School of Medicine at UCLA. “We found that obesity has similar genetic signatures in mice and humans, indicating the mice are a highly relevant model system to study obesity. Overall, our work has broad implications concerning the genetic nature of obesity and weight gain.”

 

The dramatic increase in obesity over the past few decades has been tightly associated with an increase in obesity-related conditions such as type 2 diabetes, heart disease and cancer. And while high-calorie diets containing high levels of fat and sugar, along with sedentary lifestyles, have been considered the most significant environmental factors contributing to this epidemic, the new UCLA research demonstrates that body-fat responses to food are strongly inherited and linked to our DNA.

 

During the two-year study, researchers measured obesity traits, adipose (fat) tissue, global gene expression and intestinal flora (normal intestinal bacteria) in response to a high-fat, high-sugar diet in more than 100 inbred strains of mice. They identified 11 genome-wide “regions” associated with obesity and fat gain due to high-fat, high-sugar intake. Several identified regions overlap with genes identified in human studies.

 

For the study, the mice were placed on a normal diet for the first eight weeks of life and were subsequently switched to a high-fat, high-sugar diet for eight weeks.

 

“We measured the change in fat dynamically, at five different points following a high-fat, high-sugar feeding, providing strong evidence for a genetically controlled body-fat set-point,” Parks said. “Our use of inbred mice strains also enabled detailed analysis of the relationship between obesity traits, gene expression, intestinal flora and diet.”

 

Dietary responses, as assessed by the body-fat percentage increase during high-fat, high-sugar feeding, varied widely among the strains, with increases in body-fat percentage ranging from 0 to more than 600 percent in the various strains of mice. Most strains responded during the first four weeks of the high-fat, high-sugar feeding and did not accumulate additional fat during the remainder of the study. This suggests an upper body-fat set-point whereby continued gain in body fat is resisted by genetic mechanisms, the researchers said.

 

Additionally, “We observed high heritability of about 80 percent for body-fat percentage across the study timeline,” said principal investigator Dr. Jake Lusis, a professor of medicine and human genetics and of microbiology, immunology and molecular genetics at the Geffen School of Medicine. “Changes in body-fat percentage after high-fat, high-sugar feeding were also highly heritable, suggesting that dietary responses are strongly controlled by genetics.”

 

The results are consistent with the inheritance of body mass index (BMI) and obesity in humans and emphasize the importance of genetics in controlling obesity, the study authors said.

 

The researchers note that overconsumption of high-calorie, high-sugar food is an important factor contributing to the obesity epidemic but stress that food consumption is only one of many environmental factors that affect obesity.

 

“Our results emphasize the importance of gene-by-environment interactions, with important implications for an understanding of the overall genetic architecture of obesity,” Lusis said. “In particular, it will be of interest to examine behavioral and neurological differences among the strains as they relate to obesity traits.”

 

The researchers noted that mice strains with extremely fast and extremely slow metabolisms must be further studied to understand the effect of energy expenditure on body-fat percentage and the likelihood of obesity.

 

“Our future studies will investigate the development of metabolic syndrome and diabetes after high-fat, high-sugar feeding,” Parks said. “We will also begin to focus on specific, identified genetic factors and their role in dietary interactions and obesity.”

 

The researchers conclude that, based on their data, there appears to be a strong link between DNA and the amount of fat gained when a high-calorie, high-sugar diet is consumed.

 

The study was funded by the National Institutes of Health (grant HL028481) and a Howard Hughes Medical Institute Early Career Scientist award. Additional funders are listed in the manuscript.

 

Additional authors include Elizabeth Nam, Elin Org, Emrah Kostem, Frode Norheim, Simon T. Hui, Calvin Pan, Mete Civelek, Christoph D. Rau, Brian J. Bennett, Margarete Mehrabian, Luke K. Ursell, Aiqing He, Lawrence W. Castellani, Bradley Zinker, Mark Kirby, Thomas A. Drake, Christian A. Drevon, Rob Knight, Peter Gargalovic, Todd Kirchgessner and Eleazar Eskin.

 

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Leonidas Hill recently made history at Mattel Children’s Hospital UCLA, when the 5-year-old became the first pediatric patient in the western United States to undergo transoral robotic surgery (TORS) — a minimally invasive surgery performed with the help of a robot — to repair a rare congenital condition known as a laryngeal cleft.

 

Mattel Children’s Hospital UCLA is one of only a handful of medical centers in the country offering this type of surgery, which is rarely done on pediatric patients. The technology allows surgeons to perform the operation through the mouth of the patient, rather than in the traditional manner, which requires external incisions and the splitting of the patient’s voice box.

 

Hill was born with both a laryngeal cleft and a cleft lip/palate, defects that occur during embryonic development. The cleft is an extremely rare airway defect in the laryngo-tracheal wall, which results in an abnormal opening between the larynx and the esophagus. This allows food to get into the airways and even the lungs.

 

Hill’s cleft, which was classified as Type 3 (Type 4 is the most severe), extended beyond his voice box and into his trachea, leading to tracheomalacia, a condition that occurs in newborns in which the cartilage of the trachea, or windpipe, has not developed properly. Because of this, the trachea walls, instead of being rigid, are floppy and collapse, resulting in breathing difficulties.

 

Hill’s breathing difficulties began soon after birth, and he underwent a tracheotomy-tube placement as an infant to help with his airway issues. Due to his chronic aspirating, he also had a gastrostomy tube placed in his stomach to minimize respiratory infections such as pneumonia and bronchitis.

 

Dr. Nina Shapiro, director of pediatric otolaryngology at Mattel Children’s Hospital UCLA and an associate professor of surgery at the David Geffen School of Medicine at UCLA, diagnosed Hill’s cleft and recommended him for the TORS procedure. 

 

“The benefit of the surgical robot is that it gives more access to the pediatric airway using minimally invasive techniques,” she said. “For Leonidas, this surgery repaired his cleft, which will greatly improve his airway issues and put him in a better position for removing the tracheotomy tube.”

 

The Da Vinci robotic surgical system, the state-of-the-art technology used at UCLA, is a minimally invasive procedure in which a surgical robot, under the full control of a specially trained physician, operates with a three-dimensional, high-definition video camera and robotic arms. 

 

These miniature “arms” can navigate through the small, tight and delicate areas of the mouth without the need for external incisions. A retraction system allows the surgeon to see the entire surgical area at once. While working from an operating console, every movement of the surgeon’s wrists and fingers are transformed into movement of the surgical instruments. 

 

Dr. Abie Mendelsohn, an assistant professor of surgery at UCLA, developed the TORS program at the UCLA Department of Head and Neck Surgery. Mendelsohn operated on Hill and repaired the cleft in the back of his larynx. 

 

After examining the cleft, Mendelsohn used a special carbon-dioxide laser-fiber adapter for the robot to destroy the cleft’s inner lining, which allowed for wound-healing of the cleft. Following the laser procedure, Mendelsohn used the robot to transorally place sutures within the larynx and trachea to hold the two ends of the cleft together.

 

“This type of laryngeal cleft repair traditionally requires open surgery, which entails a very large neck incision, splitting the voice box, and direct suturing of the cleft,” Mendelsohn said. “This approach is highly invasive, has a prolonged surgical time and requires an extensive healing period. Using the TORS method, our approach did not require any skin incisions, there was direct access to the closure site, no visible scars and a faster healing time, so Leonidas was able to go home the next day. The TORS procedure shortens hospital stays for patients, and they can get back to their lives faster and with fewer limitations.”

 

Hill made a speedy recovery and was back at school within days. His prognosis is good, and Shapiro said that the next step will be to perform additional tests, with the hope of removing Hill’s tracheotomy tube. 

 

“The ultimate goal is to remove the tracheotomy and gastrostomy tubes so that Leonidas can swallow liquids and solids by mouth,” she said. “This surgery will help him breathe easier and work toward eating and drinking on his own.”

 

With continuing pediatric adaptations made to the robotic surgical instruments, physicians and surgeons at UCLA will continue to search for appropriate pediatric candidates for robotic surgical procedures.

 

“The initial robotic surgical instruments had an outer diameter of 8 millimeters, which has now been improved to 5 millimeters,” Mendelsohn said. “Additionally, the initial robotic endoscope had an outer diameter of 15 millimeters, which has now been improved to 8.5 millimeters. These improvements have led to our ability to fit the instrumentation successfully through the mouth of a pediatric patient. In our eyes, this experience was successful, and we believe that with selected pediatric patients, robotics will have a continued use at the Mattel Children’s Hospital UCLA.”

 

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Young children in Los Angeles County who are in need of vision services will soon be seeing things a lot clearer, thanks to a new collaboration between the Jules Stein Eye Institute at UCLA and First 5 LA, the child advocacy and grant-making organization. 

 

The UCLA Mobile Eye Clinic, an outreach program of the Jules Stein Institute, has received an allocation of $4.1 million from the First 5 LA commission that will be used to screen more than 90,000 children between the ages of 3 and 5 from underserved populations in the county over the next five years. 

 

Under the collaboration, the UCLA Mobile Eye Clinic will provide services to preschoolers, including initial vision screenings at preschool locations; full-eye exams conducted by ophthalmologists and optometrists for children who fail the initial exam; referrals to partner specialists for visually impaired children who need special medical or surgical treatment; and free eyeglasses for those with refractive errors. 

 

Additionally, the mobile clinic has an automated scheduling, coordination and data-registration program that makes it easy for parents to schedule appointments, and the clinic’s staff will work hand-in-hand with preschool teachers and parents to ensure follow-up care and compliance.

 

“Much of children’s health and learning abilities is greatly dependent on their sight,” said Dr. Anne L. Coleman, who directs the Mobile Eye Clinic and the Jules Stein Eye Institute Center for Community Outreach and is vice chair of academic affairs for the UCLA Department of Ophthalmology. “It is estimated that one in five preschool children has a vision problem that

 

affects their learning ability. Improving vision in these children not only helps improve their academic performance, but it also protects them from environmental hazards and enhances the quality of their social and personal lives.”

 

“The Jules Stein Institute is dedicated to the preservation and restoration of vision worldwide,” said Dr. Bartly J. Mondino, the institute’s director and chair of the UCLA Department of Ophthalmology since 1994. “The First 5 collaboration supports the Jules Stein Eye Institute’s mission, part of which is to address the needs of some of the most vulnerable in Los Angeles County who are at risk of losing their sight unnecessarily.”

 

The Jules Stein Eye Institute at UCLA is a vision science campus dedicated to the preservation and restoration of vision through its global programs in innovative research, quality patient care, and multidisciplinary and integrative education. The institute’s community outreach efforts range from its Mobile Eye Clinic, which travels to schools, shelters, health fairs and other organizations that assist homeless and low-income families, to programs like Vision IN-School, for vision education; Shared Vision, for the collection and  donation of used eyeglasses; the Preschool Vision Screening program; and the Indigent Children and Families program. For more information or to make an appointment, call 310-825-5000 or visit www.jsei.org.

 

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