Going Back to the Future of Obesity and Osteoporosis

In medicine, prevention costs a lot less than a time machine. Fifty to 60 years in the future, many of today’s healthy children and teens will develop later-onset chronic conditions including heart disease, cancer, and osteoporosis. But some of the factors that put them at risk are already beginning now. Prevention of these chronic diseases during childhood may be far more effective than treating them later in adulthood, particularly if we can predict today who will benefit most from these preventive efforts in the future.

This childhood prevention of adult disease is the pursuit of Jonathan Mitchell, PhD, an instructor of Pediatrics in the Division of Gastroenterology, Hepatology and Nutrition at The Children’s Hospital of Philadelphia. Dr. Mitchell was recently awarded a training grant from the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health for a study of connections between sleep and obesity risk in teenagers as they transition from middle school to high school. Obese teens tend to become obese adults who face increased risk for heart disease and cancers, so there could be a major long-term public health benefit in understanding how sleep patterns, physical activity-related factors, and genetic factors influence obesity in early adolescence.

“I want to address the question of whether or not short sleep duration leads to the development of adolescent obesity, but we know that other factors, such as physical activity and genetics are also important,” Dr. Mitchell said.

The study will enroll 100 13- and 14-year-olds and measure their sleep and body composition at a baseline visit to CHOP and one year later. The one-year follow-up is timed to capture the transition between middle school and high school when the amount of sleep teens get tends to drop off dramatically due to earlier school start times, more extracurricular activities, and other lifestyle changes.

Dr. Mitchell plans to improve on past studies that have addressed these questions by using more precise measures of sleep and body composition, specifically actigraphy — a wearable device to measure movement — and dual energy X-ray absorbitometry (DXA) — a high-tech means of measuring body composition (the amount of muscle and fat in the body) in the lab. Dr. Mitchell will also explore whether teens who are genetically predisposed to obesity respond differently to sleep changes than do teens who are not at genetic risk.

Under the grant, Dr. Mitchell will receive advanced training from senior colleagues at CHOP, in nutrition and body composition research methods from Babette Zemel, PhD; in the genetics of pediatric growth and obesity from Struan Grant, PhD; and in pediatric sleep research from Carole Marcus, MBBch. Senior investigators at Penn will also contribute to his training under this grant: David Dinges, PhD, Kathyrn Schmitz, PhD and Knashawn Morales, PhD.

Got Bone Density Genes?

The new study of sleep and obesity in teens is not the first collaboration between these investigators looking at childhood indicators of later health risk. Drs. Mitchell, Zemel and Grant have teamed up for research on the genetic determinants of bone mineral accretion during childhood. The NIH funded study led by Drs. Zemel and Grant focuses on whether the known genetic variants that are associated with low bone mineral density (BMD) in adults are also found in children with lower bone mineral density. “

You can’t make the assumption that they would be the same because kids are accruing bone, and adults are losing bone,” Dr. Mitchell said. “They could be under different genetic regulation.”

In a paper published in September in the Journal of Bone Mineral Research, they reported finding weak associations between genes linked with adult BMD susceptibility and BMD in children and adolescents — until they accounted for sex differences and pubertal development.

They found that the strongest locus of BMD-associated genes, on chromosome 7, acts much more strongly in girls compared to boys. Some genetic loci show stronger associations to BMD in pre-pubertal kids, and other genetic loci are more strongly associated with BMD in post-pubertal kids.

Building on this work, the researchers calculated genetic risk scores based on the number of BMD-lowering gene variants children carry. They reported in the Journal of Bone Mineral Research in November that a higher score was associated with lower bone density in children, and again found sex-specific differences with stronger genetic influence in girls. They are also looking into whether children with greater genetic susceptibility to lower BMD experience greater or lesser benefits than other children from physical activity — which is overall a good way of building bone mass.

“If you accrue sufficient bone in childhood, you can maximize your peak bone mass, and that’s all the bone you will ever have to see you through life,” Dr. Mitchell said. “The motivation to do this work is to identify kids at risk for lower bone density, and see what helps them maximize their bone density and reduce their risk of fracture and osteoporosis in adulthood.”