By Randolph Fillmore
Women with excess abdominal subcutaneous fat (A-FAT) and the distinctive “apple” body shape those deposits create are at greater risk for future obesity-related health problems, such as diabetes, hypertension, stroke and heart attack, compared to “pear” shaped women with the same overall weight but where the excess is deposited as subcutaneous fat in the hips and thighs (GF-FAT). The apple vs. pear distinction with differential influences on metabolic health was first proposed in 1956, and it prompted a recent study by a team of researchers at Johns Hopkins All Children’s Hospital in collaboration with colleagues at the Translational Research Institute for Metabolism and Diabetes at AdventHealth in Orlando, Florida, and, co-led by Timothy F. Osborne, Ph.D., associate dean for Basic Research and director of the Johns Hopkins All Children’s Institute for Fundamental Biomedical Research in St. Petersburg, Florida, that was recently published in the journal Frontiers in Genetics.
“We hypothesized that the DNA in the A-FAT vs. G-FAT of apples vs. pears might be differentially programmed through epigenetic modifications and these differences might contribute to the differential pattern for fat accumulation,” explains Osborne, a professor of Medicine and Biological Chemistry and member of the Division of Endocrinology, Diabetes and Metabolism of the Johns Hopkins University School of Medicine. Epigenetic modifications to your DNA do not alter the fundamental gene sequence, but they encompass chemical modifications to your DNA structure that change how your genes are regulated. These modifications are stable, which means that in many cases they are passed on as cells divide. In the case of fat tissue, it means they are stable through adipose expansion and development of obesity.
To test their hypothesis, Osborne and colleagues enrolled 21 healthy, premenopausal, “weight-stable” younger women into a study at AdventHealth. The women were divided into groups based on their respective body shapes resulting from having either preferential A-FAT or GF-FAT deposits. The women underwent adipose (fat) tissue biopsies and blood draw.
The researchers then evaluated one epigenetic chemical change to DNA called “DNA methylation” to understand how the altered chemical mark is differentially present in A-FAT vs. GF-FAT, and according to the body shape, apple or pear.
“We found unique DNA methylation patterns within both fat deposits that are significantly different, depending on the body shape created by fat distribution,” Osborne explains. “Because the DNA methylation profiles are stable over time, young girls will likely harbor similar DNA methylation patterns before they potentially gain weight as they age. Even more interestingly, we found that many of the different DNA-methylation signatures were also present in DNA isolated from whole blood. Thus, we hypothesized that we might be able to use the different DNA methylation signatures easily characterized from a simple blood draw to predict which young girls might have a higher tendency to develop into “apples” vs. “pears” with a greater risk for developing obesity-related complications later in life.”
‘Apples’ and ‘Pears’ Go Back to 1956
Interest in the link between body shape, fat deposition sites, and diseases, such as diabetes and cardiovascular diseases, goes back to a 1956 paper by Jean Vague. The French physician suggested that belly fat creates an “apple-shaped” body, while fat around the hips and thighs creates a “pear-shaped body.” Using those visual imaging measures, Vague defined excess fat and its abnormal distribution as “partial lipodystrophy.”
“The apple- and pear-shaped body shape imagery, as well as the term lipodystrophy, are still used today,” says study first author Adeline Divoux, Ph.D., a research scientist at AdventHealth. She also adds that these body shapes represent extremes in fat deposition.
According to Divoux, the researchers will be conducting future validation studies, this time with many more participants, perhaps hundreds with A-FAT and GF-FAT body shapes. The researchers will use blood samples to investigate DNA methylation as they did in their recently published study.
Children at risk for obesity might not yet be presenting a specific body shape, but could also be enrolled in a study since a blood sample is all that is needed. Divoux added that before puberty, children don’t generally have the distinctive apple or pear body shapes that Vague said indicated lipodystrophy, but that after puberty those body shapes may begin to develop in childhood obesity. Their blood samples, however, may reveal the potential for developing preferential A-FAT or GF-FAT deposits.
The finding that A-FAT in younger women and the related body shape may be more likely to cause health problems as women age is of particular interest to Raquel Hernandez, M.D., M.P.H., assistant professor of pediatrics at the Johns Hopkins University School of Medicine and medical director of the Johns Hopkins All Children’s Healthy Weight Initiative. Her focus is on pediatric weight issues, including rapid weight gain and unhealthy weight, and she has developed innovative and evidence-based approaches to promote healthy lifestyles to fight against the current “child obesity epidemic” in the United States. She says her “mission” is to intervene early in a child’s life to prevent obesity – possibly even at the pre-school stage.
“Dr. Osborne and I co-chair the Johns Hopkins All Children’s Obesity Cardiovascular Metabolic Health Interdisciplinary Research Group (IRG),” Hernandez explains. “The IRG is a great mechanism to connect our basic scientists with clinical investigators on this topic.”
She finds value in this study and suggests that the methodology can be applied to children.
“This research adds to our understanding of how fat deposition may affect hormonal receptivity and what the impact of that might be for the risk of such diseases as diabetes and hypertension,” she explains. “Obesity is a heterogeneous disease – not all fat is the same,” and this line of research is designed to explore this heterogeneity further.
While children might not yet demonstrate the distinctive body shapes of preferential A-FAT (apple-like) or GF-FAT (pear shape) the DNA methylation approach used by Osborne can be useful because the chemical markers that can predict the potential for those body shapes may already reside in children who, Hernandez explains, may be exposed not only to the genetic potential for obesity, but as they develop in the womb may experience “environmental” conditions that can make them susceptible to obesity as children and as adults.
Hernandez hopes to apply this research to her studies on childhood obesity, for which there are currently a limited number of measurements that can be predictive for children at risk for obesity. Body mass index (BMI) is one measure, but Hernandez says that BMI is “an imperfect measure” and the differential DNA methylation analysis coupled to the apple vs. pear distinction provides the beginnings of a personalized medicine approach to the obesity epidemic.
Research Not ‘Lost in Translation’
“Translational medicine” is the practice of putting research to work in the clinic, and the results of this study are translatable to the clinic, Osborne says, adding that translational medicine is a top priority at Johns Hopkins All Children’s.
“Our researchers are charged with integrating basic science research with clinical practice,” he explains. “‘Beefing up’ our academic portfolio and translating basic research into clinical practice is an important goal of our research mission.”
In that effort, the Johns Hopkins All Children’s Institute for Clinical and Translational Research, launched in 2019 and spearheaded by Neil Goldenberg, M.D., Ph.D., associate dean for Clinical and Translational Research and professor of Pediatrics and Medicine, is partnering with the Institute for Fundamental Biomedical Research headed by Osborne with a vision of bringing together researchers and trainees from multiple departments and programs throughout the institution, whose academic work involves clinical/translational science.
Translational research — a process by which basic research can be translated to clinical use — aims to improve health care by identifying fundamental cellular mechanisms that might be manipulated to help target myriad diseases and related health conditions.