Researcher: Female rat models needed for more thorough investigation of obesity

Writer: Paul Schattenberg, 210-859-5752, paschattenberg@ag.tamu.edu

Dr. Erin Giles, 979-458-1849, egiles@tamu.edu

COLLEGE STATION — A study by researchers from Texas A&M AgriLife Research and the University of Colorado found male-only rat models used for studying obesity are limited and  don’t address critical factors for understanding it.

The study can be found at http://bit.ly/2v5U14T.

“Obesity negatively affects virtually every system of the body and increases the risk for cardiovascular disease, diabetes, osteoarthritis and many cancers,” said Dr. Erin Giles, AgriLife Research scientist in the nutrition and food science department at Texas A&M University, College Station.

Dr. Erin Giles is in the nutrition and food science department of the College of Agriculture and Life Sciences at Texas A&M University in College Station. (Texas A&M AgriLife Research photo)

Giles, the study’s primary investigator, said efforts to stop the growing global epidemic of obesity are not working so there is an urgent need to understand what causes obesity and develop new strategies, interventions and therapies to prevent and treat it.

She said one impediment to this goal is the common scientific practice of using only male rats in diet-induced obesity research.

Giles said those in her lab and the research community as a whole have recognized the importance of studying females, not only in clinical research but also at the preclinical level.

“In general, there has been an over-reliance on male animals in preclinical research in the past, as often it was simply easier for researchers to use male-only rats,” she noted. “As we have worked to study female specific physiological conditions such as menopause and breast cancer, we realized that there were even aspects of our basic model of diet induced obesity, including the ability to identify obesity-prone and resistant animals early in life, that were different in females.

Giles said while their research was focused in diet-induced obesity, the failure to include females has also limited the research in such areas as cardiovascular disease, cancer and diabetes.

Fortunately, she said, funding agencies, including the National Institutes of Health, a major research funder, have recognized this limitation and are now encouraging and/or requiring study designs that address sex-differences across all disciplines.

“The purpose in writing this review was to provide an overview of our rodent model of obesity, where we use a strain of rats that have underlying genetic variability,” she explained. “We studied both the animals that are resistant to and susceptible to becoming obese when fed a high-fat, energy dense diet.”

Giles said one of the greatest benefits of this specific rodent model is it reflects the diverse susceptibility to the development of obesity in response to the freely available high-fat diet, which is common in our environment.

“A primary environmental factor leading to obesity is an energy-dense diet, which is a diet with a high number of calories per bite, usually in the form of high sugar and fat content,” Giles said. “For several decades, researchers have been developing and studying models of diet-induced obesity in males, and we are only just beginning to understand how the same models differ in females. In this current study, we combined data from more than 300 female rats to find the optimal point in early life when an animal develops a predisposition to become obese.”

Magnified adipose tissue from an obese rat. The brown cells are macrophages — major effector cells for immunity. (Texas A&M AgriLife Research photo)

She said for the vast majority of the human population, the variability in the predisposition for obesity is not linked to a single mutation or gene expression.

“Sometimes there are individuals who can eat a lot and not gain weight, then there are some who gain weight easily, and this is mimicked in these rats,” she noted.

Giles said there are many factors involved in obesity, and while the study highlights the progress  made in understanding weight loss and subsequent weight regain, it also demonstrates there are many sex-specific differences that are not yet understood.

“When we tried to apply the measurements that were used to reliably predict long-term adiposity in males, they were surprised at how inadequate these measurements were at predicting long-term adiposity in females,” she said  “For example, in males, a change in body weight in response to a high-fat diet early in life was the strongest predictor of long-term obesity, while percentage of body fat later in life proved to be a more reliable predictor of obesity in females. As a result, we needed to wait until the female rats were much older than their male counterparts to make this prediction.”

Giles said while previously there was anecdotal evidence that separating female rats into lean and obese phenotypes needed to be done later in life than in males to get a clean separation, this study was the first time they were able to generate the data required to accurately demonstrate these sex-specific differences.

She also noted studies in males have identified metabolic changes that occur during weight loss  may promote weight regain in the future.

“Studies in obese males have shown that the longer an animal is kept at a weight reduced state, the faster they gain weight back when they are allowed to go off their diet,” she explained. “We want to understand if the same metabolic changes occur in females as males.”

Giles said she and the other researchers have already published a number of studies in this field using only male rats and are now in the process of performing similar studies in females.

“What we are currently investigating is the impact of weight gain during menopause, and the effect that this has on breast cancer,” she said. “As you can imagine, this is the type of research where using male rats would not be particularly useful.”

Giles said while her research group and others are working to understand many of the differences between male and female physiology, they are still essentially playing catch-up from years of studies conducted primarily in males.

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