Weill Cornell Medicine study finds stress hormones drive obesity in mice

This physiological distinction allows adipose tissue to continue storing lipids while largely protecting the liver from the fat accumulation typically seen in diet-induced obesity. Dr. Mary Teruel, associate professor of biochemistry at Weill Cornell Medicine, led the research team alongside postdoctoral associates and co-first authors Dr. Agnieszka Agas and Dr. Sanjeev Sharma, isolating the hormonal rhythm effects from diet by independently varying both factors in mice.

How Stress Hormone Rhythms Alter Fat Storage

In the study, researchers evaluated mice exposed to normal or flattened glucocorticoid rhythms combined with either a standard diet or a high-fat diet. Under normal conditions, glucocorticoid levels drop during the animal’s resting phase and spike at the start of their active period. Researchers flattened this rhythm by elevating the low hormone levels during rest and dampening the daily peak.

“We realized that there are two different mechanisms, hormones and diet, that drive obesity in mice,” Dr. Teruel said. The findings build upon a 2022 study from the Teruel laboratory demonstrating that disrupted glucocorticoid rhythms cause mice to accumulate substantial fat without increasing food intake, while maintaining normal blood glucose and relatively low liver fat.

Mice fed a high-fat diet tripled their fat mass in 30 days. Animals on a standard diet with glucocorticoid-induced fat accumulation accumulated roughly 2.5 times more fat than control groups. Mice exposed to both the high-fat diet and the hormone disruption accumulated the most fat, illustrating an additive effect between the two obesity drivers.

Insulin Resistance Patterns in Muscle and Liver

Mice treated with glucocorticoids lost lean muscle mass during the first week before stabilizing and increasing it. Despite developing severe obesity, these subjects avoided the pathological fatty liver observed in high-fat diet groups, instead storing fat preferentially in white adipose tissue beneath the skin and around organs.

“It wasn’t just the number of calories they were consuming. The timing of the hormone signals changed how the body processed those calories and where the energy was stored, which I found quite striking,” Dr. Teruel noted. Both high-fat diet groups and glucocorticoid-treated groups developed insulin resistance, but the resistance distributed differently.

In glucocorticoid-treated subjects, insulin resistance concentrated in skeletal muscle, whereas adipose tissue maintained its ability to suppress fat release. Concurrently, insulin levels spiked dramatically, a pattern that helps animals maintain metabolic balance by directing lipids into adipose tissue instead of accumulating them pathologically in the liver.

Implications for Human Metabolic Health

Human studies previously linked disruptions in normal circadian cortisol rhythms to obesity and abdominal fat, with rhythm alterations frequently observed in individuals experiencing chronic stress or shift work. According to the Centers for Disease Control and Prevention, approximately 40% of adults and 20% of children in the United States live with obesity.

“We’re asking, is it really just food, or is there something else?” Dr. Teruel said. “Have factors like lack of sleep or stress altered our normal daily glucocorticoid rhythms?” While further investigation is required, Dr. Teruel emphasizes that researchers and clinicians should stop treating obesity and insulin resistance as single problems.

“Our preclinical results show that muscle, fat, and liver can respond very differently to insulin depending on what factor is driving the metabolic change,” Dr. Teruel stated. Consequently, metabolic health depends not only on total stored fat volume, but also on the anatomical distribution of insulin resistance and the ongoing capacity of adipose tissue to safely store lipids.