Disrupting the daily rhythm of stress hormones caused mice to gain substantial fat while producing a different pattern of insulin resistance than a high-fat diet, according to a Weill Cornell Medicine study. The preclinical findings suggest that the cause of weight gain may matter to how the body stores fat and responds to insulin, but they do not establish that the same mechanism operates in people.
The study, published Sept. 8 in Cell Reports, compared mice with normal or flattened glucocorticoid rhythms on either a standard or high-fat diet. Mary Teruel, an associate professor of biochemistry, led the work with postdoctoral associates and co-first authors Agnieszka Agas and Sanjeev Sharma.
Glucocorticoid levels normally fall during the mice's rest period and rise near the start of their active period. The researchers flattened that cycle by raising the normally low resting level and reducing the daily peak, without substantially increasing the animals' average hormone levels. Varying hormone timing and diet separately let the team compare their effects.
After 30 days, mice on a high-fat diet had about three times the fat mass of controls. Mice with flattened hormone rhythms on a standard diet accumulated nearly as much — about 2.5 times the control level. Animals exposed to both conditions gained the most fat, indicating that the effects were largely additive.
The hormone-rhythm group also lost lean muscle mass during the first week, though that measure later stabilized and began to rise. Earlier work from Teruel's laboratory, published in 2022, found that flattened rhythms caused substantial fat gain without increased food intake while blood glucose stayed normal and relatively little fat accumulated in the liver. The new experiment examined how that metabolic pattern persists.
The two routes to obesity did not affect insulin response in the same way. Mice with flattened hormone rhythms had insulin resistance concentrated in skeletal muscle, while fat tissue retained an important response to insulin that limits the release of stored fat. Their liver also remained largely protected from the fatty buildup seen in mice fed a high-fat diet.
Insulin levels in the rhythm-disrupted mice rose sharply. The researchers said that pattern may help keep lipids in white fat tissue under the skin and around organs instead of allowing them to accumulate in the liver. It does not mean the animals were free of metabolic effects: Both the high-fat-diet and hormone-rhythm groups developed insulin resistance, but in different tissues.
Teruel said the timing of hormonal signals changed how the mice handled calories and where they stored energy, not simply how much they ate. The results point to a distinction between total fat gain and where insulin resistance develops — a distinction the researchers say could matter for understanding metabolic health.
Human studies have linked disrupted daily cortisol rhythms with obesity and abdominal fat, and altered rhythms have been reported alongside chronic stress and shift work. Those associations do not prove that stress or shift schedules cause the mouse-like metabolic pattern in humans. Teruel said more research is needed to examine whether hormone timing contributes to different forms of obesity in people.
The study received support from the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health, as well as the Drukier Institute and Weill Cornell Medicine.
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