What is it about?

Glucocorticoids (cortisol in humans and corticosterone in mice) are essential hormones that regulate whole body metabolism and are secreted in circadian rhythms that, in humans, peak during the day and go low at night. Chronic stress due to depression, jet lag, irregular eating and sleeping cycles flattens circadian glucocorticoid oscillations, meaning that peak levels are reduced and trough levels are increased. Flattened glucocorticoid oscillations result in obesity, insulin resistance, and diabetes, but the underlying mechanisms are poorly understood. Here we made the unexpected finding that flattening of circadian glucocorticoid oscillations rapidly induces a unique metabolic state marked by hyperinsulinemia and low blood glucose and fatty acid levels that then gradually drives adipocyte hypertrophy over three weeks but without accumulation of lipids in the liver or increased lipids in the circulation. Our experiments and transcriptomic analysis show that the molecular mechanism causing triglycerides to accumulate in this unique metabolic state is primarily due to increased de novo insulin-driven fatty acid synthesis from glucose. We show that for periods of up to approximately three-weeks of flattened glucocorticoids, this unique state of hyperinsulinemia and adipocyte hypertrophy in response to glucocorticoid flattening remains reversible with a role to remove fatty acids and glucose from the circulation and initially protect the metabolic health of the organism during multi-week periods of chronic stress.

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Why is it important?

We mimicked constant stress in mice by flattening glucocorticoid circadian rhythms, meaning that the normal daily GC troughs were elevated and the normal daily GC peaks were blunted. We were careful to keep the total level of GC in the circulation at normal physiological levels. Strikingly, all fat mass (both WAT and BAT) more than doubled in the mice within 21 days, despite that the mice ate a healthy normal chow diet and the GC-flattened mice did not eat more than control mice. Surprisingly, flattening of glucocorticoid circadian rhythms caused rapid onset of a state of high insulin but low glucose that drove the adipocyte hypertrophy and obesity. Also surprisingly, this unique hyperinsulinemic, obese stress state is protective, keeping circulating glucose and fatty acids low for weeks and is initially reversible.

Perspectives

Obesity is epidemic in today's society, and the food quantity, quality, and timing of eating are often blamed as the reasons. Here we show that even without any change to the amount or type of food they ate - or any significant change to their metabolism (as measured by metabolic cage experiments), the mice more than doubled their fat mass within 3 weeks. The Times of London wrote a article on our work and entitled it "Don't blame the ice cream. Stressed-out cells are making you fat." Indeed our work supports that stress and subsequent disruption of circadian glucocorticoid rhythms is a significant contributor to obesity, independently of type and timing of diet.

Mary Teruel
Cornell University

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This page is a summary of: Flattening of circadian glucocorticoid oscillations drives acute hyperinsulinemia and adipocyte hypertrophy, Cell Reports, June 2022, Elsevier, DOI: 10.1016/j.celrep.2022.111018.
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