On Protein, Brown Fat, Temperature, and Obesity

The nuclear receptor Rev-erb-alpha links circadian and thermogenic networks through the regulation of brown fat and may shed light on the physiology of obesity, new animal research suggests.

The findings from the mouse research, published online in the journal Nature, identify a previously unrecognized circadian susceptibility to cold that could have implications for the prevention of obesity and its many comorbidities, Mitchell A. Lazar, MD, PhD, of the Institute for Diabetes, Obesity and Metabolism at the Perelman School of Medicine, University of Pennsylvania, told MedPage Today.

Rev-erb-alpha, also known as Nr1d1, is a component of the circadian clock that modulates hepatic lipid and glucose metabolism, fat cell development, and the inflammatory response in macrophages.

The University of Pennsylvania research team showed how body temperature rhythms are synchronized while maintaining the ability to adapt to changes in environmental temperatures over a 24-hour period.

Rev-erb-alpha Ups Exercise Capacity

Last July, a different group of researchers reported that Rev-erb-alpha increased metabolic activity in skeletal muscle and allowed mice to run 50% longer and further, suggesting that pharmacological activation of Rev-erb-alpha may be a promising approach for the treatment of skeletal muscle disease with compromised exercise capacity.

Lazar said that while the Rev-erb-alpha molecule, which was discovered in his lab, has positive effects in the muscle, it appears to have detrimental effects under certain circumstances in brown fat -- at least in mice.

For close to 300 years, body temperature has been recognized as having a circadian rhythm, with body temperatures in animals reaching their highest levels while they are awake and their lowest levels while they are sleeping.

But the mechanism responsible for coordinating body temperature rhythm and adaptability to environmental challenges has been poorly understood.

In their newly published work, Lazar's team, including lead author Zachary Gerhart-Hines, PhD, shows that Rev-erb-alpha is a key player in how body temperature rhythms are synchronized and that its effects were produced mainly by circadian regulation in brown adipose tissue.

To examine the role of the nuclear receptor in brown fat, the researchers exposed normal mice and mice genetically engineered to lack the Rev-erb-alpha protein to cold challenges at different times of the day.

They found that:

  • Mice exposed to cold fared considerably better at 05.00 when Rev-erb-alpha was barely expressed than at 17:00 when Rev-erb-alpha was abundant.
  • Deletion of Rev-erb-alpha markedly improved cold tolerance at 17:00, indicating that overcoming Rev-erb-alpha-dependent repression was a fundamental feature of the thermogenic response to cold.
  • Physiological induction of uncoupling protein 1 (Ucp1) by cold temperatures was preceded by rapid down-regulation of Rev-erb-alpha in brown adipose tissue (BAT).
  • Rev-erb-alpha repressed Ucp1 in a brown-adipose-cell-autonomous manner, and BAT Ucp1 levels were higher in Rev-erb-alpha-null mice, even at thermoneutrality.

The genetically altered mice did not show the normal rhythms of body temperature and brown-fat activity.

"Thus, Rev-erb-alpha acts as a thermogenic focal point required for establishing and maintaining body temperature rhythm in a manner that is adaptable to environmental demands," the researchers wrote.

Lazar said the discovery turns nearly 300 years of thinking about how body temperature is controlled on its head, and it provides a new avenue of research for weight-loss therapies.

Lower body temperatures during sleep may have conveyed an evolutionary advantage by preserving energy stores when food was scarce, but today it is more likely to contribute to obesity.

"If we had a drug that raised body temperatures at night -- at the time when brown fat is naturally low -- people would theoretically burn more calories at night and lose weight," Lazar said.

He added that many years of research will be needed to determine if such a drug is possible.

"What we can say is that American scientists have pushed the envelope on our knowledge of what is regulating our basic physiology," he said. "This is stuff that we thought we understood, but now 300 years later we realize there's more to know."

This research was supported by grants from the Natinal Institutes of Health and the JPB Foundation.

ResearcherAnn Bugge was funded by the Novo Nordisk STAR postdoctoral program.

The authors declaire no competing financial interests.

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