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PHILADELPHIA— Nearly every cell in the body has its own 24-hour clock, and new research from the Perelman School of Medicine at the University of Pennsylvania shows the way those clocks interact with each other plays a critical role in the health of a person’s metabolism. It’s widely reported that shift workers suffer from high rates of obesity and diabetes when their internal clocks do not coordinate with each other, as well as due to irregular eating times. However, little is known about the interaction between internal clocks and eating schedules, and specifically, the impact on overall health.

Now, in a new study published today in Science, a team of researchers led by Mitchell Lazar, MD, PhD, the Willard and Rhoda Ware Professor in Diabetes and Metabolic Diseases and director of Penn’s Institute for Diabetes, Obesity, and Metabolism, sheds new light on the question.

“The internal clocks in the brain synchronize clocks in peripheral tissues, and misalignment of this system is associated with metabolic dysfunction,” said Lazar, the senior author of the study. “But how the environment and genetic factors control the clocks in peripheral tissue and whether communication exists between clocks in different cell types are largely unknown.”

Lazar’s team, led by postdoctoral fellow Dongyin Guan, PhD, established a new mouse model that can specifically disrupt the internal clock in hepatocytes, the major cell type in the liver, which is the body’s metabolic hub. As a result of this disruption, researchers observed an accumulation of triglycerides in the blood that increase the risk of heart disease, diabetes, and stroke. These results indicate the importance of the internal clocks in peripheral tissue of the liver in maintaining metabolic homeostasis.

Surprisingly, the metabolism of other cell types in the liver were also reprogrammed when the internal clock of hepatocytes was disrupted.

“Our discovery of clock communication between different cell types is very exciting as it suggests a previously unappreciated way that the body’s rhythms are coordinated,” said Guan.

Although day/night cycles influence behavioral rhythms, such as sleeping, emerging evidence suggests that food consumption is an important factor in synchronizing peripheral clocks. Recent research showed time-restricted eating can benefit metabolism, and many dieters try intermittent fasting to lose weight. The Lazar team observed that both food timing and the integrity of the internal clock in the liver altered rhythms of metabolism. Specifically, they showed that nearly half of rhythmic genes are regulated by both the internal clock and when the mice ate their food.

Lazar is hopeful that a better understanding of how food affects the body’s internal rhythms could lead to an optimized diet schedule, which could be an important preventive approach for shift workers as well as a potential therapeutic strategy for patients with metabolic disorders such as obesity and diabetes.

Penn co-authors include Ying Xiong, Trang Minh Trinh, Yang Xiao, Wenxiang Hu, Chunjie Jiang, and Pieterjan Dierickx. Joshua D. Rabinowitz and Cholsoon Jang from Princeton University were also involved in the study.

The study was supported by the National Institutes of Health (R01-DK045586, DK19525, and F32DK116519), the JPB Foundation, American Diabetes Association Training Grant (1-17-PDF-076 and 1-18-PDF-132) and American Heart Association Training Grant (20POST35210738).

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Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $8.6 billion enterprise.

The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $494 million awarded in the 2019 fiscal year.

The University of Pennsylvania Health System’s patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center—which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report—Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nation’s first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

Penn Medicine is powered by a talented and dedicated workforce of more than 43,900 people. The organization also has alliances with top community health systems across both Southeastern Pennsylvania and Southern New Jersey, creating more options for patients no matter where they live.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2019, Penn Medicine provided more than $583 million to benefit our community.

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