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How nutrition influences metabolism through circadian rhythms

Nutrition influences metabolism through circadian rhythms, a recent University of California - Irvine (UCI) study, "Reprogramming of the Circadian Clock by Nutritional Challenge," published in the December 19, 2013 issue of the journal Cell, finds.

The genetics of circadian rhythms.
Photo credit: Daniel A. Anderson / UC Irvine. Paolo Sassone-Corsi is one of the world’s leading researchers on the genetics of circadian rhythms.

Reprogramming of your liver 'clock' may contribute to metabolic disorders. A high-fat diet affects the molecular mechanism controlling the internal body clock that regulates metabolic functions in the liver, UC Irvine scientists have found. Disruption of these circadian rhythms may contribute to metabolic distress ailments, such as diabetes, obesity and high blood pressure. This reprogramming of your liver's internal circadian rhythm clock takes place independent of the state of obesity. Rather, it's solely dependent upon caloric intake – showing the remarkable adaptability of the circadian clock.

There's good news, though. The researchers also discovered that returning to a balanced, low-fat diet normalized the rhythms. This study reveals that the circadian clock is able to reprogram itself depending on a diet's nutritional content – which could lead to the identification of novel pharmacological targets for controlled diets.

UC Irvine's Paolo Sassone-Corsi, the Donald Bren Professor of Biological Chemistry and one of the world's leading researchers on the genetics of circadian rhythms, led the study, which appears in the journal Cell.

Circadian rhythms of 24 hours govern fundamental physiological functions in virtually all organisms. The circadian clocks are intrinsic time-tracking systems in our bodies that anticipate environmental changes and adapt themselves to the appropriate time of day. Changes to these rhythms can profoundly influence human health. Up to 15 percent of people's genes are regulated by the day-night pattern of circadian rhythms, including those involved with metabolic pathways in the liver.

A high-fat diet reprograms the liver clock through two main mechanisms. One blocks normal cycles by impeding the clock regulator genes called CLOCK:BMAL1. The other initiates a new program of oscillations by activating genes that normally do not oscillate, principally through a factor called PPAR-gamma. Previously implicated in inflammatory responses and the formation of fatty tissue, this factor oscillates with a high-fat diet

A high-fat diet reprograms the liver's internal biorhythm clock

It's noteworthy, Sassone-Corsi said, according to the December 19, 2013 news release, Nutrition influences metabolism through circadian rhythms, UCI study finds, that this reprogramming takes place independent of the state of obesity. Rather, it's solely dependent upon caloric intake – showing the remarkable adaptability of the circadian clock. The authors will extend their research to the effects of a high-fat diet on other body components, including muscle, fat, the brain and blood plasma.

Pierre Baldi, Kristin Eckel-Mahan, Vishal Patel, Sara de Mateo Lopez, Ricardo Orozco Solis, Nicholas Ceglia, Saurabh Sahar and Sherry Dilag-Penilla of UC Irvine; and Kenneth Dyar of the Venetian Institute of Molecular Medicine in Padova, Italy, contributed to the study, which received support from the National Institutes of Health (grants F32 DK083881, GM081634, AG033888, LM010235 and T15 LM07443), the National Science Foundation, the Merieux Research Institute and Sirtris/GSK.

You also may wish to see the abstracts of similar studies and articles such as, "Circadian rhythms have profound influence on metabolic output, UCI study reveals," "Body clock controls how body burns fat," "Circadian rhythms can be modified for potential treatment of disorders," and "Circadian rhythms control body’s response to intestinal infections, UCI-led study finds."

How would a disruption of your internal body clock contribute to obesity?

If there's a disruption of your internal body clock, it could contribute to obesity. Here's how it works. Your eating patterns are subject to circadian rhythms. That's your internal body clock. Interrupt your internal body clock, and up pops certain metabolic disorders known as body clock dysregulation, which in turn may lead to inflammation and insulin resistance.

A team of Texas A&M University System scientists have investigated how "body clock dysregulation" might affect obesity-related metabolic disorders, says a new study. The team was led by Dr. Chaodong Wu, associate professor in the department of nutrition and food sciences of Texas A&M's College of Agriculture and Life Sciences, and Dr. David Earnest, professor in the department of neuroscience and experimental therapeutics, Texas A&M Health Science Center. You can check out the abstract of the study, "Myeloid cell-specific Disruption of Period1 and Period2 Exacerbates Diet-induced Inflammation and Insulin Resistance," published online April 25, 2014 in the Journal of Biological Chemistry.

"Animal sleeping and eating patterns, including those of humans, are subject to a circadian rhythmicity," Earnest said, according to the May 14, 2014 news release, Texas A&M-led study shows how 'body clock' dysregulation underlies obesity, more. "And previous studies have shown an association between the dysregulation of circadian or body clock rhythms and some metabolic disorders."

Obesity-associated metabolic disorders and diet-induced inflammation may interfere with your internal body clock

Macrophage circadian dysregulation contributes to diet-induced inflammation and metabolic phenotypes in adipose and liver tissues. Why this is significant is that interactions between circadian clocks and pathways mediating adipose tissue inflammation are critical in the development and possibly treatment of obesity-associated metabolic disorders.

Wu said circadian clocks in peripheral tissues and cells drive daily rhythms and coordinate many physiological processes, including inflammation and metabolism. "And recent scientific observations suggest that disruption of circadian clock regulation plays a key role in the development of metabolic diseases, including obesity and diabetes," he noted.

He said this study affirms that eating unhealthy foods causes health problems and that it's much worse to eat unhealthy foods at the wrong time. It also indicates that "time-based treatment may provide better management of metabolic diseases.

"To promote human health, we need not only to eat healthy foods, but also more importantly to keep a healthy lifestyle, which includes avoiding sleeping late and eating at night," he said, according to the news release

Wu and Earnest said while previous studies using mice with genetic mutation of the removal of core clock genes has indicated that specific disruption of circadian clock function alters metabolism or produces obesity, the mechanism remained unknown. As key components of inflammation in obesity, macrophages, which are immune cells, contain cell-autonomous circadian clocks that have been shown to gate inflammatory responses.

"Our hypothesis was that overnutrition causes circadian clock dysregulation, which induces pro-inflammatory activity in adipose tissue. This then worsens inflammation and fat deposition, leading to systematic insulin resistance," Wu said, according to the news release.

To test the hypothesis, the team conducted experiments with "reporter mice" in which the circadian rhythmicity of various types of cells could be monitored by looking at their reporter activity. Accordingly, the reporter mice were put on a 12-hour light-dark cycle and were fed a high-fat diet. Additional reporter mice were fed a low-fat diet and served as controls. In this set of experiments, the team was able to characterize the effects of a high-fat diet on circadian clock rhythmicity and inflammatory responses in immune cells, or macrophages.

To further define a unique role for circadian clock dysregulation in metabolic disorders, the team conducted "bone marrow transplantation" experiments, through which the rhythmicity of circadian clocks was disrupted only in a specific type of immune cells. After high-fat diet feeding, the transplanted mice were used for collection of blood and tissue samples. A number of physiological and immunological assays also were performed on the mice.

Earnest said, according to the news release, that results showed that during obesity, that is when mice were fed a high-fat diet, the rhythmicity of circadian clocks in immune cells of fat tissue is dysregulated by a prolonged rhythmic period. This is, in turn, is linked to increased accumulation of immune cells in fat tissue and decreased whole-body insulin sensitivity.

"Animals on a high-fat diet display metabolic problems associated with obesity," Earnest said in the news release. "The problems are worsened in animals whose circadian clocks in immune cells are disrupted." Earnest and Wu explained, according to the news release, that the study will help those involved in human health and nutrition better understand the underlying mechanisms related to obesity and diabetes. For more information, you may wish to check out the Texas A&M AgriLife Communications website.

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