{"id":10002,"date":"2016-05-26T14:10:36","date_gmt":"2016-05-26T21:10:36","guid":{"rendered":"https:\/\/vermont.salk.edu\/?post_type=disclosure&p=10002"},"modified":"2024-01-30T15:38:55","modified_gmt":"2024-01-30T23:38:55","slug":"powering-up-the-circadian-rhythm","status":"publish","type":"disclosure","link":"https:\/\/www.salk.edu\/de\/news-release\/powering-up-the-circadian-rhythm\/","title":{"rendered":"Powering up the circadian rhythm"},"content":{"rendered":"

LA JOLLA\u2014At noon every day, levels of genes and proteins throughout your body are drastically different than they are at midnight. Disruptions to this 24-hour cycle of physiological activity are why jet lag or a bad night\u2019s sleep can alter your appetite and sleep patterns for days\u2014and even contribute to conditions like heart disease, sleep disorders and cancers.<\/p>\n

Now, scientists at the Salk Institute and collaborators have discovered a key player\u2014a protein called REV-ERB\u03b1\u2014that controls the strength of this circadian rhythm in mammals. The discovery is unusual in the field, as most circadian genes and proteins only shift the timing or length of the daily cycle.<\/p>\n

“Whether it is Beethoven’s 9th Symphony on your stereo or the symphony of genes in our bodies, both require volume to be heard,\u201d says senior author Ronald Evans<\/a>, director of Salk\u2019s Gene Expression Laboratory, a Howard Hughes Medical Institute<\/a> investigator, and holder of the March of Dimes Chair in Molecular and Developmental Biology. \u201cOur recent work describes how REV-ERB\u03b1 acts as a molecular conductor to allows the volume or activity of thousands of genes to be dialed up or down.\u201d<\/p>\n

\"liver-left-normal-right-FBXW7-deletion\"
Researchers led by the Salk Institute are the first to discover a protein that controls the strength of the body\u2019s circadian rhythms. A mouse liver with a \u201cweak\u201d circadian clock, caused by the targeted deletion of FBXW7 (right), has disrupted the lipid metabolism program and promoted lipid accumulation, compared to the normal liver (left). <\/p>\n

Klicken Sie hier<\/a> for a high-resolution image<\/p>\n

Kredit: Salk Institut<\/figcaption><\/figure>\n

Disrupting just the amplitude\u2014or strength\u2014component of the circadian cycle, Evans adds, was enough to alter hormone levels, including those that wake us up in the morning. This means that people with lower amplitude fluctuations of the genes might feel flat and have less energy during the day. The results are described in the May 26, 2016 issue of Zelle<\/a><\/em>.<\/p>\n

Previous research in the field revealed genes that cycle on and off throughout the day and showed how altering these circadian genes can shift the timing of the cycle and make the circadian rhythm longer or shorter than 24 hours. In 2012, Evans\u2019 group showed that REV-ERB\u03b1 bound to many of these circadian genes and acted as a brake, affecting when during the day or night they were expressed.<\/p>\n

\u201cWe saw REV-ERB\u03b1 interacting with all these circadian-related genes,\u201d says Xuan Zhao, a research associate in the Evans lab and first author of the new paper. \u201cSo we wanted to see if it had a more central role in circadian rhythms.\u201d<\/p>\n

In the new work, the team analyzed levels and molecular characteristics of REV-ERB\u03b1 in the livers of mice throughout the day. They found that after its levels peaked during the day, two proteins, CDK1 and FBXW7, interacted with REV-ERB\u03b1 to help reduce its levels to a low point by the middle of the night.<\/p>\n

\"Back
Back row, from left: \u00a0Ling-wa Chong, Michael Downes, Ron Evans and Xuan Zhao
Front row, from left: \u00a0Ann Atkins, Ruth Yu and Ester Banayo <\/p>\n

Click here for a high-resolution image<\/a> <\/p>\n

Kredit: Salk Institut<\/figcaption><\/figure>\n

When Evans and his colleagues targeted these proteins to block the degradation of REV-ERB\u03b1 in the livers of mice, normal daily fluctuations in gene expression were suppressed, but the timing of the cycles wasn\u2019t affected. Interestingly, merely altering the amplitude of the gene expression oscillations profoundly affected metabolism, disrupting the levels of fats and sugars in the blood.<\/p>\n

\u201cThis study provides compelling molecular evidence for a key role for the circadian clock in regulating glucose and lipid metabolism, and points to new potential avenues for therapeutic intervention,\u201d says Steve Kay, president of The Scripps Research Institute, who collaborated with Evans on the work.<\/p>\n

The observation is the first time scientists have discovered a way to control the amplitude\u2014rather than the timing\u2014of the circadian cycle. Moreover, mice that lacked REV-ERB\u03b1 developed fatty liver disease, stressing the importance of regulating the intensity of the cycle.<\/p>\n

\u201cWe think that if you have a \u2018weak\u2019 circadian cycle, you can\u2019t get enough signal to affect physiology,\u201d says Zhao. \u201cConversely, having an extra \u2018strong\u2019 circadian cycle would probably not be good. Evolution has given us a Goldilocks, or \u2018just right,\u2019 circadian cycle that is optimal for our health.\u201d<\/p>\n

The researchers hope to investigate whether pharmacological compounds that block CDK1 may have the potential to treat circadian rhythm disruptions.<\/p>\n

\u201cPharmacologically, we can manipulate this system,\u201d says Michael Downes, a Salk senior scientist and a co-corresponding author of the paper. \u201cThe more we understand about how to do this, the better we can treat metabolic diseases and cancers related to the circadian cycle.\u201d<\/p>\n

Other researchers on the study were Han Cho, Ling-Wa Chong, Katja Lamia, Sihao Liu, Annette R. Atkins, Ester Banayo, and Ruth T. Yu of the Salk Institute; Tsuyoshi Hirota of the University of California, San Diego<\/a>; Xuemei Han and John R. Yates III of Das Scripps Research Institute<\/a>; and Christopher Liddle of the University of Sydney<\/a>.<\/p>\n

The work and the researchers involved were supported by grants from the Howard Hughes Medical Institute<\/a>, Nationale Gesundheitsinstitute<\/a>, der Glenn Stiftung f\u00fcr medizinische Forschung<\/a>, Die Leona M. und Harry B. Helmsley Charitable Trust<\/a>, Ipsen\/Biomeasure<\/a>, The Lawrence Ellison Foundation<\/a>, der Samuel Waxman Krebsforschungsstiftung<\/a>, Susan G. Komen<\/a>, and the Glenn Stiftung f\u00fcr medizinische Forschung<\/a>.<\/p>","protected":false},"featured_media":9997,"template":"","faculty":[91],"disease-research":[123],"class_list":["post-10002","disclosure","type-disclosure","status-publish","has-post-thumbnail","hentry","faculty-ronald-evans","disease-research-metabolism-and-diabetes"],"acf":[],"yoast_head":"\nPowering up the circadian rhythm - Salk Institute for Biological Studies<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.salk.edu\/de\/news-release\/powering-up-the-circadian-rhythm\/\" \/>\n<meta property=\"og:locale\" content=\"de_DE\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Powering up the circadian rhythm - Salk Institute for Biological Studies\" \/>\n<meta property=\"og:description\" content=\"LA JOLLA\u2014At noon every day, levels of genes and proteins throughout your body are drastically different than they are at midnight. 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