How liver 'talks' to muscle: A well-timed, coordinated conversation

October 23, 2013

Boston, MA - A major collaborative research effort involving scientists at Harvard School of Public Health (HSPH), Brigham and Women's Hospital (BWH) and Harvard University have uncovered a novel signal mechanism that controls how fat storage in the liver can communicate with fat burning in skeletal muscle.

Especially striking is that 1) this 'conversation' involves one nuclear receptor-controlling gene expression in the liver influencing another nuclear receptor in muscle, 2) this circuit is influenced by day-night cycles, and 3) the research team identified a specific circulating lipid molecule that plays the role of messenger between liver and muscle.

The study will appear in the October 24, 2013 issue of Nature.

Maintaining the overall balance of energy involves the ability to use fatty acids to make lipids, a process known as de novo lipogenesis that occurs in the liver. Fatty acids are also burned to generate energy, as occurs in skeletal muscle. Given differences in the need for an organism to burn fatty acids while awake versus asleep, prior work has suggested that lipogenesis, and the genes involved in these pathways, vary in circadian (day-night) patterns.

Programs for energy use and storage are regulated by nuclear receptors--transcription factors that control entire programs of genes. PPAR delta regulates lipogenesis and PPAR alpha governs fatty acid oxidation. Disordered lipogenesis and fatty acid oxidation are important contributors to obesity-associated problems like fatty liver and diabetes.

In the study, researchers demonstrate that when the liver makes fat through lipogenesis, a signal is sent to skeletal muscle cells to burn fat through fatty acid oxidation. The fat-making process in the liver is controlled by PPAR delta, while the fat-burning process in muscle is controlled by PPAR alpha. Using a process of isolating lipid molecules appearing in plasma, the researchers uncovered a specific lipid molecule, namely a phospholipid that is released by the liver into the blood stream under the control of PPAR delta and serves as the signal to PPAR alpha in skeletal muscle.

Mice lacking PPAR delta in the liver lost production of this molecule while mice lacking PPAR alpha no longer responded to this signal. This pathway between liver and muscle also exhibited a circadian rhythm. Moreover, high-fat feeding altered these processes, consistent with other data implicating obesity effects on normal day-night cycles.

"This finding uncovers a joint effort of the liver and muscle to maintain balanced fat production and burning, a biological process tailored to match the body's energy demands and maximize fuel-burning efficiencies during the day versus night," said Chih-Hao Lee, PhD, HSPH associate professor of Genetics and Complex Diseases, corresponding senior author.

"It is increasingly evident that metabolic responses and diseases influenced by metabolic abnormalities, involve coordinated changes in organs like the liver and muscle," said Jorge Plutzky, MD, director of the BWH Vascular Disease Prevention Program, senior co-author. "By identifying a liver-to-muscle circuit involving fat storage and fatty acid oxidation, and a naturally occurring candidate molecule involved in directing these effects, this study highlights the nature of such integrated responses, and the evolving power of combining traditional experimental models in cells and pre-clinical models with profiling approaches like lipidomics."

The researchers are now studying how this phospholipid is carried in the circulatory system and delivered to muscle. They hope the work generates greater understanding of normal metabolism in liver and muscle and provides new therapeutic opportunities to treat fatty liver, obesity and diabetes.
-end-
The study was also led by co-first authors Sihao Lee, PhD, Harvard School of Public Health; Jonathan Brown, MD, Brigham and Women's Hospital; senior co-author, Alan Saghatelian, PhD, Harvard University; and senior co-author, Gokhan S. Hotamisligil, MD, PhD, Harvard School of Public Health.

This research was supported by the American Heart Association, American Diabetes Association and National Institutes of Health (R01DK075046, R01HL048743, K08HL105678).

Brigham and Women's Hospital (BWH) is a 793-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare. BWH has more than 3.5 million annual patient visits, is the largest birthing center in New England and employs nearly 15,000 people. The Brigham's medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in patient care, quality improvement and patient safety initiatives, and its dedication to research, innovation, community engagement and educating and training the next generation of health care professionals. Through investigation and discovery conducted at its Biomedical Research Institute (BRI), BWH is an international leader in basic, clinical and translational research on human diseases, more than 1,000 physician-investigators and renowned biomedical scientists and faculty supported by nearly $650 million in funding. For the last 25 years, BWH ranked second in research funding from the National Institutes of Health (NIH) among independent hospitals. BWH continually pushes the boundaries of medicine, including building on its legacy in transplantation by performing a partial face transplant in 2009 and the nation's first full face transplant in 2011. BWH is also home to major landmark epidemiologic population studies, including the Nurses' and Physicians' Health Studies and the Women's Health Initiative. For more information and resources, please visit BWH's online newsroom.

Harvard School of Public Health brings together dedicated experts from many disciplines to educate new generations of global health leaders and produce powerful ideas that improve the lives and health of people everywhere. As a community of leading scientists, educators, and students, we work together to take innovative ideas from the laboratory to people's lives--not only making scientific breakthroughs, but also working to change individual behaviors, public policies, and health care practices. Each year, more than 400 faculty members at HSPH teach 1,000-plus full-time students from around the world and train thousands more through online and executive education courses. Founded in 1913 as the Harvard-MIT School of Health Officers, the School is recognized as the oldest professional training program in public health. For more information on the school visit: http://www.hsph.harvard.edu

Brigham and Women's Hospital

Related Public Health Articles from Brightsurf:

COVID-19 and the decolonization of Indigenous public health
Indigenous self-determination, leadership and knowledge have helped protect Indigenous communities in Canada during the coronavirus disease 2019 (COVID-19) pandemic, and these principles should be incorporated into public health in future, argue the authors of a commentary in CMAJ (Canadian Medical Association Journal) http://www.cmaj.ca/lookup/doi/10.1503/cmaj.200852.

Public health consequences of policing homelessness
In a new study examining homelessness, researchers find that policy such a lifestyle has massive public health implications, making sleeping on the street even MORE unhealthy.

Electronic health information exchange improves public health disease reporting
Disease tracking is an important area of focus for health departments in the midst of the COVID-19 pandemic.

Pandemic likely to cause long-term health problems, Yale School of Public Health finds
The coronavirus pandemic's life-altering effects are likely to result in lasting physical and mental health consequences for many people--particularly those from vulnerable populations--a new study led by the Yale School of Public Health finds.

The Lancet Public Health: US modelling study estimates impact of school closures for COVID-19 on US health-care workforce and associated mortality
US policymakers considering physical distancing measures to slow the spread of COVID-19 face a difficult trade-off between closing schools to reduce transmission and new cases, and potential health-care worker absenteeism due to additional childcare needs that could ultimately increase mortality from COVID-19, according to new modelling research published in The Lancet Public Health journal.

The Lancet Public Health: Access to identification documents reflecting gender identity may improve trans mental health
Results from a survey of over 20,000 American trans adults suggest that having access to identification documents which reflect their identified gender helps to improve their mental health and may reduce suicidal thoughts, according to a study published in The Lancet Public Health journal.

The Lancet Public Health: Study estimates mental health impact of welfare reform, Universal Credit, in Great Britain
The 2013 Universal Credit welfare reform appears to have led to an increase in the prevalence of psychological distress among unemployed recipients, according to a nationally representative study following more than 52,000 working-age individuals from England, Wales, and Scotland over nine years between 2009-2018, published as part of an issue of The Lancet Public Health journal on income and health.

BU researchers: Pornography is not a 'public health crisis'
Researchers from the Boston University School of Public Health (BUSPH) have written an editorial in the American Journal of Public Health special February issue arguing against the claim that pornography is a public health crisis, and explaining why such a claim actually endangers the health of the public.

The Lancet Public Health: Ageism linked to poorer health in older people in England
Ageism may be linked with poorer health in older people in England, according to an observational study of over 7,500 people aged over 50 published in The Lancet Public Health journal.

Study: Public transportation use linked to better public health
Promoting robust public transportation systems may come with a bonus for public health -- lower obesity rates.

Read More: Public Health News and Public Health Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.