Metabolic Switch for Storing or Burning Fat

Metabolic Switch for Storing or Burning Fat

  9:50:00 AM    Science Lover

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From Feast to Famine: A Metabolic Switch That May Help Diabetes Treatment

Humans are built to hunger for fat, packing it on during times of feast
and burning it during periods of famine. But when deluged by foods rich
in fat and sugar, the modern waistline often far exceeds the need to
store energy for lean times, and the result has been an epidemic of
diabetes, heart disease and other obesity-related problems.

The Salk researchers discovered that mice lacking a
protein known as fibroblast growth factor 1 (FGF1)
were unable to store and use fat normally. When these
mice were switched from a high-fat diet to a normal diet,
they developed uneven lumps of fat (seen in white in the
above image) in their body tissues, suggesting that their
fat metabolism mechanisms had gone awry. (Credit:
Courtesy of Jae Myoung Suh, research associate, Gene
Expression Laboratory)

Now, scientists at the Salk Institute for Biological Studies have identified the linchpin of fat metabolism, a protein known as fibroblast growth factor 1 (FGF1), which may open new avenues in the treatment of diabetes.

In a paper published April 22 in Nature, the Evans lab reports that FGF1 activity is triggered by a high-fat diet and that mice lacking the protein swiftly develop diabetes. This suggests that FGF1 is crucial to maintaining the body's sensitivity to insulin and normal levels of sugar in the blood.

"Because humans are good at storing fat during times of plenty, we are also excellent at surviving times of famine," says Ronald M. Evans, a professor in Salk's Gene Expression Laboratory and lead author of the paper. "The fat tissues of our body are like batteries, providing us with a steady source of energy when food is scarce. FGF1 governs the expansion and contraction of fat and thus controls the ebb and flow of energy throughout our body."

Obesity rates have soared in the United States in recent decades, with more than one third of U.S. adults and 17 percent of children and adolescents now considered obese, according to the Centers for Disease Control and Prevention.

As the number of overweight people has grown, so too has the incidence of metabolic disease, with nearly 26 million Americans estimated to have obesity-related type 2 diabetes. With annual costs exceeding well over $200 billion, obesity is a chronic disease that is consuming a huge portion of our health care dollars.

Although exercise and calorie restriction are known to be effective at preventing and treating diabetes, the obesity epidemic continues to grow and new drugs to treat the problem are desperately needed. Against this backdrop, the Evans' lab discovery is an important breakthrough -- -- and a surprise.

"The discovery of FGF1 was unexpected -- -- and intriguing -- -- because it was believed to do nothing," says Jae Myoung Suh, a postdoctoral researcher in Evans' laboratory and co-first author on the paper. "If you deplete FGF1 from the body, nothing happens when the mice are fed a steady low fat diet. But when given a high-fat, "Western-style" diet the mice develop an aggressive form of diabetes and experience a system-wide breakdown of their metabolic health."

"These abnormalities cause abdominal or stomach fat to become inflamed," says Michael Downes, a senior staff scientist in Salk's Gene Expression Laboratory and co-lead author on the paper. "This is important because inflamed visceral fat has been linked to heightened risk for diabetes and other obesity-related diseases, such as heart disease and stroke."

The scientists also found that FGF1 is regulated by the antidiabetic drug Actos, which is used to increase the body's sensitivity to insulin. But Actos and related drugs, though helpful, have side effects that limit their use.

Thus, Evans and his colleagues plan to explore whether FGF1 might point to a new way to control diabetes by avoiding the drawbacks of Actos and providing a more natural means of increasing insulin sensitivity.

The research was supported by the National Institutes of Health, the Leona M. and Harry B. Helmsley Charitable Trust and the Howard Hughes Medical Institute.

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Scientists Redraw the Blueprint of the Body's Biological Clock

Scientists Redraw the Blueprint of the Body's Biological Clock

  7:52:00 PM    Science Lover

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The discovery of a major gear in the biological clock that tells the body when to sleep and metabolize food may lead to new drugs to treat sleep problems and metabolic disorders, including diabetes.

The discovery of a major gear in the
biological clock that tells the body when
to sleep and metabolize food may lead
to new drugs to treat sleep problems and
metabolic disorders, including diabetes.
(Credit: © nicobatista / Fotolia)

Scientists at the Salk Institute for Biological Studies, led by Ronald M. Evans, a professor in Salk's Gene Expression Laboratory, showed that two cellular switches found on the nucleus of mouse cells, known as REV-ERBα and REV-ERBβ, are essential for maintaining normal sleeping and eating cycles and for metabolism of nutrients from food.

The findings, reported March 29 in Nature, describe a powerful link between circadian rhythms and metabolism and suggest a new avenue for treating disorders of both systems, including jet lag, sleep disorders, obesity and diabetes.

"This fundamentally changes our knowledge about the workings of the circadian clock and how it orchestrates our sleep-wake cycles, when we eat and even the times our bodies metabolize nutrients," says Evans. "Nuclear receptors can be targeted with drugs, which suggests we might be able to target REV-ERBα and β to treat disorders of sleep and metabolism."

Nurses, emergency personnel and others who work shifts that alter the normal 24-hour cycle of waking and sleeping are at much higher risk for a number of diseases, including metabolic disorders such as diabetes. To address this, scientists are trying to understand precisely how the biological clock works and uncover possible targets for drugs that could adjust the circadian rhythm in people with sleep disorders and circadian-associated metabolic disorders.

In mammals, the circadian timing system is orchestrated by a central clock in the brain and subsidiary clocks in most other organs. The master clock in the brain is set by light and determines the overall diurnal or nocturnal preference of an animal, including sleep-wake cycles and feeding behavior.

Scientists knew that two genes, BMAL1 and CLOCK, worked together at the core of the clock's molecular machinery to activate the network of circadian genes. In this way, BMAL1 acts like the accelerator on a car, activating genes to rev up our physiology each morning so that we are alert, hungry and physically active.

Prior to this work REV-ERBα and β were thought to play only a minor role in these cycles, possibly working together to slow CLOCK-BMAL1 activity to make minor adjustments to keep the clock running on time.

However, genetic studies of two genes with similar functions can be very difficult and thus the real importance of REV-ERBα and β remained mysterious.

The Salk scientists got around this hurdle by developing mice in which both genes could be turned off in the liver at any point by giving them an estrogen derivative called tamoxifen. Now mice could develop normally to adulthood, at which point the scientists could turn off REV-ERBα and REV-ERBβ in their livers -- -- an organ crucial to maintaining the correct balance of sugar and fat in blood -- -- to see what effects it had on circadian rhythms and metabolism.

"When we turned off both receptors, the animal's biological clocks went haywire," says Han Cho, first author on the paper and a postdoctoral researcher in Evan's laboratory. "The mice started running on their exercise wheels when they should have been resting. This suggested REV-ERBα and REV-ERBβ aren't an auxiliary system that makes minor adjustments, but an integral part of the clock's core mechanism. Without them, the clock can't function properly."

Digging more deeply into the clockworks, the Salk scientists mapped out the genes that the REV-ERBs control to keep the body operating on the right schedule, finding that they overlap with hundreds of the same genes controlled by CLOCK and BMAL1. This and other findings suggested that the REV-ERBs, act as a break on the genes BMAL1 activates.

"We thought that the core of the clock was an accelerator, and that all REV-ERBα and REV-ERBβ did was to pull the foot off that pedal," says Evans. "What we've shown is that these receptors act directly as a break to slow clock activity. Now we've got a accelerator and a break, each equally important in creating the daily rhythm of the clock."

The scientists also found that the REV-ERBs control the activity of hundreds of genes involved metabolism, including those responsible for controlling levels of fats and bile. The mice in which REV-ERBα and REV-ERBβ were turned off had high levels of fat and sugar in their blood -- -- common problems in people with metabolic disorders.

"This explains how our cellular metabolism is tied to daylight cycles determined by the movements of the sun and the earth," says Satchidananda Panda, an associate professor in Salk's Regulatory Biology Laboratory and co-author on the paper. "Now we want to find ways of leveraging this mechanism to fix a person's metabolic rhythms when they are disrupted by travel, shift work or sleep disorders."

Other researchers on the study were Xuan Zhao, Megumi Hatori, Ruth T. Yu, Grant D. Barish, Michael T. Lam, Ling-Wa Chong, Luciano DiTacchio, Annette R. Atkins and Michael Downes, from the Salk Institute; Christopher K. Glass, of University of California San Diego; Christopher Liddle, of University of Sydney, Australia; and Johan Auwerx, of Ecole Polytechnique Fédérale, Switzerland.

The research was supported by the National Institutes of Health, the National Health and Medical Research Council of Australia, the Leona M. and Harry B. Helmsley Charitable Trust, the Glenn Foundation for Medical Research and the Howard Hughes Medical Institute.

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Electricity and Carbon Dioxide Used to Generate Alternative Fuel

Electricity and Carbon Dioxide Used to Generate Alternative Fuel

  8:10:00 PM    Science Lover

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Imagine being able to use electricity to power your car -- even if it's not an electric vehicle. Researchers at the UCLA Henry Samueli School of Engineering and Applied Science have for the first time demonstrated a method for converting carbon dioxide into liquid fuel isobutanol using electricity.

Producing fuel from CO2 and sunlight. (Credit: Image
courtesy of University of California - Los Angeles)

Today, electrical energy generated by various methods is still difficult to store efficiently. Chemical batteries, hydraulic pumping and water splitting suffer from low energy-density storage or incompatibility with current transportation infrastructure.

In a study published March 30 in the journal Science, James Liao, UCLA's Ralph M. Parsons Foundation Chair in Chemical Engineering, and his team report a method for storing electrical energy as chemical energy in higher alcohols, which can be used as liquid transportation fuels.

"The current way to store electricity is with lithium ion batteries, in which the density is low, but when you store it in liquid fuel, the density could actually be very high," Liao said. "In addition, we have the potential to use electricity as transportation fuel without needing to change current infrastructure."

Liao and his team genetically engineered a lithoautotrophic microorganism known as Ralstonia eutropha H16 to produce isobutanol and 3-methyl-1-butanol in an electro-bioreactor using carbon dioxide as the sole carbon source and electricity as the sole energy input.

Photosynthesis is the process of converting light energy to chemical energy and storing it in the bonds of sugar. There are two parts to photosynthesis -- a light reaction and a dark reaction. The light reaction converts light energy to chemical energy and must take place in the light. The dark reaction, which converts CO2 to sugar, doesn't directly need light to occur.

"We've been able to separate the light reaction from the dark reaction and instead of using biological photosynthesis, we are using solar panels to convert the sunlight to electrical energy, then to a chemical intermediate, and using that to power carbon dioxide fixation to produce the fuel," Liao said. "This method could be more efficient than the biological system."

Liao explained that with biological systems, the plants used require large areas of agricultural land. However, because Liao's method does not require the light and dark reactions to take place together, solar panels, for example, can be built in the desert or on rooftops.

Theoretically, the hydrogen generated by solar electricity can drive CO2 conversion in lithoautotrophic microorganisms engineered to synthesize high-energy density liquid fuels. But the low solubility, low mass-transfer rate and the safety issues surrounding hydrogen limit the efficiency and scalability of such processes. Instead Liao's team found formic acid to be a favorable substitute and efficient energy carrier.

"Instead of using hydrogen, we use formic acid as the intermediary," Liao said. "We use electricity to generate formic acid and then use the formic acid to power the CO2 fixation in bacteria in the dark to produce isobutanol and higher alcohols."

The electrochemical formate production and the biological CO2 fixation and higher alcohol synthesis now open up the possibility of electricity-driven bioconversion of CO2 to a variety of chemicals. In addition, the transformation of formate into liquid fuel will also play an important role in the biomass refinery process, according to Liao.

"We've demonstrated the principle, and now we think we can scale up," he said. "That's our next step."

The study was funded by a grant from the U.S. Department of Energy's Advanced Research Projects Agency-Energy (ARPA-E).

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