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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It's Not an Apple a Day After All -- It's Strawberries: Flavonoids Could Represent Two-Fisted Assault On Diabetes and Nervous System Disorders

It's Not an Apple a Day After All -- It's Strawberries: Flavonoids Could Represent Two-Fisted Assault On Diabetes and Nervous System Disorders

  8:52:00 PM    Science Lover

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A recent study from scientists at the Salk Institute for Biological Studies suggests that a strawberry a day (or more accurately, 37 of them) could keep not just one doctor away, but an entire fleet of them, including the neurologist, the endocrinologist, and maybe even the oncologist.

Fisetin, a naturally-occurring flavonoid found most 
abundantly in strawberries, lessens complications of diabetes. 
(Credit: Courtesy of the Salk Institute for Biological Studies)

Investigations conducted in the Salk Institute's Cellular Neurobiology Laboratory (CNL) will appear in the June 27, 2011, issue of PLoS ONE. The report explains that fisetin, a naturally-occurring flavonoid found most abundantly in strawberries and to a lesser extent in other fruits and vegetables, lessens complications of diabetes. Previously, the lab showed that fisetin promoted survival of neurons grown in culture and enhanced memory in healthy mice. That fisetin can target multiple organs strongly suggests that a single drug could be used to mitigate numerous medical complications.

"This manuscript describes for the first time a drug that prevents both kidney and brain complications in a type 1 diabetes mouse model," says David Schubert, Ph.D., professor and head of the Cellular Neurobiology Laboratory and one of the manuscript's co-authors. "Moreover, it demonstrates the probable molecular basis of how the therapeutic is working."

Pam Maher, Ph.D., a senior staff scientist in the CNL, is the study's corresponding author. Maher initially identified fisetin as a neuroprotective flavonoid ten years ago. "In plants, flavonoids act as sunscreens and protect leaves and fruit from insects," she explains. "As foods they are implicated in the protective effect of the 'Mediterranean Diet.'"

Other celebrity flavonoids include polyphenolic compounds in blueberries and red wine.

Although her group's focus is neurobiology, Maher and colleagues reasoned that, like other flavonoids, fisetin might ameliorate a spectrum of disorders seen in diabetic patients. To test this, they evaluated effects of fisetin supplementation in Akita mice, a very robust model of type 1 diabetes, also called childhood onset diabetes.

Akita mice exhibit increased blood sugar typical of type 1 diabetes and display pathologies seen in serious human complications of both type 1 and 2 diabetes. Those include diabetic nephropathy or kidney disease, retinopathy, and neuropathies in which patients lose touch or heat sensations.

Mice fed a fisetin-enriched diet remained diabetic, but acute kidney enlargement-or hypertrophy-seen in untreated mice was reversed, and high urine protein levels, a sure sign of kidney disease, fell. Moreover, fisetin ingestion ameliorated anxiety-related behaviors seen in diabetic mice. "Most mice put in a large area become exploratory," says Maher. "But anxious mice tend not to move around. Akita mice showed enhanced anxiety behavior, but fisetin feeding restored their locomotion to more normal levels."



The study also defines a likely molecular mechanism underlying these effects. Researchers observed that blood and brain levels of sugars affixed to proteins known as advanced glycation end-products-or AGEs-were reduced in fisetin-treated compared to untreated Akita mice. These decreases were accompanied by increased activity of the enzyme glyoxalase 1, which promotes removal of toxic AGE precursors.

The discovery of an AGE-antagonizing enzyme upregulated by fisetin is very intriguing, because substantial evidence implicates high blood AGE levels with many if not most diabetic complications. "We know that fisetin increases activity of the glyoxalase enzyme and may increase its expression," says Maher. "But what is important is that ours is the first report that any compound can enhance glyoxalase 1 activity."

Interestingly, excessively high AGE levels also correlate with inflammatory activity thought to promote some cancers. In fact, studies published by others confirm that fisetin decreases tumorigenicity of prostate cancer cells both in culture and in animal models, which if supported would represent a major added incentive to eat your strawberries.

To ingest fisetin levels equivalent to those fed Akita mice, Maher estimates that humans would have to eat 37 strawberries a day, assuming that strawberry fisetin is as readily metabolizable by humans as fisetin-spiked lab chow is by mice. Rather than through diet, Maher envisions that fisetin-like drugs could be taken as a supplement.

Schubert notes that fisetin is also effective in mouse models of Alzheimer's disease. "We and others have shown that diabetes may be a risk factor for Alzheimer's disease, making identification of a safe prophylactic like fisetin highly significant," he says.

Maher acknowledges that the public may be suffering from flavonoid-fatigue, given media coverage of the promises of these compounds. "Polyphenolics like fisetin and those in blueberry extracts are found in fruits and vegetables and are related to each other chemically," she says. "There is increasing evidence that they all work in multiple diseases. Hopefully some combination of these compounds will eventually get to the clinic."

Schubert concurs that their findings only reinforce what common sense and our mothers told us was a healthy lifestyle. "Eat a balanced diet and as much freshly prepared organic food as possible, get some exercise, keep socially and mentally active and avoid sodas with sugar and highly processed foods since they can contain high levels of AGEs," he advises.

But he also worries that hoops that must be jumped through to bring a natural product like fisetin, as opposed to a totally synthetic drug, to clinical trials are daunting because it is difficult to protect patents on natural products. "We will never know if a compound like fisetin works in humans until someone is willing to support a clinical trial."

Also contributing to this study were Richard Dargusch and Jennifer L. Ehren, Ph.D.,of the Cellular Neurobiology Laboratory, and Kumar Sharma, M.D., and Shinichi Okada, M.D., Ph.D., of the Department of Medicine at University of California, San Diego.

Funding for the study came from the Fritz B. Burns Foundation, the Juvenile Diabetes Research Foundation, the Hewitt Foundation, and the National Institutes of Health.

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From Eye to Brain: Researchers Map Functional Connections Between Retinal Neurons at Single-Cell Resolution

From Eye to Brain: Researchers Map Functional Connections Between Retinal Neurons at Single-Cell Resolution

  10:00:00 AM    Science Lover

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By comparing a clearly defined visual input with the electrical output of the retina, researchers at the Salk Institute for Biological Studies were able to trace for the first time the neuronal circuitry that connects individual photoreceptors with retinal ganglion cells, the neurons that carry visuals signals from the eye to the brain.

A unique neural recording system developed by an 
international team of high energy physicists, which 
is able to record simultaneously the tiny electrical 
signals generated by hundreds of the retinal output 
neurons, is one of the essential elements of the study. 
Recording electrodes are shown in the foreground 
and retinal ganglion cells in the background. 
(Credit: Image: Courtesy of Dr. E.J. Chichilnisky, 
Salk Institute for Biological Studies)

Their measurements, published in the Oct. 7, 2010, issue of the journal Nature, not only reveal computations in a neural circuit at the elementary resolution of individual neurons but also shed light on the neural code used by the retina to relay color information to the brain.

"Nobody has ever seen the entire input-output transformation performed by complete circuits in the retina at single-cell resolution," says senior author E.J. Chichilnisky, Ph.D., an associate professor in the Systems Neurobiology Laboratories. "We think these data will allow us to more deeply understand neuronal computations in the visual system and ultimately may help us construct better retinal implants."

One of the essential elements that made the experiments possible was the unique neural recording system developed by an international team of high-energy physicists from the University of California, Santa Cruz; the AGH University of Science and Technology, Krakow, Poland; and the University of Glasgow, UK. This system is able to record simultaneously the tiny electrical signals generated by hundreds of the retinal output neurons that transmit information about the outside visual world to the brain. These recordings are made at high-speed (over ten million samples each second) and with fine spatial detail, sufficient to detect even a locally complete population of the tiny and densely spaced output cells known as "midget" retinal ganglion cells.

Retinal ganglion cells are classified based on their size, the connections they form, and their responses to visual stimulation, which can vary widely. Despite their differences, they all have one thing in common-a long axon that extends into the brain and forms part of the optic nerve.

Visual processing begins when photons entering the eye strike one or more of the 125 million light-sensitive nerve cells in the retina. This first layer of cells, which are known as rods and cones, converts the information into electrical signals and sends them to an intermediate layer, which in turn relays signals to the 20 or so distinct types of retinal ganglion cells.

In an earlier study, Chichilnisky and his team found that each type of retinal ganglion cells forms a seamless lattice covering visual space that transmits a complete visual image to the brain. In the current study, postdoctoral researcher and co-first author Greg D. Field, Ph.D., and his collaborators zoomed in on the pattern of connectivity between these layers of retinal ganglion cells and the full lattice of cone receptors.

The Salk researchers simultaneously recorded hundreds of retinal ganglion cells, and based on density and light response properties, identified five cell types: ON and OFF midget cells, ON and OFF parasol cells, and small bistratified cells, which collectively account for approximately 75 percent of all retinal ganglion cells.

To resolve the fine structure of receptive fields-the small, irregularly shaped windows through which neurons in retina view the world-the authors used stimuli with tenfold smaller pixels. "Instead of a diffuse region of light sensitivity, we detected punctate islands of light sensitivity separated by regions of no light sensitivity," he says.

When combined with information on spectral sensitivities of individual cones, maps of these punctate islands not only allowed the researchers to recreate the full cone mosaic found in the retina, but also to conclude which cone fed information to which retinal ganglion cell.

"Just by stimulating input cells and taking a high density recording from output cells, we can identify all individual input and output cells and find out who is connected to whom," says Chichilnisky.

Chichilnisky and his team discovered that populations of ON and OFF midget and parasol cells each sampled the complete population of cones sensitive to red or green light, with midget cells sampling these cones in a surprisingly non-random fashion. Only OFF midget cells frequently received strong input from cones sensitive to blue light.

The research was funded in part by the Helen Hay Whitney Foundation, the German Research Foundation, the National Institutes of Health, the Chapman Foundation, the Miller Institute for Basic Research in Science, the Polish Ministry of Science and Higher Education, the Burroughs Wellcome Trust, the McKnight Foundation, the National Science Foundation, the Sloan Foundation, the Engineering and Physical Sciences Research Council and The Royal Society of Edinburgh.

Researchers who also contributed to the work include co-first author Jeffrey L. Gauthier, Ph.D., Martin Greschner, Timothy A. Machado, Lauren H. Jepson, and Jonathon Shlens in the Systems Neurobiology Laboratory at the Salk Institute, co-first author Alexander Sher and Alan Litke at the Santa Cruz Institute for Particle Physics at the University of California, Santa Cruz, Deborah E. Gunning and Keith Mathieson in the Department of Physics and Astronomy at the University of Glasgow, Wladyslaw Dabrowski at the Faculty of Physics and Applied Computer Science at the AGH University of Science and Technology in Krakow, and Liam Paninski in the Department of Statistics and Center for Theoretical Neuroscience at Columbia University, New York.

Editor's Note: This article is not intended to provide medical advice, diagnosis or treatment.

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