Posts tagged metabolism

Twenty years after the hormone leptin was found to regulate metabolism, appetite, and weight through brain cells called neurons, Yale School of Medicine researchers have found that the hormone also acts on other types of cells to control appetite.

Published in the June 1 issue of Nature Neuroscience, the findings could lead to development of treatments for metabolic disorders such as obesity and diabetes.

"Up until now, the scientific community thought that leptin acts exclusively in neurons to modulate behavior and body weight," said senior author Tamas Horvath, the Jean and David W. Wallace Professor of Biomedical Research and chair of comparative medicine at Yale School of Medicine. "This work is now changing that paradigm."

Leptin, a naturally occurring hormone, is known for its hunger-blocking effect on the hypothalamus, a region in the brain. Food intake is influenced by signals that travel from the body to the brain. Leptin is one of the molecules that signal the brain to modulate food intake. It is produced in fat cells and informs the brain of the metabolic state. If animals are missing leptin, or the leptin receptor, they eat too much and become severely obese.

Leptin’s effect on metabolism has been found to control the brain’s neuronal circuits, but no previous studies have definitively found that leptin could control the behavior of cells other than neurons.

To test the theory, Horvath and his team selectively knocked out leptin receptors in the adult non-neuronal glial cells of mice. The team then recorded the water and food intake, as well as physical activity every five days. They found that animals responded less to feeding reducing effects of leptin but had heightened feeding responses to the hunger hormone ghrelin.

"Glial cells provide the main barrier between the periphery and the brain," said Horvath. "Thus glial cells could be targeted for drugs that treat metabolic disorders, including obesity and diabetes."

(Source: eurekalert.org)

A new study by scientists at McGill University and the University of Zurich shows a direct link between metabolism in brain cells and their ability to signal information. The research may explain why the seizures of many epilepsy patients can be controlled by a specially formulated diet. 

(Image caption: Neurons in the cerebellum. Credit: Bowie Lab/McGill University)

The findings, published Jan. 16 in Nature Communications, reveal that metabolism controls the processes that inhibit brain activity, such as that involved in convulsions. The study uncovers a link between how brain cells make energy and how the same cells signal information – processes that neuroscientists have often assumed to be distinct and separate. 

“Inhibition in the brain is commonly targeted in clinical practice,” notes Derek Bowie, Canada Research Chair in Receptor Pharmacology at McGill and corresponding author of the study. “For example, drugs that alleviate anxiety, induce anesthesia, or even control epilepsy work by strengthening brain inhibition. These pharmacological approaches can have their drawbacks, since patients often complain of unpleasant side effects.” 

The experiments showed an unexpected link between how the mitochondria of brain cells make energy and how the same cells signal information. Brain cells couple these two independent functions by using small chemical messengers, called reactive oxygen species (or ROS), that are normally associated with signaling cell death. While ROS are known to have roles in diseases of aging, such as Alzheimer’s and Parkinson’s, the new study shows they also play important roles in the healthy brain.  

The findings emerged from an ongoing collaboration between Prof. Bowie’s laboratory in McGill’s Department of Pharmacology and Therapeutics and a research team headed by Dr. Jean-Marc Fritschy, Professor of Pharmacology at the University of Zurich and current director of the Neuroscience Center Zurich (ZNZ). The researchers have the longer term aim of trying to understand why the seizures of many epilepsy patients — especially young children – can be treated with a high-fat, low-carbohydrate diet known as the ketogenic diet. 

The idea that diet can control seizures was noticed as far back as ancient Greece, during periods of fasting. From the 1920s until the 1950s, the ketogenic diet was widely used to treat epilepsy patients. With the introduction of anticonvulsant drugs in the 1950s, the dietary approach fell out of favour with doctors. But because anticonvulsant drugs don’t work for 20% to 30% of patients, there has been a resurgence in use of the ketogenic diet. 

“Since our study shows that brain cells have their own means to strengthen inhibition,” explains Prof Bowie, “our work points to potentially new ways in which to control a number of important neurological conditions including epilepsy.”

(Source: mcgill.ca)

Australian researchers have shed more light on an underexplored aspect of the important brain-signaling system that controls appetite, body composition and energy use. Their findings suggest that a specific gene regulating our body clock may play a central role in determining how fat we become.

Evolution has preserved the ‘neuropeptide Y (NPY) system’, as it is known, in most species – indicating its importance – and much of our understanding comes from studying it in mice. There is one important difference, however, between the NPY system in mouse and man.

In man, the neurotransmitter NPY communicates with four well-known ‘cell surface receptors’ in the brain (Y1, Y2, Y4 and Y5), which in turn trigger the system’s effects.

The new study has shown that mice have an additional receptor, Y6, which has profound effects on their body composition. Y6 is produced in a very small region of the brain that regulates the body clock, as well as growth hormone production.

PhD student Ernie Yulyaningsih, Dr Kim Loh, Dr Shu Lin and Professor Herbert Herzog from Sydney’s Garvan Institute of Medical Research, together with Associate Professor Amanda Sainsbury-Salis, now at the University of Sydney, deleted the Y6 gene from mice to understand its effects. Their study showed that mice without the Y6 gene were smaller, and had less lean tissue, than normal mice. On the other hand, as they aged, these ‘knockout mice’ grew fatter than the normal mice, especially when fed a high-fat diet. In that case, they became obese and developed metabolic problems similar to diabetes. These findings are now published online in the prestigious international journal, Cell Metabolism.

While the gene encoding the Y6 receptor is altered in man, Professor Herzog believes it would be unwise to ignore it because the development of anti-obesity drugs relies heavily on mouse studies.

“It is now clear to us that signaling through the Y6 receptor system is critical for the ways in which energy is used at different times of the day,” said Professor Herbert Herzog.

“Our work shows that Pancreatic Polypeptide has a very high affinity for Y6 in mice. It’s a satiety signal, and probably controls the circadian aspect of food intake – because the same amount of calories eaten at different times of the day has different effects on body weight.”

“The Y6 gene is highly expressed in a part of the brain called the ‘hypothalamic suprachiasmatic nucleus’, which is known to control the body’s circadian rhythm and may also critically modulate metabolic processes in response to food. The gene stimulates higher levels of certain peptides, including vasoactive intestinal peptide (VIP) – which controls growth hormone release.”

“While it is not clear whether the Y6 receptor is fully active in humans, Pancreatic Polypeptide is highly expressed – even more so than in mice – and it’s possible that another receptor to which the peptide has high affinity, such as Y4, could have taken over this function.”

Associate Professor Amanda Sainsbury-Salis expressed surprise at the impact of the Y6 gene deletion on mice, commenting “I find it amazing that one gene, which is expressed in the small part of the brain that controls the body clock, has such a profound impact on how much fat is stored on the body, and how much lean tissue is maintained.”

“Importantly, we use mice as models of human beings in research, and so when looking for anti-obesity drugs, we need to fully understand the function of the NPY system in this animal model to understand how similar circuits in humans connect with the body clock.”

(Source: garvan.org.au)

Although problems with memory become increasingly common as people age, in some persons, memories last long time, even a life time. On the other hand, some people experience milder to substantial memory problems even at an earlier age.

Although there are several risk factors of dementia, abnormal fat metabolism has been known to pose a risk for memory and learning. People with high amounts of abdominal fat in their middle age are 3.6 times as likely to develop memory loss and dementia later in their life.

Neurological scientists at the Rush University Medical Center in collaboration with the National Institutes of Health have discovered that same protein that controls fat metabolism in the liver resides in the memory center of the brain (hippocampus) and controls memory and learning.

Results from the study funded by the Alzheimer’s Association and the National Institutes of Health were recently published in Cell Reports.

“We need to better understand how fat is connected to memory and learning so that we can develop effective approach to protect memory and learning,” said Kalipada Pahan, PhD, the Floyd A. Davis professor of neurology at Rush University Medical Center.

The liver is the body’s major fat metabolizing organ. Peroxisome proliferator-activated receptor alpha (PPARalpha) is known to control fat metabolism in the liver. Accordingly, PPARalpha is highly expressed in the liver.

“We are surprised to find high level of PPARalpha in the hippocampus of animal models,” said Pahan.

“While PPARalpha deficient mice are poor in learning and memory, injection of PPARα to the hippocampus of PPARalpha deficient mice improves learning and memory,” said Pahan.

Since PPARalpha directly controls fat metabolism, people with abdominal fat levels have depleted PPARalpha in the liver and abnormal lipid metabolism. At first, these individuals lose PPARalpha from the liver and then eventually from the whole body including the brain. Therefore, abdominal fat is an early indication of some kind of dementia later in life, according to Pahan.

By bone marrow chimera technique, researchers were able to create some mice having normal PPARalpha in the liver and depleted PPARalpha in the brain. These mice were poor in memory and learning. On the other hand, mice that have normal PPARalpha in the brain and depleted PPARalpha in the liver showed normal memory.

“Our study indicates that people may suffer from memory-related problems only when they lose PPARalpha in the hippocampus”, said Pahan.

CREB (cyclic AMP response element-binding protein) is called the master regulator of memory as it controls different memory-related proteins. “Our study shows that PPARalpha directly stimulates CREB and thereby increases memory-related proteins”, said Pahan.

“Further research must be conducted to see how we could potentially maintain normal PPARalpha in the brain in order to be resistant to memory loss”, said Pahan.

(Source: rush.edu)

Scientists discover key function in molecule that regulates sleep, metabolism and hunger

Why does hunger keep us awake and a full belly make us tired? Why do people with sleep disorders such as insomnia often binge eat late at night? What can sleep patterns tell us about obesity?

Sleep, hunger and metabolism are closely related, but scientists are still struggling to understand how they interact. Now, Brandeis University researchers have discovered a function in a molecule in fruit flies that may provide insight into the complicated relationship between sleep and food.

In the October issue of the journal Neuron, Brandeis scientists report that sNPF, a neuropeptide long known to regulate food intake and metabolism, is also an important component in regulating and promoting sleep. When researchers activated sNPF in fruit flies, the insects fell asleep almost immediately, awaking only long enough to eat before nodding off again. The flies were so sleepy that once they found a food source, they slept right on top of it for days — like falling asleep on a giant hamburger bun and waking up long enough to take a few nibbles before falling back to sleep.

When researchers returned sNPF functions to normal, the flies resumed their normal level of activity, leaving behind their couch potato ways.

The researchers, led by professor of biology Leslie Griffith, concluded that sNPF has an important regulatory function in sleep in addition to its previously known function coordinating behaviors such as eating and metabolism.

"This paper provides a nice bridge between feeding behavior and sleep behavior with just a single molecule," says Nathan Donelson, a post doctoral fellow in Griffith’s lab and one of the study’s lead authors.

Neurons use neuropeptides to communicate a range of brain functions including learning, metabolism, memory and social behaviors. In humans, Neuropeptide Y functions similarly to sNPF and has been studied as a possible drug target for obesity treatment.

But scientists don’t fully understand how regulating neuropeptide function at specific times and in specific cells affects sleeping and eating. By studying sNPF in fruit flies, scientists can learn which cells, neurotransmitters and genes are involved in eating and sleeping; what processes turn on and inhibit the behaviors, and how sleep cells are relevant to hunger drive.

"Our paper makes a significant step into tying all these things together," says Donelson, "and that is extremely important down the road to our understanding of human health."

(Source: eurekalert.org)

Clock’s rhythm ensures steady energy supply to cells during times of fasting

Each of our cells has an energy furnace, and it is called a mitochondrion. A Northwestern University-led research team now has identified a new mode of timekeeping that involves priming the cell’s furnace to properly use stored fuel when we are not eating.

The interdisciplinary team has identified the “match” and “flint” responsible for lighting this tiny furnace. And the match is only available when the circadian clock says so, underscoring the importance of the biological timing system to metabolism.

“Circadian clocks are with us on Earth because they have everything to do with energy,” said Joe Bass, M.D., who led the research. “If an organism burns its energy efficiently, it has a better chance of survival. Our results tell us how the circadian clock triggers the cell’s energy-burning process. Cells are most capable of using fuel when the clock is working properly.”

Bass is the Charles F. Kettering Professor and chief of the division of endocrinology, metabolism and molecular medicine at Northwestern University Feinberg School of Medicine and an endocrinologist at Northwestern Memorial Hospital.

Mitochondria regulate the supply of energy to cells when we are at rest, with no glucose available from food. In a study of mice, the researchers found that the circadian clock supplies the match to light the furnace and on the match tip is a critical compound called NAD+. It combines with an enzyme in mitochondria called Sirtuin 3, which acts as the flint, to light the furnace. When the clock in an animal isn’t working, the animal can’t metabolize stored energy and the process doesn’t ignite.

This pathway through which the body clock controls activities within the mitochondria shows how energy generation is tied tightly to the light-dark/activity-rest cycle each day. 

The findings, which could be useful in the development of therapies to treat metabolic disorders related to circadian disruption, is published today (Sept. 19) by the journal Science.

The results demonstrate that the circadian clock, a genetic timekeeper that evolved to enable organisms to track the daily transition from light to darkness early in evolution, generates oscillations in mitochondrial energy capacity through rhythmic regulation of NAD+ biosynthesis.

The clock facilitates oxidative rhythms that anticipate an animal’s fasting/feeding cycle that occurs during the transition from light to darkness and wakefulness to sleep each day, and, in so doing, prevents the cell from “starving” during the night.

To understand how mitochondria are affected by circadian clock disorder, the researchers genetically removed the clocks in laboratory mice and compared them to controls. Both groups of mice were studied in a state of fasting; this “stress” test enabled the researchers to pinpoint just how the clock maintains “energy reserves” (akin to stress testing of a bank).

Bass and his research group worked together with Navdeep S. Chandel, a colleague of Bass’ at Feinberg, and John M. Denu, at the University of Wisconsin-Madison. They found the mice lacking clocks had defects in their mitochondria: the mitochondria could not metabolize stored energy and had no reserve to prevent depletion of the main currency, ATP. (Adenosine triphosphate is an energy-bearing molecule found in all living cells.)

Working with Northwestern colleague Milan Mrksich, they went on to show that removal of the clock depletes the necessary ingredient to turn on an enzyme within mitochondria, Sirtuin 3, which activates energy burning during fasting.

The researchers also showed that when the circadian clock was disrupted, resulting in a lack of NAD+, they could provide NAD+ supplements and restore function to the mitochondrion.

The findings expand the understanding of the molecular pathways linking the circadian clock with metabolism and show that the clock provides an essential buffer to stabilize the cell as organisms transition between eating and fasting each day. This knowledge has implications for disease intervention and prevention, including of diabetes, and potentially for states of increased cell demand for metabolism (including inflammation and cancer). 

“We have established the chain of events that couples the clock’s control switch with the machinery of the mitochondria,” said Bass, who also is a member of the department of neurobiology at the Weinberg College of Arts and Sciences. “We now have identified an additional link in the supply chain that provides energy to the cell at different phases of our daily sleep-wake cycle. These findings establish a key role for the NAD+ biosynthetic cycle in this process.”

Major senior authors from Northwestern include Chandel, a professor in medicine-pulmonary and cell and molecular biology at Feinberg, and Mrksich, the Henry Wade Rogers Professor of Biomedical Engineering, Chemistry and Cell and Molecular Biology at Feinberg, Weinberg and the McCormick School of Engineering and Applied Science. Chandel and Mrksich are members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

The co-first authors are Clara Bien Peek, a postdoctoral fellow, and Alison H. Affinati, an M.D./Ph.D. candidate, both working in Bass’ lab. They have literally worked around the clock on the research, which builds on the earlier work of co-author Kathryn Moynihan Ramsey. In 2009, she and colleagues reported in Science that the compound NAD, together with the enzyme SIRT1, functions as a molecular “switch” to coordinate the internal clock with metabolic systems.

The current research team combined Northwestern expertise in basic circadian clock research, chemistry and physiology with outside collaborators who were able to verify the Northwestern findings.

Co-author Eric Goetzman, from the University of Pittsburgh School of Medicine, an expert in the rare children’s disease called metabolic myopathy, was able to confirm that the pattern the researchers observed in mice was the same as that seen in these children. Fasting can be life-threatening for children with this disorder because they can’t metabolize stored energy due to defects in their mitochondria.

Analyses by co-author Christopher B. Newgard at Duke University Medical Center identified a signature profile of the metabolic myopathy in mice with altered circadian clock genes.

(Source: northwestern.edu)

Researchers with the UC Davis MIND Institute and Agilent Laboratories have found that Prader-Willi syndrome — a genetic disorder best known for causing an insatiable appetite that can lead to morbid obesity — is associated with the loss of non-coding RNAs, resulting in the dysregulation of circadian and metabolic genes, accelerated energy expenditure and metabolic differences during sleep.

The research was led by Janine LaSalle, a professor in the UC Davis Department of Medical Microbiology and Immunology who is affiliated with the MIND Institute. It is published online in Human Molecular Genetics.

“Prader-Willi syndrome children do not sleep as well at night and have daytime sleepiness,” LaSalle said. “Parents have to lock up their pantries because the kids are rummaging for food in the middle of the night, even breaking into their neighbors’ houses to eat.”

The study found that these behaviors are rooted in the loss of a long non-coding RNA that functions to balance energy expenditure in the brain during sleep. The finding could have a profound effect on how clinicians treat children with Prader-Willi, as well as point the way to new, innovative therapies, LaSalle said.

The leading cause of morbid obesity among children in the United States, Prader-Willi involves a complex, and sometimes contradictory, array of symptoms. Shortly after birth children with Prader-Willi experience failure to thrive. Yet after they begin to feed themselves, they have difficulty sleeping and insatiable appetites that lead to obesity if their diets are not carefully monitored.

The current study was conducted in a mouse model of Prader-Willi syndrome. It found that mice engineered with the loss of a long non-coding RNA showed altered energy use and metabolic differences during sleep.

Prader-Willi has been traced to a specific region on chromosome 15 (SNORD116), which produces RNAs that regulate gene expression, rather than coding for proteins. When functioning normally, SNORD116 produces small nucleolar (sno) RNAs and a long non-coding RNA (116HG), as well as a third non-coding RNA implicated in a related disorder, Angelman syndrome. The 116HG long non-coding RNA forms a cloud inside neuronal nuclei that associates with proteins and genes regulating diurnal metabolism in the brain, LaSalle said.

“We thought the cloud would be activating transcription, but in fact it was doing the opposite,” she said. “Most of the genes were dampened by the cloud. This long non-coding RNA was acting as a decoy, pulling the active transcription factors away from genes and keeping them from being expressed.”

As a result, losing snoRNAs and 116HG causes a chain reaction, eliminating the RNA cloud and allowing circadian and metabolic genes to get turned on during sleep periods, when they should be dampened down. This underlies a complex cycle in which the RNA cloud grew during sleep periods (daytime for nocturnal mice), turning down genes associated with energy use, and receded during waking periods, allowing these genes to be expressed. Mice without the 116HG gene lacked the benefit of this neuronal cloud, causing greater energy expenditure during sleep.

The researchers said that the work provides a clearer picture of why children with Prader-Willi syndrome can’t sleep or feel satiated and may change therapeutic approaches. For example, many such children have been treated with growth hormone because of short stature, but this actually may boost other aspects of the disease.

“People had thought the kids weren’t sleeping at night because of the sleep apnea caused by obesity,” said LaSalle. “What this study shows is that the diurnal metabolism is central to the disorder, and that the obesity may be as a result of that. If you can work with that, you could improve therapies, for example figuring out the best times to administer medications.”

(Source: ucdmc.ucdavis.edu)

A new study from investigators at the Benson-Henry Institute for Mind/Body Medicine at Massachusetts General Hospital and Beth Israel Deaconess Medical Center finds that eliciting the relaxation response—a physiologic state of deep rest induced by practices such as meditation, yoga, deep breathing and prayer—produces immediate changes in the expression of genes involved in immune function, energy metabolism and insulin secretion.

“Many studies have shown that mind/body interventions like the relaxation response can reduce stress and enhance wellness in healthy individuals and counteract the adverse clinical effects of stress in conditions like hypertension, anxiety, diabetes and aging,” said Herbert Benson, HMS professor of medicine at Mass General and co-senior author of thereport.

Benson is director emeritus of the Benson-Henry Institute.

“Now for the first time we’ve identified the key physiological hubs through which these benefits might be induced,” he said.

Published in the open-access journal PLOS ONE, the study combined advanced expression profiling and systems biology analysis to both identify genes affected by relaxation response practice and to determine the potential biological relevance of those changes.

“Some of the biological pathways we identify as being regulated by relaxation response practice are already known to play specific roles in stress, inflammation and human disease. For others, the connections are still speculative, but this study is generating new hypotheses for further investigation,” said Towia Libermann, HMS associate professor of medicine at Beth Israel Deaconess and co-senior author of the study.

Benson first described the relaxation response—the physiologic opposite of the fight-or-flight response—almost 40 years ago, and his team has pioneered the application of mind/body techniques to a wide range of health problems. Studies in many peer-reviewed journals have documented how the relaxation response both alleviates symptoms of anxiety and many other disorders and also affects factors such as heart rate, blood pressure, oxygen consumption and brain activity. 

In 2008, Benson and Libermann led a study finding that long-term practice of the relaxation response changed the expression of genes involved with the body’s response to stress. The current study examined changes produced during a single session of relaxation response practice, as well as those taking place over longer periods of time.

The study enrolled a group of 26 healthy adults with no experience in relaxation response practice, who then completed an 8-week relaxation-response training course.

Before they started their training, they went through what was essentially a control group session: Blood samples were taken before and immediately after the participants listened to a 20-minute health education CD and again 15 minutes later. After completing the training course, a similar set of blood tests was taken before and after participants listened to a 20-minute CD used to elicit the relaxation response as part of daily practice. 

The sets of blood tests taken before the training program were designated “novice,” and those taken after training completion were called “short-term practitioners.” For further comparison, a similar set of blood samples was taken from a group of 25 individuals with 4 to 25 years’ experience regularly eliciting the relaxation response through many different techniques before and after they listened to the same relaxation response CD.

Blood samples from all participants were analyzed to determine the expression of more than 22,000 genes at the different time points.

The results revealed significant changes in the expression of several important groups of genes between the novice samples and those from both the short- and long-term sets. Even more pronounced changes were shown in the long-term practitioners. 

A systems biology analysis of known interactions among the proteins produced by the affected genes revealed that pathways involved with energy metabolism, particularly the function of mitochondria, were upregulated during the relaxation response. Pathways controlled by activation of a protein called NF-κB—known to have a prominent role in inflammation, stress, trauma and cancer—were suppressed after relaxation response elicitation. The expression of genes involved in insulin pathways was also significantly altered.

“The combination of genomics and systems biology in this study provided great insight into the key molecules and physiological gene interaction networks that might be involved in relaying beneficial effects of relaxation response in healthy subjects,” said Manoj Bhasin, HMS assistant professor of medicine, co-lead author of the study, and co-director of the Beth Israel Deaconess Genomics, Proteomics, Bioinformatics and Systems Biology Center.

Bhasin noted that these insights should provide a framework for determining, on a genomic basis, whether the relaxation response will help alleviate symptoms of diseases triggered by stress. The work could also lead to developing biomarkers that may suggest how individual patients will respond to interventions.

Benson stressed that the long-term practitioners in this study elicited the relaxation response through many different techniques—various forms of meditation, yoga or prayer—but those differences were not reflected in the gene expression patterns.

“People have been engaging in these practices for thousands of years, and our finding of this unity of function on a basic-science, genomic level gives greater credibility to what some have called ‘new age medicine,’ ” he said.

“While this and our previous studies focused on healthy participants, we currently are studying how the genomic changes induced by mind/body interventions affect pathways involved in hypertension, inflammatory bowel disease and irritable bowel syndrome. We have also started a study—a collaborative undertaking between Dana-Farber Cancer Institute, Mass General and Beth Israel Deaconess—in patients with precursor forms of multiple myeloma, a condition known to involve activation of NF-κB pathways,” said Libermann, who is the director of the Beth Israel Deaconess Medical Center Genomics, Proteomics, Bioinformatics and Systems Biology Center.

(Source: hms.harvard.edu)