Posts tagged hunger
Articles and news from the latest research reports.
Hunger Games: How the brain ‘browns’ fat to aid weight loss
Researchers at Yale School of Medicine have uncovered a molecular process in the brain known to control eating that transforms white fat into brown fat. This process impacts how much energy we burn and how much weight we can lose. The results are published in the Oct. 9 issue of the journal Cell.
Obesity is a rising global epidemic. Excess fatty tissue is a major risk factor for type 2 diabetes, cardiovascular disease, hypertension, neurological disorders, and cancer. People become overweight and obese when energy intake exceeds energy expenditure, and excess calories are stored in the adipose tissues. The adipose organ is made up of both white and brown fat. While white fat primarily stores energy as triglycerides, brown fat dissipates chemical energy as heat. The more brown fat you have, the more weight you can lose.
It has previously been shown that energy-storing white fat has the capacity to transform into energy-burning “brown-like” fat. In this new study, researchers from the Yale Program in Integrative Cell Signaling and Neurobiology of Metabolism, demonstrate that neurons controlling hunger and appetite in the brain control the “browning” of white fat.
Lead author Xiaoyong Yang, associate professor of comparative medicine and physiology at Yale School of Medicine, conducted the study with Tamas Horvath, professor and chair of comparative medicine, and professor of neurobiology and Obstetrics/gynecology at Yale School of Medicine, and their co-authors.
The team stimulated this browning process from the brain in mice and found that it protected the animals from becoming obese on a high-fat diet. The team then studied the molecular changes in hunger-promoting neurons in the hypothalamus and found that the attachment of a unique sugar called “O-GlcNAc” to potassium ion channels acts as a switch to control brain activity to burn fat.
“Our studies reveal white fat “browning” as a highly dynamic physiological process that the brain controls,” said Yang. “This work indicates that behavioral modifications promoted by the brain could influence how the amount of food we eat and store in fat is burned.”
Yang said hunger and cold exposure are two life-history variables during the development and evolution of mammals. “We observed that food deprivation dominates over cold exposure in neural control of white fat browning. This regulatory system may be evolutionarily important as it can reduce heat production to maintain energy balance when we are hungry. Modulating this brain-to-fat connection represents a potential novel strategy to combat obesity and associated illnesses.”
Study provides surprising new clue to the roots of hunger
While the function of eating is to nourish the body, this is not what actually compels us to seek out food. Instead, it is hunger, with its stomach-growling sensations and gnawing pangs that propels us to the refrigerator – or the deli or the vending machine. Although hunger is essential for survival, abnormal hunger can lead to obesity and eating disorders, widespread problems now reaching near-epidemic proportions around the world.
Over the past 20 years, Beth Israel Deaconess Medical Center (BIDMC) neuroendocrinologist Bradford Lowell, MD, PhD, has been untangling the complicated jumble of neurocircuits in the brain that underlie hunger, working to create a wiring diagram to explain the origins of this intense motivational state. Key among his findings has been the discovery that Agouti-peptide (AgRP) expressing neurons – a group of nerve cells in the brain’s hypothalamus – are activated by caloric deficiency, and when either naturally or artificially stimulated in animal models, will cause mice to eat voraciously after conducting a relentless search for food.
Now, in a new study published on-line this week in the journal Nature, Lowell’s lab has made the surprising discovery that the hunger-inducing neurons that activate these AgRP neurons are located in the paraventricular nucleus — a brain region long thought to cause satiety, or feelings of fullness. This unexpected finding not only provides a critical addition to the overall wiring diagram, but adds an important extension to our understanding of what drives appetite.
"Our goal is to understand how the brain controls hunger," explains Lowell, an investigator in BIDMC’s Division of Endocrinology, Diabetes and Metabolism and Professor of Medicine at Harvard Medical School. "Abnormal hunger can lead to obesity and eating disorders, but in order to understand what might be wrong – and how to treat it – you first need to know how it works. Otherwise, it’s like trying to fix a car without knowing how the engine operates."
Hunger is notoriously complicated and questions abound: Why do the fed and fasted states of your body increase or decrease hunger? And how do the brain’s reward pathways come into play – why, as we seek out food, especially after an otherwise complete meal, do we prefer ice cream to lettuce?
"Psychologists have explained how cues from the environment and from the body interact, demonstrating that food and stimuli linked with food [such as a McDonald’s sign] are rewarding and therefore promote hunger," explains Lowell. "It’s clear that fasting increases the gain on how rewarding we find food to be, while a full stomach decreases this reward. But while this model has been extremely important in understanding the general features of the ‘hunger system,’ it’s told us nothing about what’s inside the ‘black box’ – the brain’s neural circuits that actually control hunger."
To deal with this particularly complex brain region – a dense and daunting tangle of circuits resembling a wildly colorful Jackson Pollack painting – the Lowell team is taking a step-by-step approach to find out how the messages indicating whether the body is in a state of feeding or fasting enter this system. Their search has been aided by a number of extremely powerful technologies, including rabies circuit mapping and channelrhodopsin-assisted circuit mapping, which enable their highly specific, neuron-by-neuron analysis of the region.
"By making use of these new technologies, we are able to follow the synapses, follow the axons, and see how it all works," says Lowell. "While this sounds like a relatively straightforward concept, it’s actually been a huge challenge for the neuroscience field."
In this new paper, first authors Michael Krashes, PhD, and Bhavik Shah, PhD, postdoctoral fellows in the Lowell lab, employed rabies circuit mapping, a technology in which a modified version of the rabies virus is engineered to “infect” just one type of neuron – in this case, the AgRP neurons that drive hunger. The virus moves upstream one synapse and identifies all neurons that are providing input to AgRP starter neurons. Then, using a host of different neuron-specific cre-recombinase expressing mice (a group of genetically engineered animals originally developed in the Lowell lab) the investigators were able to map inputs to just these nerve cells, and then manipulate these upstream neurons so that they could be targeted for activation by an external stimulus.
"We wanted to know, of all the millions of neurons in a mouse brain, which provided input to the AgRP neurons," explains Lowell. "And the shocking result was that there were only two sites in the brain that were involved – the dorsal medial hypothalamus and the paraventricular nucleus, with the input from the paraventricular neurons shown to be extremely strong."
With this new information, the investigators now had a model to pursue. “We hypothesized that neurons in the paraventricular nucleus were communicating with and turning on the AgRP neurons. We developed mice that expressed cre-recombinase in many subsets of the paraventricular neurons and then, mapping the neurons one-by-one, we determined which was talking to which,” says Lowell. Their results revealed that subsets of neurons expressing thyrotropin-releasing hormone (TRH) and pituitary adenylate cylcase-activating polypeptide (PACAP) were in on the neuronal chatter.
Finally, through a chemogenetic technique known as DREADDs – Designer Receptor Exclusively Activated by Designer Drug – the authors used chemicals to specifically and selectively stimulate or inhibit these upstream neurons in the animal models. The fed mice, which had already consumed their daily meal and otherwise had no interest in food, proceeded to search out and voraciously eat after DREADD stimulation. Conversely, the fasting mice – which should have been hungry after a period of no food – ate very little when these upstream neurons were turned off.
"This has led us to the discovery of a novel, previously unknown means of activating AgRP neurons and producing hunger," explains Lowell. "Surprisingly, these hunger-inducing neurons were found in a region of the brain which has long been thought to have the opposite effect – causing satiety. This unexpected discovery, made possible only through the use of the new wiring diagram-elucidating technologies, highlights the importance of following the labeled neuronal lines of information flow. We are getting closer and closer to completing our wiring diagram, and the nearer we come to understanding how it all works, the better our chances of being able to treat obesity and eating disorders, the consequences of abnormal hunger."
(Source: eurekalert.org)
Drowsy Drosophila shed light on sleep and hunger
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)
Hunger affects decision making and perception of risk
Hungry people are often difficult to deal with. A good meal can affect more than our mood, it can also influence our willingness to take risks. This phenomenon is also apparent across a very diverse range of species in the animal kingdom. Experiments conducted on the fruit fly, Drosophila, by scientists at the Max Planck Institute of Neurobiology in Martinsried have shown that hunger not only modifies behaviour, but also changes pathways in the brain.
Animal behaviour is radically affected by the availability and amount of food. Studies prove that the willingness of many animals to take risks increases or declines depending on whether the animal is hungry or full. For example, a predator only hunts more dangerous prey when it is close to starvation. This behaviour has also been documented in humans in recent years: one study showed that hungry subjects took significantly more financial risks than their sated colleagues.
Also the fruit fly, Drosophila, changes its behaviour depending on its nutritional state. The animals usually perceive even low quantities of carbon dioxide to be a sign of danger and opt to take flight. However, rotting fruit and plants – the flies’ main sources of food – also release carbon dioxide. Neurobiologists in Martinsried have now discovered how the brain deals with this constant conflict in deciding between a hazardous substance and a potential food source taking advantage of the fly as a great genetic model organism for circuit neuroscience.
In various experiments, the scientists presented the flies with environments containing carbon dioxide or a mix of carbon dioxide and the smell of food. It emerged that hungry flies overcame their aversion to carbon dioxide significantly faster than fed flies – if there was a smell of food in the environment at the same time. Facing the prospect of food, hungry animals are therefore significantly more willing to take risks than sated flies. But how does the brain manage to decide between these options?
Avoiding carbon dioxide is an innate behaviour and should therefore be generated outside the mushroom body in the fly’s brain: previously, the nerve cells in the mushroom body were linked only with learning and behaviour patterns that are based on learned associations. However, when the scientists temporarily disabled these nerve cells, hungry flies no longer showed any reaction whatsoever to carbon dioxide. The behaviour of fed flies, on the other hand, remained the same: they avoided the carbon dioxide.
In further studies, the researchers identified a projection neuron which transports the carbon dioxide information to the mushroom body. This nerve cell is crucial in triggering a flight response in hungry, but not in fed animals. “In fed flies, nerve cells outside the mushroom body are enough for flies to flee from the carbon dioxide. In hungry animals, however, the nerve cells are in the mushroom body and the projection neuron, which carries the carbon dioxide information there, is essential for the flight response. If mushroom body or projection neuron activity is blocked, only hungry flies are no longer concerned about the carbon dioxide,” explains Ilona Grunwald-Kadow, who headed the study.
The results show that the innate flight response to carbon dioxide in fruit flies is controlled by two parallel neural circuits, depending on how satiated the animals are. “If the fly is hungry, it will no longer rely on the ‘direct line’ but will use brain centres to gauge internal and external signals and reach a balanced decision,” explains Grunwald-Kadow. “It is fascinating to see the extent to which metabolic processes and hunger affect the processing systems in the brain,” she adds.
Hunger-spiking neurons could help control autoimmune diseases
Neurons that control hunger in the central nervous system also regulate immune cell functions, implicating eating behavior as a defense against infections and autoimmune disease development, Yale School of Medicine researchers have found in a new study published in the Proceedings of the National Academies of Sciences (PNAS).
Autoimmune diseases have been on a steady rise in the United States. These illnesses develop when the body’s immune system turns on itself and begins attacking its own tissues. The interactions between different kinds of T cells are at the heart of fighting infections, but they have also been linked to autoimmune disorders.
“We’ve found that if appetite-promoting AgRP neurons are chronically suppressed, leading to decreased appetite and a leaner body weight, T cells are more likely to promote inflammation-like processes enabling autoimmune responses that could lead to diseases like multiple sclerosis,” said lead author Tamas Horvath, the Jean and David W. Wallace Professor of Biomedical Research and chair of comparative medicine at Yale School of Medicine.
“If we can control this mechanism by adjusting eating behavior and the kinds of food consumed, it could lead to new avenues for treating autoimmune diseases,” he added.
Horvath and his research team conducted their study in two sets of transgenic mice. In one set, they knocked out Sirt1, a signaling molecule that controls the hunger-promoting neuron AgRP in the hypothalamus. These Sirt1-deficient mice had decreased regulatory T cell function and enhanced effector T cell activity, leading to their increased vulnerability in an animal model of multiple sclerosis.
“This study highlights the important regulatory role of the neurons that control appetite in peripheral immune functions,” said Horvath. “AgRP neurons represent an important site of action for the body’s immune responses.”
The team’s data support the idea that achieving weight loss through the use of drugs that promote a feeling of fullness “could have unwanted effects on the spread of autoimmune disorders,” he notes.
Can Going Hungry As a Child Slow Down Cognitive Decline in Later Years?
People who sometimes went hungry as children had slower cognitive decline once they were elderly than people who always had enough food to eat, according to a new study published in the December 11, 2012, print issue of Neurology®, the medical journal of the American Academy of Neurology.
“These results were unexpected because other studies have shown that people who experience adversity as children are more likely to have problems such as heart disease, mental illness and even lower cognitive functioning than people whose childhoods are free of adversity,” said study author Lisa L. Barnes, PhD, of Rush University Medical Center in Chicago.
For the African American participants, the 5.8 percent who reported that they went without enough food to eat sometimes, often or always were more likely to have a slower rate of cognitive decline, or decline that was reduced by about one-third, than those who rarely or never went without enough food to eat. The 8.4 percent of African American participants who reported that they were much thinner at age 12 than other kids their age also were more likely to have a slower rate of cognitive decline, also by one-third, than those who said they were about the same size or heavier than other kids their age. For Caucasians, there was no relationship between any of the childhood adversity factors and cognitive decline. Barnes said researchers aren’t sure why childhood hunger could have a possible protective effect on cognitive decline. One potential explanation for the finding could be found in research that has shown that calorie restriction can delay the onset of age-related changes in the body and increase the life span. Another explanation could be a selective survival effect. The older people in the study who experienced childhood adversity may be the hardiest and most resilient of their era; those with the most extreme adversity may have died before they reached old age.
Barnes noted that the results stayed the same after researchers adjusted for factors such as amount of education and health problems. The results also did not change after researchers repeated the analysis after excluding people with the lowest cognitive function at the beginning of the study to help rule out the possibility that people with mild, undiagnosed Alzheimer’s disease were included in the study.
Because relatively few Caucasians in the study reported childhood adversity, the study may not have been able to detect an effect of adversity on cognitive decline in Caucasians, Barnes said.