Posts tagged appetite
Articles and news from the latest research reports.
Leptin also influences brain cells that control appetite
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)
Neuroscience Study Uncovers New Player in Obesity
A new neuroscience study sheds light on the biological underpinnings of obesity. The in vivo study, published in the January 8 issue of The Journal of Neuroscience, reveals how a protein in the brain helps regulate food intake and body weight. The findings reveal a potential new avenue for the treatment of obesity and may help explain why medications that are prescribed for epilepsy and other conditions that interfere with this protein, such as gabapentin and pregabalin, can cause weight gain.
The protein – alpha2/delta-1 – has not been linked previously to obesity. A team led by Maribel Rios, Ph.D., associate professor in the department of neuroscience at Tufts University School of Medicine, discovered that alpha2/delta-1 facilitates the function of another protein called brain-derived neurotrophic factor (BDNF). A previous study by Rios determined that BDNF plays a critical role in appetite suppression, while the current study identifies a central mechanism mediating the inhibitory effects of BDNF on overeating.
“We know that low levels of the BDNF protein in the brain lead to overeating and dramatic obesity in mice. Deficiencies in BDNF have also been linked to obesity in humans. Now, we have discovered that the alpha2/delta-1 protein is necessary for normal BDNF function, giving us a potential new target for novel obesity treatments,” said Rios, also a member of the cellular and molecular physiology and neuroscience program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts.
Rios and colleagues discovered that low levels of BDNF were associated with decreased function of alpha2/delta-1 in the hypothalamus, a brain region that is critical to the regulation of food intake and weight. When the team inhibited the alpha2/delta-1 protein in normal mice, mice ate significantly more food and gained weight. Conversely, when the team corrected the alpha 2/delta-1 deficiency in mice with reduced BDNF levels, overeating and weight gain were mitigated. In addition, blood sugar levels (related to diabetes in humans) were normalized.
“We blocked activity of the alpha2/delta-1 protein in mice using gabapentin. These mice ate 39 percent more food, and as a consequence gained substantially more weight than control mice over a seven-day period,” said first author Joshua Cordeira, Ph.D., a graduate of the neuroscience program at the Sackler School and member of Rios’s lab. This study is related to his Ph.D. thesis.
“When we re-introduced alpha2/delta-1 in obese mice lacking BDNF in the brain, we saw a 15-20 percent reduction in food intake and a significant reduction in weight gain. Importantly, metabolic disturbances associated with obesity, including hyperglycemia and deficient glucose metabolism, were greatly reduced by restoring the function of alpha2/delta-1,” added Rios.
Some individuals who take gabapentin and pregabalin report weight gain. Both gabapentin and pregabalin are anticonvulsants, also used to treat nerve pain from, for example, shingles or diabetes. The findings from the Rios lab suggest that these drugs might contribute to weight gain by interfering with alpha2/delta-1 in the hypothalamus. This new understanding of alpha2/delta-1’s role in appetite may allow researchers to develop complementary treatments that can prevent weight gain for patients taking these medications.
“We now know that alpha2/delta-1 plays a critical role in healthy BDNF function. The finding improves our understanding of the intricate neuroscience involved in appetite control. The next phase of our research will be to unravel the mechanisms mediating the satiety effects of alpha2/delta-1 in the hypothalamus,” said Rios.
This latest finding builds on Rios’s previous studies of BDNF and its role in regulating body weight. Earlier work by Rios established BDNF as an essential component of the neural circuits governing body weight in adult mice. Rios also determined that BDNF expression in two regions of the brain is required to suppress appetite.
Does obesity reshape our sense of taste?
Obesity may alter the way we taste at the most fundamental level: by changing how our tongues react to different foods.
In a Nov. 13 study in the journal PLOS ONE, University at Buffalo biologists report that being severely overweight impaired the ability of mice to detect sweets.
Compared with slimmer counterparts, the plump mice had fewer taste cells that responded to sweet stimuli. What’s more, the cells that did respond to sweetness reacted relatively weakly.
The findings peel back a new layer of the mystery of how obesity alters our relationship to food.
“Studies have shown that obesity can lead to alterations in the brain, as well as the nerves that control the peripheral taste system, but no one had ever looked at the cells on the tongue that make contact with food,” said lead scientist Kathryn Medler, PhD, UB associate professor of biological sciences.
“What we see is that even at this level — at the first step in the taste pathway — the taste receptor cells themselves are affected by obesity,” Medler said. “The obese mice have fewer taste cells that respond to sweet stimuli, and they don’t respond as well.”
The research matters because taste plays an important role in regulating appetite: what we eat, and how much we consume.
How an inability to detect sweetness might encourage weight gain is unclear, but past research has shown that obese people yearn for sweet and savory foods though they may not taste these flavors as well as thinner people.
Medler said it’s possible that trouble detecting sweetness may lead obese mice to eat more than their leaner counterparts to get the same payoff.
Learning more about the connection between taste, appetite and obesity is important, she said, because it could lead to new methods for encouraging healthy eating.
“If we understand how these taste cells are affected and how we can get these cells back to normal, it could lead to new treatments,” Medler said. “These cells are out on your tongue and are more accessible than cells in other parts of your body, like your brain.”
The new PLOS ONE study compared 25 normal mice to 25 of their littermates who were fed a high-fat diet and became obese.
To measure the animals’ response to different tastes, the research team looked at a process called calcium signaling. When cells “recognize” a certain taste, there is a temporary increase in the calcium levels inside the cells, and the scientists measured this change.
The results: Taste cells from the obese mice responded more weakly not only to sweetness but, surprisingly, to bitterness as well. Taste cells from both groups of animals reacted similarly to umami, a flavor associated with savory and meaty foods.
Genetic identification of a neural circuit that suppresses appetite
Scientists at the University of Washington have used genetic engineering to identify a population of neurons that tell the brain to shut off appetite. Their study, “Genetic identification of a neural circuit that suppresses appetite,” was published Oct. 13 in Nature.
To identify these neurons, or cells that process and transmit information in the brain, researchers first considered what makes an animal lose its appetite. There are a number of natural reasons, including infection, nausea, pain or simply having eaten too much already.
Nerves within the gut that are distressed or insulted send information to the brain through the vagus nerve. Appetite is suppressed when these messages activate specific neurons – ones that contain CGRP, (calcitonin gene-related peptide) in a region of the brain called the parabrachial nucleus.
In mouse trials, researchers used genetic techniques and viruses to introduce light-activatable proteins into CGRP neurons. Activation of these proteins excites the cells to transmit chemical signals to other regions of the brain. When they activated the CGRP neurons with a laser, the hungry mice immediately lost their appetite and walked away from their liquid diet (Ensure); when the laser was turned off, the mice resumed drinking the liquid diet.
"These results demonstrate that activation of the CGRP-expressing neurons regulates appetite. This is a nice example of how the brain responds to unfavorable conditions in the body, such as nausea caused by food poisoning" said Richard Palmiter, UW professor of biochemistry and investigator of the Howard Hughes Medical Institute.
Using a similar approach, neurons in other brain regions have been identified that can stimulate the appetite of mice that are not hungry. Researchers hope to identify the complete neural circuit (wiring diagram) in the brain that regulates feeding behavior. By identifying these neural circuits, scientists may be able to design therapies that promote or decrease appetite.
(Source: eurekalert.org)
Why One Cream Cake Leads to Another
Continuously eating fatty foods perturbs communication between the gut and brain, which in turn perpetuates a bad diet.
A chronic high-fat diet is thought to desensitize the brain to the feeling of satisfaction that one normally gets from a meal, causing a person to overeat in order to achieve the same high again. New research published today (August 15) in Science, however, suggests that this desensitization actually begins in the gut itself, where production of a satiety factor, which normally tells the brain to stop eating, becomes dialed down by the repeated intake of high-fat food.
“It’s really fantastic work,” said Paul Kenny, a professor of molecular therapeutics at The Scripps Research Institute in Jupiter, Florida, who was not involved in the study. “It could be a so-called missing link between gut and brain signaling, which has been something of a mystery.”
While pork belly, ice cream, and other high-fat foods produce an endorphin response in the brain when they hit the taste buds, according to Kenny, the gut also sends signals directly to the brain to control our feeding behavior. Indeed, mice nourished via gastric feeding tubes, which bypass the mouth, exhibit a surge in dopamine—a neurotransmitter promoting reinforcement in the brain’s reward circuitry—similar to that experienced by those eating normally.
This dopamine surge occurs in response to feeding in both mice and humans. But evidence suggests that dopamine signaling in the brain is deficient in obese people. Ivan de Araujo, a professor of psychiatry at the Yale School of Medicine, has now discovered that obese mice on a chronic high-fat diet also have a muted dopamine response when receiving fatty food via a direct tube to their stomachs.
To determine the nature of the dopamine-regulating signal emanating from the gut, Araujo and his team searched for possible candidates. “When you look at animals chronically exposed to high-fat foods, you see high levels of almost every circulating factor—leptin, insulin, triglycerides, glucose, et cetera,” he said. But one class of signaling molecule is suppressed. Of these, Araujo’s primary candidate was oleoylethanolamide. Not only is the factor produced by intestinal cells in response to food, he said, but during chronic high-fat exposure, “the suppression levels seemed to somehow match the suppression that we saw in dopamine release.”
Araujo confirmed oleoylethanol’s dopamine-regulating ability in mice by administering the factor via a catheter to the tissues surrounding their guts. “We discovered that by restoring the baseline level of [oleoylethanolamide] in the gut … the high-fat fed animals started having dopamine responses that were indistinguishable from their lean counterparts.”
The team also found that oleoylethanolamide’s effect on dopamine was transmitted via the vagus nerve, which runs between the brain and abdomen, and was dependent on its interaction with a transcription factor called PPAR-a.
Oleoylethanolamide levels are also reduced in fasting animals and increase in response to eating, communicating with the brain to stop further consumption once the belly is full. Indeed, oleoylethanolamide is a known satiety factor. Therefore, when chronic consumption of high-fat food diminishes its production, the satisfaction signal is not achieved, and the brain is essentially “blind to the presence of calories in the gut,” said Araujo, and thus demands more food.
It is not clear why a chronic high-fat diet suppresses the production of oleoylethanolamide. But once the vicious cycle starts, it is hard to break because the brain is receiving its information subconsciously, said Daniele Piomelli, a professor at the University of California, Irvine, and director of drug discovery and development at the Italian Institute of Technology in Genoa.
“We eat what we like, and we think we are conscious of what we like, but I think what this [paper] and others are indicating is that there is a deeper, darker side to liking—a side that we’re not aware of,” Piomelli said. “Because it is an innate drive, you can not control it.” Put another way, even if you could trick your taste buds into enjoying low-fat yogurt, you’re unlikely to trick your gut.
The good news, however, is that “there is no permanent impairment in the [animals’] dopamine levels,” Araujo said. This suggests that if drugs could be designed to regulate the oleoylethanolamide–to-PPAR-a pathway in the gut, Kenny added, it could have “a huge impact on people’s ability to control their appetite.”
(Source: the-scientist.com)
Study identifies key shift in the brain that creates drive to overeat
A team of American and Italian neuroscientists has identified a cellular change in the brain that accompanies obesity. The findings could explain the body’s tendency to maintain undesirable weight levels, rather than an ideal weight, and identify possible targets for pharmacological efforts to address obesity.
The findings, published in the Proceedings of the National Academy of Sciences Early Edition this week, identify a switch that occurs in neurons within the hypothalamus. The switch involves receptors that trigger or inhibit the release of the orexin A peptide, which stimulates the appetite, among other behaviors. In normal-weight mice, activation of this receptor decreases orexin A release. In obese mice, activation of this receptor stimulates orexin A release.
"The striking finding is that you have a massive shift of receptors from one set of nerve endings impinging on these neurons to another set," said Ken Mackie, professor in the Department of Psychological and Brain Sciences in the College of Arts and Sciences at IU Bloomington. "Before, activating this receptor inhibited the secretion of orexin; now it promotes it. This identifies potential targets where an intervention could influence obesity."
The work is part of a longstanding collaboration between Mackie’s team at the Gill Center for Biomolecular Science at IU Bloomington and Vincenzo Di Marzo’s team at the Institute of Biomolecular Chemistry in Pozzuoli, Italy. Both teams study the endocannabinoid system, which is composed of receptors and signaling chemicals that occur naturally in the brain and have similarities to the active ingredients in cannabis, or marijuana. This neurochemical system is involved in a variety of physiological processes, including appetite, pain, mood, stress responses and memory.
Food consumption is controlled in part by the hypothalamus, a portion of the brain that regulates many essential behaviors. Like other important body systems, food consumption is regulated by multiple neurochemical systems, including the endocannabinoid system, representing what Mackie describes as a “balance of a very fine web of regulatory networks.”
An emerging idea, Mackie said, is that this network is reset during obesity so that food consumption matches maintenance of current weight, not a person’s ideal weight. Thus, an obese individual who loses weight finds it difficult to keep the weight off, as the brain signals the body to eat more in an attempt to return to the heavier weight.
Using mice, this study found that in obesity, CB1 cannabinoid receptors become enriched on the nerve terminals that normally inhibit orexin neuron activity, and the orexin neurons produce more of the endocannabinoids to activate these receptors. Activating these CB1 receptors decreases inhibition of the orexin neurons, increasing orexin A release and food consumption.
"This study identifies a mechanism for the body’s ongoing tendency to return to the heavier weight," Mackie said.
The researchers conducted several experiments with mice to understand how this change takes place. They uncovered a role of leptin, a key hormone made by fat cells that influences metabolism, hunger and food consumption. Obesity causes leptin levels to be chronically high, making brain cells less sensitive to its actions, which contributes to the molecular switch that leads to the overproduction of orexin.
(Source: eurekalert.org)
Blood marrow derived cells regulate appetite
Bone marrow cells that produce brain-derived eurotrophic factor (BDNF), known to affect regulation of food intake, travel to part of the hypothalamus in the brain where they “fine-tune” appetite, said researchers from Baylor College of Medicine and Shiga University of Medical Science in Otsu, Shiga, Japan, in a report that appears online in the journal Nature Communications.
"We knew that blood cells produced BDNF," said Dr. Lawrence Chan, professor of molecular and cellular biology and professor and chief of the division of diabetes, endocrinology & metabolism in the department of medicine and director of the federally funded Diabetes Research Center, all at BCM. The factor is produced in the brain and in nerve cells as well. "We didn’t know why it was produced in blood cells."
Fluorescent marker reveals surprise
Dr. Hiroshi Urabe and Dr. Hideto Kojima, current and former postdoctoral fellows in Chan’s laboratory respectively, looked for BDNF in the brains of mice who had not been fed for about 24 hours. The bone marrow-derived cells had been marked with a fluorescent protein that showed up on microscopy. To their surprise, they found cells producing BDNF in a part of the brain’s hypothalamus called the paraventricular nucleus.
"We knew that in embryonic development, some blood cells do go to the brain and become microglial cells," said Chan. (Microglial cells form part of the supporting structure of the central nervous system. They are characterized by a nucleus from which "branches" expand in all directions.) "This is the first time we have shown that this happens in adulthood. Blood cells can go to one part of the brain and become physically changed to become microglial-like cells."
However, these bone marrow cells produce a bone marrow-specific variant of BDNF, one that is different from that produced by the regular microglial cells already in the hypothalamus.
Only a few of these blood-derived cells actually reach the hypothalamus, said Chan.
"It’s not very impressive if you look casually under the microscope," he said. However, a careful scrutiny showed that the branching nature of these cells allow them to come into contact with a whole host of brain cells.
"Their effects are amplified," said Chan.
Curbing the urge
Mice that are born lacking the ability to produce blood cells that make BDNF overeat, become obese and develop insulin resistance (a lack of response to insulin that affects the ability to metabolize glucose). A bone marrow transplant that restores the gene for making the cells that produce BDNF can normalize appetite, said Chan. However, a transplant of bone marrow that does not contain this gene does not reverse overeating, obesity or insulin resistance.
When normal bone marrow cells that produce BDNF are injected into the third ventricle (a fluid-filled cavity in the brain) of mice that lack BDNF, they no longer have the urge to overeat, said Chan.
All in all, the studies represent a new mechanism by which these bone-marrow derived cells control feeding through BDNF and could provide a new avenue to attack obesity, said Chan.
He and his colleagues hypothesize that the bone marrow cells that produce BDNF fine tune the appetite response, although a host of different appetite-controlling hormones produced by the regular nerve cells in the hypothalamus do the lion’s share of the work.
"Bone marrow cells are so accessible," said Chan. “If these cells play a regulatory role, we could draw some blood, modify something in it or add something that binds to blood cells and give it back. We may even be able to deliver medication that goes to the brain," crossing the blood-brain barrier. Even a few of these cells can have an effect because their geometry means that they have contact with many different neurons or nerve cells.
Scientists Discover How Animals Taste, and Avoid, High Salt Concentrations
For consumers of the typical Western diet—laden with levels of salt detrimental to long-term health—it may be hard to believe that there is such a thing as an innate aversion to very high concentrations of salt.
But Charles Zuker, PhD, and colleagues at Columbia University Medical Center have discovered how the tongue detects high concentrations of salt (think seawater levels, not potato chips), the first step in a salt-avoiding behavior common to most mammals.
The findings, which were published online in the journal Nature, could serve as a springboard for the development of taste modulators to help control the appetite for a high-salt diet and reduce the ill effects of too much sodium.
The sensation of saltiness is unique among the five basic tastes. Whereas mammals are always attracted to the tastes of sweet and umami, and repelled by sour and bitter, their behavioral response to salt dramatically changes with concentration.
“Salt taste in mammals can trigger two opposing behaviors,” said Dr. Zuker, professor in the Departments of Biochemistry & Molecular Biophysics and of Neuroscience at Columbia University College of Physicians & Surgeons. “Mammals are attracted to low concentrations of salt; they will choose a salty solution over a salt-free one. But they will reject highly concentrated salt solutions, even when salt-deprived.”
Over the past 15 years, the receptors and other cells on the tongue responsible for detecting sweet, sour, bitter, and umami tastes—as well as low concentrations of salt—have been uncovered largely through the efforts of Dr. Zuker and his collaborator Nicholas Ryba from the National Institute of Dental and Craniofacial Research.
“But we didn’t understand what was behind the aversion to high concentrations of salt,” said Yuki Oka, a postdoctoral fellow in Dr. Zuker’s laboratory and the lead author of the study.
The researchers expected high-salt receptors to reside in cells committed only to detecting high salt. “Over the years our studies have shown that each taste quality—sweet, bitter, sour, umami, and low-salt—is mediated by different cells,” Dr. Ryba said. “So we thought there must be different taste receptor cells for high-salt. But unexpectedly, Dr. Oka found high salt is mediated by cells we already knew.”