Posts tagged hypothalamus
Articles and news from the latest research reports.
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.
Estrogen: Not just produced by the ovaries
A UW-Madison research team reports today that the brain can produce and release estrogen — a discovery that may lead to a better understanding of hormonal changes observed from before birth throughout the entire aging process.
The new research shows that the hypothalamus can directly control reproductive function in rhesus monkeys and very likely performs the same action in women.
Scientists have known for about 80 years that the hypothalamus, a region in the brain, is involved in regulating the menstrual cycle and reproduction. Within the past 40 years, they predicted the presence of neural estrogens, but they did not know whether the brain could actually make and release estrogen.
Most estrogens, such as estradiol, a primary hormone that controls the menstrual cycle, are produced in the ovaries. Estradiol circulates throughout the body, including the brain and pituitary gland, and influences reproduction, body weight, and learning and memory. As a result, many normal functions are compromised when the ovaries are removed or lose their function after menopause.
"Discovering that the hypothalamus can rapidly produce large amounts of estradiol and participate in control of gonadotropin-releasing hormone neurons surprised us," says Ei Terasawa, professor of pediatrics at the UW School of Medicine and Public Health and senior scientist at the Wisconsin National Primate Research Center. "These findings not only shift the concept of how reproductive function and behavior is regulated but have real implications for understanding and treating a number of diseases and disorders."
For diseases that may be linked to estrogen imbalances, such as Alzheimer’s disease, stroke, depression, experimental autoimmune encephalomyelitis and other autoimmune disorders, the hypothalamus may become a novel area for drug targeting, Terasawa says. “Results such as these can point us in new research directions and find new diagnostic tools and treatments for neuroendocrine diseases.”
The study, published today in the Journal of Neuroscience, “opens up entirely new avenues of research into human reproduction and development, as well as the role of estrogen action as our bodies age,” reports the first author of the paper, Brian Kenealy, who earned his Ph.D. this summer in the Endocrinology and Reproductive Physiology Program at UW-Madison. Kenealy performed three studies. In the first experiment, a brief infusion of estradiol benzoate administered into the hypothalamus of rhesus monkeys that had surgery to remove their ovaries rapidly stimulated GnRH release. The brain took over and began rapidly releasing this estrogen in large pulsing surges.
In the second experiment, mild electrical stimulation of the hypothalamus caused the release of both estrogen and GnRH (thus mimicking how estrogen could induce a neurotransmitter-like action). Third, the research team infused letrazole, an aromatase inhibitor that blocks the synthesis of estrogen, resulting in a lack of estrogen as well as GnRH release from the brain. Together, these methods demonstrated how local synthesis of estrogen in the brain is important in regulating reproductive function.
The reproductive, neurological and immune systems of rhesus macaques have proven to be excellent biomedical models for humans over several decades, says Terasawa, who focuses on the neural and endocrine mechanisms that control the initiation of puberty. “This work is further proof that these animals can teach us about so many basic functions we don’t fully understand in humans.”
Leading up to this discovery, Terasawa said, recent evidence had shown that estrogen acting as a neurotransmitter in the brain rapidly induced sexual behavior in quails and rats. Kenealy’s work is the first evidence of this local hypothalamic action in primates, and in those that don’t even have ovaries.
"The discovery that the primate brain can make estrogen is key to a better understanding of hormonal changes observed during every phase of development, from prenatal to puberty, and throughout adulthood, including aging," Kenealy says.
(Source: news.wisc.edu)
What do bullies and sex have in common? Based on work by scientists at the European Molecular Biology Laboratory (EMBL) in Monterotondo, Italy, it seems that the same part of the brain reacts to both. In a study published today in Nature Neuroscience, the researchers found that – at least in mice – different types of fear are processed by different groups of neurons, even if the animals act out those fears in the same way. The findings could have implications for addressing phobias and panic attacks in humans.
“We found that there seems to be a circuit for handling fear of predators – which has been described anatomically as a kind of defence circuit – but fear of members of the same species uses the reproductive circuit instead,” says Bianca Silva, who carried out the work, “and fear of pain goes through yet another part of the brain.”
Working in the lab of Cornelius Gross at EMBL, Silva exposed mice to three threats: another mouse (chosen for being particularly aggressive), a rat (the mouse’s natural predator) or a mild electric shock to the feet. The mice showed the same typical fearful behaviours – running away, freezing – in response to all threats, but their brains painted a different picture. When the scientists mapped the brain activity of mice exposed to the aggressive mouse and the rat, they saw that different parts of a region called the ventromedial hypothalamus (VMH) ‘lit up’ depending on the threat. Fear of the mouse seemed to activate the bottom and sides of the VMH, while fear of the rat seemed to be processed by the VMH’s central and upper areas. This was confirmed when the scientists used drugs to block only the neurons in those ‘rat fear’ areas: mice were no longer afraid of the rat, but were still afraid of the mouse, showing that mice need this brain circuit specifically to process fear of predators.
The human brain has similar circuits, and we too experience different kinds of fear, so the results hint at the possibility of developing more efficient treatments for specific phobias or panic attacks, by targeting only the relevant region of the brain.
For their part, the EMBL scientists plan to probe these fears further.
“What we’re interested in, in the long-run, is if these results represent a kind of mental state,” says Cornelius Gross, who led the work. “If so, mice should be able to be in that state without expressing it in their behaviour – do they re-live that fear, for example? These are not easy questions to ask in the mouse, but we’re looking into them.”
Gross’s lab are also looking at how these different fears – and the neural circuits that process them – may have evolved. Working with Detlev Arendt’s group at EMBL Heidelberg, they have discovered a similar brain region in a marine worm thought to closely resemble our ancestors from 600 million years ago. Now the team is exploring the possibility that this represents an ancestral core fear circuit that those ancestors handed down to us all, from worms to man.
Aging really is ‘in your head’
Scientists answer hotly debated questions about how calorie restriction delays aging process
Among scientists, the role of proteins called sirtuins in enhancing longevity has been hotly debated, driven by contradictory results from many different scientists. But new research at Washington University School of Medicine in St. Louis may settle the dispute.
Reporting Sept. 3 in Cell Metabolism, Shin-ichiro Imai, MD, PhD, and his colleagues have identified the mechanism by which a specific sirtuin protein called Sirt1 operates in the brain to bring about a significant delay in aging and an increase in longevity. Both have been associated with a low-calorie diet.
The Japanese philosopher and scientist Ekiken Kaibara first described the concept of dietary control as a method to achieve good health and longevity in 1713. He died the following year at the ripe old age of 84—a long life for someone in the 18th century.
Since then, science has proven a link between a low-calorie diet (without malnutrition) and longevity in a variety of animal models. In the new study, Imai and his team have shown how Sirt1 prompts neural activity in specific areas of the hypothalamus of the brain, which triggers dramatic physical changes in skeletal muscle and increases in vigor and longevity.
“In our studies of mice that express Sirt1 in the brain, we found that the skeletal muscular structures of old mice resemble young muscle tissue,” said Imai. “Twenty-month-old mice (the equivalent of 70-year-old humans) look as active as five-month-olds.”
Imai and his team began their quest to define the critical junctures responsible for the connection between dietary restriction and longevity with the knowledge from previous studies that the Sirt1 protein played a role in delaying aging when calories are restricted. But the specific mechanisms by which it carried out its function were unknown.
Imai’s team studied mice that had been genetically modified to overproduce Sirt1 protein. Some of the mice had been engineered to overproduce Sirt1 in body tissues, while others were engineered to produce more of the Sirt1 protein only in the brain.
“We found that only the mice that overexpressed Sirt1 in the brain (called BRASTO) had significant lifespan extension and delay in aging, just like normal mice reared under dietary restriction regimens,” said Imai, an expert in aging research and a professor in the departments of Developmental Biology and Medicine.
The BRASTO mice demonstrated significant life span extension without undergoing dietary restriction. “They were free to eat regular chow whenever they wished,” he said.
In addition to positive skeletal muscle changes in the BRASTO mice, the investigators also observed significant increases in nighttime physical activity, body temperature and oxygen consumption compared with age-matched controls.
Mice are characteristically most active at night. The BRASTO mice also experienced better or deeper sleep, and both males and females had significant increases in longevity.
The median life span of BRASTO mice in the study was extended by 16 percent for females and 9 percent for males. Translated to humans, this could mean an extra 13 or 14 years for women, making their average life span almost 100 years, Shin said. For men, this would add another seven years, increasing their average life span to the mid-80s.
Delay in cancer-dependent death also was observed in the BRASTO mice relative to control mice, the researchers noted.
Imai said that the longevity and health profile associated with the BRASTO mice appears to be the result of a shift in the onset of aging rather than the pace of aging. “What we have observed in BRASTO mice is a delay in the time when age-related decline begins, so while the rate of aging does not change, aging and the risk of cancer has been postponed.”
Having narrowed control of aging to the brain, Imai’s team then traced the control center of aging regulation to two areas of the hypothalamus called the dorsomedial and lateral hypothalamic nuclei. They then were able to identify specific genes within those areas that partner with Sirt1 to kick off the neural signals that elicit the physical and behavioral responses observed.
“We found that overexpression of Sirt1 in the brain leads to an increase in the cellular response of a receptor called orexin type 2 receptor in the two areas of the hypothalamus,” said first author Akiko Satoh, PhD, a postdoctoral staff scientist in Imai’s lab.
“We have demonstrated that the increased response by the receptor initiates signaling from the hypothalamus to skeletal muscles,” said Satoh. She noted that the mechanism by which the signal is specifically directed to skeletal muscle remains to be discovered.
According to Imai, the tight association discovered between Sirt1-prompted brain activation and the regulation of aging and longevity raises the tantalizing possibility of a “control center of aging and longevity” in the brain, which could be manipulated to maintain youthful physiology and extend life span in other mammals as well.
(Source: news.wustl.edu)
Double-barreled attack on obesity in no way a no-brainer
In the constant cross talk between our brain and our gut, two gut hormones are already known to tell the brain when we have had enough to eat. New research suggests that boosting levels of these hormones simultaneously may be an effective new weapon in the fight against obesity.
Dr Shu Lin, Dr Yan-Chuan Shi and Professor Herbert Herzog, from Sydney’s Garvan Institute of Medical Research, have shown that when mice are injected with PYY3-36 and PP, they eat less, gain less fat, and tend not to develop insulin-resistance, a precursor to diabetes. At the same time, the researchers have shown that the hormones stimulate different nerve pathways, ultimately, however, affecting complementary brain regions. Their findings are now published online in the journal Obesity.
While the double-barreled approach may seem like a no-brainer, the strongly enhanced effect seen was by no means inevitable. In the complex world of neuroscience, two plus two does not always make four.
Drug companies are in the process of conducting pre-clinical trials to examine the separate effects of boosting the hormones PYY3-36 and PP. Until now, there is no research to indicate the detailed molecular interactions that might occur when they are boosted in tandem.
When used together, the hormones independently, yet with combined force, reduce the amount of neuropeptide Y (NPY) produced by the brain, a powerful neurotransmitter that affects a variety of things including appetite, mood, heart rate, temperature and energy levels.
Each hormone also communicates with a different part of the arcuate nucleus in the hypothalamus, a region of the brain where signals can cross the normally impermeable blood / brain barrier. The stimulated regions then produce other neuronal signals deep within the hypothalamus, bringing about a powerful combined effect.
“There are many factors that influence appetite control – and we now realise that there won’t be a single molecular target, or a single drug, that will be effective,” said Dr Yan-Chuan Shi.
“It will be important for drug companies to try different combinations of targets, to see which combinations are most potent, and at the same time have no side effects, or at least minimal side effects.”
“At the moment, the only effective tool against obesity is surgery. Drug companies have so far failed to produce an effective drug without unacceptable side effects, such as mood disorders, nausea or cardiovascular problems.”
(Source: garvan.org.au)
The link between circadian rhythms and aging
Human sleeping and waking patterns are largely governed by an internal circadian clock that corresponds closely with the 24-hour cycle of light and darkness. This circadian clock also controls other body functions, such as metabolism and temperature regulation.
Studies in animals have found that when that rhythm gets thrown off, health problems including obesity and metabolic disorders such as diabetes can arise. Studies of people who work night shifts have also revealed an increased susceptibility to diabetes.
A new study from MIT shows that a gene called SIRT1, previously shown to protect against diseases of aging, plays a key role in controlling these circadian rhythms. The researchers found that circadian function decays with aging in normal mice, and that boosting their SIRT1 levels in the brain could prevent this decay. Conversely, loss of SIRT1 function impairs circadian control in young mice, mimicking what happens in normal aging.
Since the SIRT1 protein itself was found to decline with aging in the normal mice, the findings suggest that drugs that enhance SIRT1 activity in humans could have widespread health benefits, says Leonard Guarente, the Novartis Professor of Biology at MIT and senior author of a paper describing the findings in the June 20 issue of Cell.
“If we could keep SIRT1 as active as possible as we get older, then we’d be able to retard aging in the central clock in the brain, and health benefits would radiate from that,” Guarente says.
Staying on schedule
In humans and animals, circadian patterns follow a roughly 24-hour cycle, directed by the circadian control center of the brain, called the suprachiasmatic nucleus (SCN), located in the hypothalamus.
“Just about everything that takes place physiologically is really staged along the circadian cycle,” Guarente says. “What’s now emerging is the idea that maintaining the circadian cycle is quite important in health maintenance, and if it gets broken, there’s a penalty to be paid in health and perhaps in aging.”
Last year, Guarente found that a robust circadian period correlated with longer lifespan in mice. That got him wondering what role SIRT1, which has been shown to prolong lifespan in many animals, might play in that phenomenon. SIRT1, which Guarente first linked with aging more than 15 years ago, is a master regulator of cell responses to stress, coordinating a variety of hormone networks, proteins and genes to help keep cells alive and healthy.
To investigate SIRT1’s role in circadian control, Guarente and his colleagues created genetically engineered mice that produce different amounts of SIRT1 in the brain. One group of mice had normal SIRT1 levels, another had no SIRT1, and two groups had extra SIRT1 — either twice or 10 times as much as normal.
Mice lacking SIRT1 had slightly longer circadian cycles (23.9 hours) than normal mice (23.6 hours), and mice with a 10-fold increase in SIRT1 had shorter cycles (23.1 hours).
In mice with normal SIRT1 levels, the researchers confirmed previous findings that when the 12-hour light/dark cycle is interrupted, younger mice readjust their circadian cycles much more easily than older ones. However, they showed for the first time that mice with extra SIRT1 do not suffer the same decline in circadian control as they age.
The researchers also found that SIRT1 exerts this control by regulating the genes BMAL and CLOCK, the two major keepers of the central circadian clock.
Enhancing circadian function
A growing body of evidence suggests that being able to respond to large or small disruptions of the light/dark cycle is important to maintaining healthy metabolic function, Guarente says.
“Essentially we experience a mini jet lag every day because the light cycle is constantly changing. The critical thing for us is to be able to adapt smoothly to these jolts,” Guarente says. “Many studies in mice say that while young mice do this perfectly well, it’s the old mice that have the problem. So that could well be true in humans.”
If so, it could be possible to treat or prevent diseases of aging by enhancing circadian function — either by delivering SIRT1 activators in the brain or developing drugs that enhance another part of the circadian control system, Guarente says.
“I think we should look at every aspect of the machinery of the circadian clock in the brain, and any intervention that can maintain that machinery with aging ought to be good,” he says. “One entry point would be SIRT1, because we’ve shown in mice that genetic maintenance of SIRT1 helps maintain circadian function.”
Some SIRT1 activators are now being tested against diabetes, inflammation and other diseases, but they are not designed to cross the blood-brain barrier and would likely not be able to reach the SCN. However, Guarente believes it could be possible to design SIRT1 activators that can get into the brain.
Roman Kondratov, an associate professor of biology at Cleveland State University, says the study raises several exciting questions regarding the potential to delay or reverse age-related changes in the brain through rejuvenation of the circadian clock with SIRT1 enhancement.
“The importance of this study is that it has both basic and potentially translational applications, taking into account the fact that pharmacological modulators of SIRT1 are currently under active study,” Kondratov says.
Researchers in Guarente’s lab are now investigating the relationship between health, circadian function and diet. They suspect that high-fat diets might throw the circadian clock out of whack, which could be counteracted by increased SIRT1 activation.
(Image: Wikimedia Commons)
Breakthrough on Huntington’s disease
Researchers at Lund University have succeeded in preventing very early symptoms of Huntington’s disease, depression and anxiety, by deactivating the mutated huntingtin protein in the brains of mice.
“We are the first to show that it is possible to prevent the depression symptoms of Huntington’s disease by deactivating the diseased protein in nerve cell populations in the hypothalamus in the brain. This is hugely exciting and bears out our previous hypotheses”, explains Åsa Petersén, Associate Professor of Neuroscience at Lund University.
Huntington’s is a debilitating disease for which there is still neither cure nor sufficient treatment. The dance-like movements that characterise the disease have long been the focus for researchers, but the emotional problems affect the patient earlier than the motor symptoms. These are now believed to stem from a different part of the brain – the small emotional centre called the hypothalamus.
“Now that we have been able to show in animal experiments that depression and anxiety occur very early in Huntington’s disease, we want to identify more specifically which nerve cells in the hypothalamus are critical in the development of these symptoms. In the long run, this gives us better opportunities to develop more accurate treatments that can attack the mutated huntingtin where it does the most damage”, says Åsa Petersén.
As the role of the hypothalamus in Huntington’s disease is gradually mapped, knowledge might be gained from drug research for other psychiatric diseases. It is likely that similar mechanisms control different types of depression, according to Åsa Petersén.
Publication:
Hypothalamic expression of mutant huntingtin contributes to the development of depressive-like behavior in the BAC transgenic mouse model of Huntington’s disease
Human Molecular Genetics
Sofia Hult Lundh, Nathalie Nilsson, Rana Soylu, Deniz Kirik and Åsa Petersén
(Source: lunduniversity.lu.se)
Changes in brain chemistry sustain obesity
With obesity reaching epidemic levels in some parts of the world, scientists have only begun to understand why it is such a persistent condition. A study in the Journal of Biological Chemistry adds substantially to the story by reporting the discovery of a molecular chain of events in the brains of obese rats that undermined their ability to suppress appetite and to increase calorie burning.
It’s a vicious cycle, involving a breakdown in how brain cells process key proteins, that allows obesity to beget further obesity. But in a finding that might prove encouraging in the long term, the researchers at Brown University and Lifespan also found that they could intervene to break that cycle by fixing the core protein-processing problem.
Before the study, scientists knew that one mechanism in which obesity perpetuates itself was by causing resistance to leptin, a hormone that signals the brain about the status of fat in the body. But years ago senior author Eduardo A. Nillni, professor of medicine at Brown University and a researcher at Rhode Island Hospital, observed that after meals obese rats had a dearth of another key hormone — alpha-MSH — compared to rats of normal weight.
Alpha-MSH has two jobs in parts of the hypothalamus region of the brain. One is to suppress the activity of food-seeking brain cells. The second is to signal other brain cells to produce the hormone TRH, which prompts the thyroid gland to spur calorie burning activity in the body.
In the obese rats alpha-MSH was low, despite an abundance of leptin and despite normal levels of gene expression both for its biochemical precursor protein called pro-opiomelanocortin (POMC) and for a key enzyme called PC2 that processes POMC in brain cells. There had to be more to the story than just leptin, and it wasn’t a problem with expressing the needed genes.
Nillni and his co-authors, including lead authors Isin Cakir and Nicole Cyr, conducted the new study to find out where the alpha-MSH deficit was coming from. Nillni said he suspected that the problem might lie in the brain cells’ mechanism for processing the POMC protein to make alpha-MSH.
Protein processing problems
To do their work, the team fed some rats a high-calorie diet and fed others a normal diet for 12 weeks. The overfed rats developed the condition of “diet-induced obesity.” The team then studied the hormone levels and brain cell physiology of the rats. They also tested their findings by experimenting with the biochemistry of key individual cells on the lab bench.
They found that in the obese rats, a key “machine” in the brain cells’ assembly line of protein-making, called the endoplasmic reticulum (ER), becomes stressed and overwhelmed. The overloaded ER apparently fumbles the proper handling of PC2, perhaps discarding it because it can’t be folded up properly. The PC2 levels they measured in obese rats, for example, were 53 percent lower than in normal rats. Alpha-MSH peptides were also barely more than half as abundant in obese rats as they were in healthy rats.
“In our study we showed that what actually prevents the production of more alpha-MSH peptide is that ER stress was decreasing the biosynthesis of POMC by affecting one key enzyme that is essential for the formation of alpha-MSH,” Nillni said. “This is so novel. Nobody ever looked at that.”
Novel as it was, the story — a stressed ER mishandles PC2, which leaves POMC unfolded, which impedes alpha-MSH production — needed experimental confirmation.
The team provided that confirmation in several ways: In obese rats they measured elevated levels of known markers of ER stress. They also purposely induced ER stress in cells using pharmacological agents and saw that both PC2 and Alpha-MSH levels dropped.
Next they conducted an experiment to see if fixing ER stress would improve alpha-MSH production. They treated lean and obese rats for two days with a chemical called TUDCA, which is known to alleviate ER stress. If ER stress is responsible for alpha-MSH production problems, the researchers would see alpha-MSH recover in obese rats treated with TUDCA. Sure enough, while TUDCA didn’t increase alpha-MSH production in normal rats, it increased it markedly in the obese rats.
Similarly on the benchtop they took mouse neurons that produce PC2 and POMC and pretreated some with a similar chemical called PBA that prevents ER stress. They left others untreated. Then they induced ER stress in all the cells. Under that ER stress, those that had been pretreated with PBA produced about twice as much PC2 as those that had not.
Nillni cautioned that although his team found ways to restore PC2 and alpha-MSH by treating ER stress in living rats and individual cells, the agents used in the study are not readily applicable as medicines for treating obesity in humans. There could well be unknown and unwanted side effects, for example, and TUDCA is not approved for human use by the U.S. Food and Drug Administration.
But by laying out the exact mechanism responsible for why the brains of the obese rats failed to curb appetite or spur greater calorie burning, Nillni said, the study points drug makers to several opportunities where they can intervene to break this new, vicious cycle that helps obesity to perpetuate itself.
“Understanding the central control of energy-regulating neuropeptides during diet-induced obesity is important for the identification of therapeutic targets to prevent and or mitigate obesity pathology,” the authors wrote.
Hypothalamus and Aging: Brain Region May Hold Key to Aging
While the search continues for the Fountain of Youth, researchers may have found the body’s “fountain of aging”: the brain region known as the hypothalamus. For the first time, scientists at Albert Einstein College of Medicine of Yeshiva University report that the hypothalamus of mice controls aging throughout the body. Their discovery of a specific age-related signaling pathway opens up new strategies for combating diseases of old age and extending lifespan. The paper was published today in the online edition of Nature.
“Scientists have long wondered whether aging occurs independently in the body’s various tissues or if it could be actively regulated by an organ in the body,” said senior author Dongsheng Cai, M.D., Ph.D., professor of molecular pharmacology at Einstein. “It’s clear from our study that many aspects of aging are controlled by the hypothalamus. What’s exciting is that it’s possible — at least in mice — to alter signaling within the hypothalamus to slow down the aging process and increase longevity.”
The hypothalamus, an almond-sized structure located deep within the brain, is known to have fundamental roles in growth, development, reproduction, and metabolism. Dr. Cai suspected that the hypothalamus might also play a key role in aging through the influence it exerts throughout the body.
“As people age,” he said, “you can detect inflammatory changes in various tissues. Inflammation is also involved in various age-related diseases, such as metabolic syndrome, cardiovascular disease, neurological disease and many types of cancer.” Over the past several years, Dr. Cai and his research colleagues showed that inflammatory changes in the hypothalamus can give rise to various components of metabolic syndrome (a combination of health problems that can lead to heart disease and diabetes).
To find out how the hypothalamus might affect aging, Dr. Cai decided to study hypothalamic inflammation by focusing on a protein complex called NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells). “Inflammation involves hundreds of molecules, and NF-κB sits right at the center of that regulatory map,” he said.
In the current study, Dr. Cai and his team demonstrated that activating the NF-κB pathway in the hypothalamus of mice significantly accelerated the development of aging, as shown by various physiological, cognitive, and behavioral tests. “The mice showed a decrease in muscle strength and size, in skin thickness, and in their ability to learn — all indicators of aging. Activating this pathway promoted systemic aging that shortened the lifespan,” he said.
Conversely, Dr. Cai and his group found that blocking the NF-κB pathway in the hypothalamus of mouse brains slowed aging and increased median longevity by about 20 percent, compared to controls.
The researchers also found that activating the NF-κB pathway in the hypothalamus caused declines in levels of gonadotropin-releasing hormone (GnRH), which is synthesized in the hypothalamus. Release of GnRH into the blood is usually associated with reproduction. Suspecting that reduced release of GnRH from the brain might contribute to whole-body aging, the researchers injected the hormone into a hypothalamic ventricle (chamber) of aged mice and made the striking observation that the hormone injections protected them from the impaired neurogenesis (the creation of new neurons in the brain) associated with aging. When aged mice received daily GnRH injections for a prolonged period, this therapy exerted benefits that included the slowing of age-related cognitive decline, probably the result of neurogenesis.
According to Dr. Cai, preventing the hypothalamus from causing inflammation and increasing neurogenesis via GnRH therapy are two potential strategies for increasing lifespan and treating age-related diseases. This technology is available for licensing.
(Source: einstein.yu.edu)
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)