Smoking induces early signs of cancer in cheek swabs

DNA damage caused by smoking can be detected in cheek swabs, finds research published in JAMA Oncology. The study provides evidence that smoking induces a general cancer program that is also present in cancers which aren't usually associated with it -- including breast and gynaecological cancers.

The research team, led by Professor Martin Widschwendter, Head of the Department of Women's Cancer at the UCL Institute for Women's Health and Dr Andrew Teschendorff (UCL Cancer Institute) looked at epigenetic alterations -- changes to the DNA that switch genes on and off. Epigenetic changes are associated with cancer development and can be caused by exposure to environmental factors such as cigarette smoke.
The researchers aimed to explore whether normal cells from the inside of the cheek would demonstrate epigenetic changes which are associated with lung and other epithelial cancers. These types of cancers originate in the epithelial cells -- which cover the outside of the body as skin or the inside of the body as lining for organs and body cavities -- and make up 85% of all cancer cases in the UK. The buccal cells taken from the cheek swabs are easy to collect and are directly exposed to cigarette smoke in those who smoke.
To do this, in collaboration with Prof Diana Kuh (UCL Epidemiology & Public Health) and her team, they analysed buccal samples from 790 women all born in 1946 and 152 matched blood samples from the Medical Research Council National Survey of Health and Development. The dataset included information about smoking history and smoking status at the time the samples were collected.
This analysis showed that buccal cells in women who have smoked had numerous changes to their epigenomes -- known as DNA-methylation (DNAme). Buccal cells showed a 40-fold increase in abnormal methylation sites compared to matched blood samples, making them a more reliable indicator of DNA changes.
The team then went on to analyse this smoke-triggered epigenetic program in over 5000 tissue samples, including normal tissue, pre-cancerous tissue and cancer tissue from 15 different epithelial cancer types. In doing so, they tested whether they were able to discriminate normal tissue from cancerous tissue. They found that this program -- which they originally derived in normal buccal cells of smokers -- is able to discriminate between normal and cancerous tissue with almost 100% sensitivity and 100% specificity irrespective of the organ from which the cancer arose.
Researchers also found that the absence or presence of this program was able to predict the fate of pre-invasive cancer lesions. The presence of the faulty program in the cells makes it very likely that a pre-invasive cancer will progress to a full-blown invasive cancer. However, the absence of the faulty program makes it likely that the pre-cancer can potentially regress and disappear.
An individuals' DNA works like the hardware within a cell, with the epigenome being the software. Smoking misprograms the epigenome and the genetic code becomes difficult or impossible to read. Misprogramming of a cells' software, in conjunction with genetic mutations, eventually lead to an inability of these cells to develop into specific differentiated cells. These cells are then trapped in an undifferentiated status and can grow indefinitely and spread into other organs.
Professor Martin Widschwendter commented: 'These are significant results for our core interest which is decoding women's cancers. We are a big step closer now to unravelling how environmental factors cause cancer. These results pave the way for other studies in which easily accessible cells can be used as proxies to highlight epigenetic changes that may indicate a risk of developing cancer at a site where cells are inaccessible. This is incredibly exciting for women's cancers such as ovary, breast and endometrial cancer where predicting the cancer risk is a big challenge,'
'The results also demonstrate that smoking-related DNA damage to the epigenome of certain genes had been reversed in ex-smokers who had quit 10 years previously before sample collection, highlighting the key health benefits of quitting smoking, or not taking it up at all.
Athena Lamnisos, CEO of The Eve Appeal said: 'We know that what's going to save most lives from gynaecological cancers is prevention -- decoding why these cancers start and stopping them. That's why we fund research into the earlier diagnosis, risk prediction and prevention. This research shows how signs of developing cancer may be detected using accessible cells from inside the mouth. It points the way for pioneering further studies that will help detect women's cancers.'
Lead author Andrew Teschendorff (UCL Cancer Institute) said: 'Our work shows that smoking has a major impact on the epigenome of normal cells that are directly exposed to the carcinogen. Of particular significance is that these epigenetic changes are also seen in both smoking-related and non-smoking related cancers, pointing towards a universal cancer program. This research gets us closer to understanding the very first steps in carcinogenesis and in future may provide us with much-needed tests for risk prediction and early detection.'
 

Journal Reference:

1. Andrew E. Teschendorff, Zhen Yang, Andrew Wong, Christodoulos P. Pipinikas, Yinming Jiao, Allison Jones, Shahzia Anjum, Rebecca Hardy, Helga B. Salvesen, Christina Thirlwell, Samuel M. Janes, Diana Kuh, Martin Widschwendter. Correlation of Smoking-Associated DNA Methylation Changes in Buccal Cells With DNA Methylation Changes in Epithelial Cancer. JAMA Oncology, 2015; DOI: 10.1001/jamaoncol.2015.1053 

 Courtesy: ScienceDaily

New test detects drug use from a single fingerprint

Research published in the journal Analyst has demonstrated a new, non-invasive test that can detect cocaine use through a simple fingerprint. For the first time, this new fingerprint method can determine whether cocaine has been ingested, rather than just touched.

Researchers believe that the applications for this test could be far-reaching. Drug testing is used routinely by probation services, prisons, courts and other law enforcement agencies. However, traditional testing methods have limitations.

Credit: © ILYA AKINSHIN / Fotolia

Led by the University of Surrey, a team of researchers from the Netherlands Forensic Institute (NL), the National Physical Laboratory (UK), King's College London (UK) and Sheffield Hallam University (UK), used different types of an analytical chemistry technique known as mass spectrometry to analyse the fingerprints of patients attending drug treatment services. They tested these prints against more commonly used saliva samples to determine whether the two tests correlated. While previous fingerprint tests have employed similar methods, they have only been able to show whether a person had touched cocaine, and not whether they have actually taken the drug.
"When someone has taken cocaine, they excrete traces of benzoylecgonine and methylecgonine as they metabolise the drug, and these chemical indicators are present in fingerprint residue," said lead author Dr Melanie Bailey from the University of Surrey. "For our part of the investigations, we sprayed a beam of solvent onto the fingerprint slide (a technique known as Desorption Electrospray Ionisation, or DESI) to determine if these substances were present. DESI has been used for a number of forensic applications, but no other studies have shown it to demonstrate drug use."
Researchers believe that the applications for this test could be far-reaching. Drug testing is used routinely by probation services, prisons, courts and other law enforcement agencies. However, traditional testing methods have limitations. For example, blood testing requires trained staff and there are privacy concerns about urine testing. Where bodily fluids are tested, there can be biological hazards and often a requirement for particular storage and disposal methods. Often these tests also require analysis off-site.
"The beauty of this method is that, not only is it non-invasive and more hygienic than testing blood or saliva, it can't be faked," added Dr Bailey. "By the very nature of the test, the identity of the subject is captured within the fingerprint ridge detail itself."
It is anticipated that this technology could see the introduction of portable drug tests for law enforcement agencies to use within the next decade.
"We are only bound by the size of the current technology. Companies are already working on miniaturised mass spectrometers, and in the future portable fingerprint drugs tests could be deployed. This will help to protect the public and indeed provide a much safer test for drug users," said Dr Bailey.
 

ournal Reference:

1. Melanie Bailey, Robert Bradshaw, Simona Francese, Tara La Roche Salter, Catia Costa, Mahado Ismail, Roger Webb, Ingrid Bosman, Kim Wolff, Marcel de Puit. Rapid Detection of Cocaine, Benzoylecgonine and Methylecgonine in Fingerprints using Surface Mass Spectrometry. The Analyst, 2015; DOI: 10.1039/C5AN00112A 

Courtesy: ScienceDaily
 

Phage spread antibiotic resistance

Investigators found that nearly half of the 50 chicken meat samples purchased from supermarkets, street markets, and butchers in Austria contained viruses that are capable of transferring antibiotic resistance genes from one bacterium to another--or from one species to another. "Our work suggests that such transfer could spread antibiotic resistance in environments such as food production units and hospitals and clinics," said corresponding author Friederike Hilbert, DVM. The research is published ahead of print May 1, in Applied and Environmental Microbiology, a journal of the American Society for Microbiology.

This was the first demonstration that a high proportion of phage randomly isolated from meat were able to transfer antimicrobial resistance among different bacteria, said Hilbert, who is a professor at the Institute for Meat Hygiene, Meat Technology and Food Science, at the University of Veterinary Medicine, Vienna, Austria. Phage are viruses that infect bacteria.
"One quarter of all phages isolated were able to transduce [transfer] one or more of the five antimicrobial resistances under study," said Hilbert. These included resistances to tetracycline, ampicillin, kanamycin, and chloramphenicol, as well as resistance to extended spectrum betalactam antibiotics. The results suggest that the number of phages that can transduce antibiotic resistance genes must be far higher, since the experiments were restricted to resistance to only five antibiotics via five randomly chosen phages per sample of chicken, said Hilbert.
"Strategies to combat antimicrobial resistance have enjoyed only limited success, and there are still many questions relating to how and when resistance transfer occurs," Hilbert writes. "The presence of phages that transfer antimicrobial resistance could explain the failures to combat antimicrobial resistance."
Until recently, transduction of antibiotic resistance via phage was assumed to be a very minor source of the spread of resistance, said Hilbert. "New information from the sequencing of bacterial DNA has shown that transduction must be a driving force in bacterial evolution, and thus, quite common."
In the study, the investigators rinsed the chicken they had purchased, and then isolated coliphage, using the International Organization for Standardization (ISO) method for isolating such viruses from water, said Hilbert.
Unlike bacteria, which are true living creatures, viruses, including phages, can be thought of more as complex molecular machinery. As such, the latter are much more resistant to disinfectants, including those used in the food industry. Alcohol, in particular, is harmless to most viruses. "It is thus highly likely that phages survive under routine conditions of disinfection, not only in the food industry," Hilbert writes.
The research, Hilbert concludes, demonstrates that transduction is an efficient way to transfer antimicrobial resistance to E. coli in different environments. That, she says, needs to be addressed for concerns related to hygiene, sanitation, and public health.
 

Journal Reference:

1. Amira Shousha, Nattakarn Awaiwanont, Dmitrij Sofka, Frans J.M. Smulders, Peter Paulsen, Michael P. Szostak, Tom Humphrey, Friederike Hilbert. Bacteriophages isolated from chicken meat and the horizontal transfer of antimicrobial resistance genes. Applied and Environmental Microbiology, 2015; AEM.00872-15 DOI: 10.1128/AEM.00872-15 

Courtesy: ScienceDaily
 

Biologist advances cancer research with new data analysis techniques

Patience and persistence are beginning to pay off for University of Montana Professor Mark Grimes, whose research about the behavior of cell proteins in childhood cancer recently was published by the Public Library of Science Computational Biology.

UM cell biologist Mark Grimes stands in front of a poster displaying the findings in his research paper.

Credit: Todd Goodrich

In his quest to understand the childhood cancer called neuroblastoma -- which is not the most common type of childhood cancer, but is the most lethal -- Grimes started at the subcellular level, isolating organelles containing molecules that signal to cells to divide, die or differentiate. As a cell biologist, he wanted to understand why cancer cells behave differently than other cells.
Grimes laid the groundwork for his research by identifying a large number of signaling proteins using mass spectrometry in collaboration with Cell Signaling Technology, a company in Danvers, Massachusetts. He collected more data than he knew what to do with.
"I spent an embarrassingly long time staring at a spreadsheet trying to figure out what it all meant," Grimes said.
Perplexed, he set off on a five-year adventure in unknown territory: data analytics.
"I felt like Don Quixote for a while, wandering through the wilderness, because I'm really a cell biologist," Grimes said, "I'm not a statistician. I'm not a computer programmer."
So he sought out people who had those skills. He teamed up with Laurens van der Maaten, a pattern recognition specialist at Delft University of Technology in the Netherlands, and Paul Shannon, senior software engineer at the Fred Hutchison Cancer Research in Seattle, and started learning the skills himself.
"And after many trials and errors, I learned about a pattern-recognition technique that works really well and discovered a few new tricks that are actually pretty fundamental," he said. "Which is why I'm excited about this paper, because not only the results are interesting, but the way we analyze the data brings new tools to bear on these kinds of problems in general."
By collaborating with people in the field of pattern recognition and bioinformatics, Grimes developed a way to calculate relationships in the data, even when that data contains a lot of missing information, as his did.
"I figured out a way to calculate relationships leaving the holes in there," he said, "because there are so many holes that if you put zeroes in there, the zeroes all correlate with each other and you get no information."
Grimes' new technique labels the zeroes as "data not available" rather than a numerical value, telling his algorithm only to analyze relationships among data that exists. Once he applied the new technique to the data he collected, the methods of sorting data into groups, called clustering, became more robust and the relationships became clearer: in cancer cells, the components that determine the cell's behavior -- whether the cell will live, die, migrate or change identity (differentiate) -- are functionally compartmentalized into distinct collaborative groups.
Therapeutic progress has been slow for neuroblastoma. Grimes and his research partners at Cell Signaling Technology analyzed a large number of neuroblastoma cells, dissecting them to find the specific location of their signaling proteins. The analysis found two related proteins act like central hubs that distinguish responses to the activation of different receptors.
Grimes hopes that by understanding the fundamentals of cell signaling, scientists eventually might be able to change the signals within cancer cells. For instance, they could trigger cancer cells to die rather than metastasize.
Since humans are born with more cells than we need to survive, many cells in our bodies already are "programmed" to die. And by harnessing the same signals in those cells, Grimes said it just might be possible to tell cancer cells to do the same.
"If we can understand the fundamentals of signaling, then we can hope to manipulate these pathways and maybe apply it to neuroblastoma," he said. "If we can get them to march a little bit further in their differentiation, we could use that differentiation to make each cell susceptible to programmed cell death."
And if this signaling works for neuroblastoma cells, scientists possibly could use the same technology on all cancer cells.
"If we understand how different receptors elicit distinct cell responses," Grimes said, "we can devise strategies to manipulate cancer cells to cease proliferation, differentiate or commit cell suicide."
He said it's important to understand the highly dynamic network of interacting proteins and how they communicate inside the cellular environment to understand the cause of cancer.
"We've made tremendous progress on cancer, but we also have to acknowledge we've really just sampled a teaspoonful of an ocean full of things we need to do," he said. "We have a huge amount to do to increase the quality of life, survival and even lifespan. There's a lot to do on many fronts."
 

Journal Reference:

1. Juan Palacios-Moreno, Lauren Foltz, Ailan Guo, Matthew P. Stokes, Emily D. Kuehn, Lynn George, Michael Comb, Mark L. Grimes. Neuroblastoma Tyrosine Kinase Signaling Networks Involve FYN and LYN in Endosomes and Lipid Rafts. PLOS Computational Biology, 2015; 11 (4): e1004130 DOI: 10.1371/journal.pcbi.1004130 

Courtesy: ScienceDaily
 

Eat dark chocolate to beat the midday slump?

Larry Stevens eats a piece of high-cacao content chocolate every afternoon, which is in part because he has developed a taste for the unsweetened dark chocolate. It's also because research shows that it lowers blood pressure and his new study reveals that it improves attention, which is especially important when hitting that midday slump.

Chocolate. The results for the participants who consumed 60 percent cacao chocolate showed that the brain was more alert and attentive after consumption. Their blood pressure also increased for a short time.

Credit: © joanna wnuk / Fotolia

"Chocolate is indeed a stimulant and it activates the brain in a really special way," said Stevens, a professor of psychological sciences at NAU. "It can increase brain characteristics of attention, and it also significantly affects blood pressure levels."
The study, published in the journal NeuroRegulation and sponsored by the Hershey Company, is the first to examine the acute effects of chocolate on attentional characteristics of the brain and the first-ever study of chocolate consumption performed using electroencephalography, or EEG technology. EEG studies take images of the brain while it is performing a cognitive task and measure the brain activity.
Historically, chocolate has been recognized as a vasodilator, meaning that it widens blood vessels and lowers blood pressure in the long run, but chocolate also contains some powerful stimulants. Stevens said his team wanted to investigate if people who consume chocolate would see an immediate stimulant effect.
Stevens and his colleagues in the Department of Psychological Sciences performed the EEG study with 122 participants between the ages of 18 and 25 years old. The researchers examined the EEG levels and blood pressure effects of consuming a 60 percent cacao confection compared with five control conditions.
Michelle Montopoli, an NAU alumna and student at the time of the study, led the EEG testing phase which included measuring serving sizes of the samples based on participant weight and packaging them so the participants were blind to what they were tasting. Constance Smith, professor of psychological sciences, assisted with the physiological analyses.
The results for the participants who consumed the 60 percent cacao chocolate showed that the brain was more alert and attentive after consumption. Their blood pressure also increased for a short time.
"A lot of us in the afternoon get a little fuzzy and can't pay attention, particularly students, so we could have a higher cacao content chocolate bar and it would increase attention," Stevens said. He added that a regular chocolate bar with high sugar and milk content won't be as good, it's the high-cacao content chocolate that can be found from most manufacturers that will have these effects.
The most interesting results came from one of the control conditions, a 60 percent cacao chocolate which included L-theanine, an amino acid found in green tea that acts as a relaxant. This combination hasn't been introduced to the market yet, so you won't find it on the candy aisle. But it is of interest to Hershey and the researchers.
"L-theanine is a really fascinating product that lowers blood pressure and produces what we call alpha waves in the brain that are very calm and peaceful," Stevens said. "We thought that if chocolate acutely elevates blood pressure, and L-theanine lowers blood pressure, then maybe the L-theanine would counteract the short-term hypertensive effects of chocolate."
For participants who consumed the high-cacao content chocolate with L-theanine, researchers recorded an immediate drop in blood pressure. "It's remarkable. The potential here is for a heart healthy chocolate confection that contains a high level of cacao with L-theanine that is good for your heart, lowers blood pressure and helps you pay attention," Stevens said.
Stevens hopes the results of this study will encourage manufacturers to investigate further and consider the health benefits of developing a chocolate bar made with high-cacao content and L-theanine.
"People don't generally eat chocolate and think it's going to be healthy for them," Stevens said. He added that there is a possibility the millions of hypertension patients in the country could eat a bar of this heart healthy chocolate every afternoon and their blood pressure would drop into the normal range, and they would be more alert and attentive.
 

Journal Reference:

1. Michelle Montopoli, Larry C Stevens, Constance Smith, George Montopoli, Stephanie Passino, Somer Brown, Lena Camou, Katie Carson, Shannon Maaske, Kathleen Knights, William Gibson, Joyce Wu. The Acute Electrocortical and Blood Pressure Effects of Chocolate. Neuro Regulation, 2015 [link]

Courtesy: ScienceDaily
 

Light in sight: A step towards a potential therapy for acquired blindness

Hereditary blindness caused by a progressive degeneration of the light-sensing cells in the eye, the photoreceptors, affects millions of people worldwide. Although the light-sensing cells are lost, cells in deeper layers of the retina, which normally cannot sense light, remain intact. A promising new therapeutic approach based on a technology termed "optogenetics" is to introduce light-sensing proteins into these surviving retinal cells, turning them into "replacement photoreceptors" and thereby restoring vision. However, several factors limit the feasibility of a clinical optogenetic therapy using traditional light-sensitive proteins, as they require unnaturally high and potentially harmful light intensities and employ a foreign signaling mechanism within the target retinal cells.

New research publishing May 7th in the Open Access journal PLOS Biology from van Wyk and colleagues demonstrates how optogenetic proteins can be tailored to bring this promising technology closer to medical application. "We were asking the question, 'Can we design light-activatable proteins that gate specific signaling pathways in specific cells?', in other words, can the natural signaling pathways of the target cells be retained and just modified in a way to be turned on by light instead of a neurotransmitter released from a preceding neuron?" says Dr. Sonja Kleinlogel, corresponding author of the paper (whose research group is based at the University of Berne, Switzerland). The aim of molecular engineering was to achieve maximal compatibility with native signaling whilst retaining all the advantages of traditional optogenetic proteins, such as fast kinetics and resistance to bleaching by light.
The novel light-sensing protein, termed Opto-mGluR6, is a chimeric protein composed of the light-sensing domains of the retinal photopigment melanopsin and the ON-bipolar cell-specific metabotropic glutamate receptor mGluR6, which is naturally activated by glutamate released from the photoreceptors and amplifies the incoming signal through a coupled intracellular enzymatic pathway. Unlike rhodopsin, for example, the "light antenna" of melanopsin is resistant to bleaching. In other words, the response strength of Opto-mGluR6 never attenuates, no matter how often and hard the protein is hit by light. Moreover, since Opto-mGluR6 is a chimeric protein consisting of two "local" retinal proteins it is also likely to be "invisible" to the immune system, another improvement over traditional optogenetic proteins.
In their study van Wyk and colleagues targeted the retinal ON-bipolar cells, which naturally receive direct input from the photoreceptors. Targeting the surviving cells at the top end of the visual cascade has the advantage that signal computation of the retina is maximally utilized. Turning the native chemical receptor (mGluR6) into a light-activated receptor ensures conservation of native signaling within the ON-bipolar cells, conferring high light-sensitivity and fast "normal" responsiveness. In their study they show proof-of-principle that mice suffering from Retinitis pigmentosa can be treated to regain daylight vision. "The new therapy can potentially restore sight in patients suffering from any kind of photoreceptor degeneration" says Dr. Kleinlogel, "for example also those suffering from severe forms of age-related macular degeneration, a very common disease that affects to some degree about one in every 10 people over the age of 65."
"The major improvement of the new approach is that patients will be able to see under normal daylight conditions without the need for light intensifiers or image converter goggles" Dr. Kleinlogel further notes "and retaining the integrity of the intracellular enzymatic cascade through which native mGluR6 acts ensures consistency of the visual signal, as the enzymatic cascade is intricately modulated at multiple levels." The mGluR6 receptor of ON-bipolar cells belongs to the large family of so-called G-protein-coupled transmembrane receptors (

 

The retina of a blind mouse treated with the new approach: A 'light antenna' has been attached to the red cells.

Credit: Sonja Kleinlogel

GPCRs). The novel principle of engineering bleach-resistant chimeric Opto-GPCRs opens a whole palette of new possibilities. For example, as GPCRs are prime targets for pharmaceutical interventions, Opto-GPCRs could potentially be used to treat conditions such as pain, depression and epilepsy.
 

Journal Reference:

1. Michiel van Wyk, Justyna Pielecka-Fortuna, Siegrid Löwel, Sonja Kleinlogel. Restoring the ON Switch in Blind Retinas: Opto-mGluR6, a Next-Generation, Cell-Tailored Optogenetic Tool. PLOS Biology, 2015; 13 (5): e1002143 DOI: 10.1371/journal.pbio.1002143 

Courtesy: ScienceDaily
 

Fat tissue controls brain's response to food scarcity, helping regulate optimal amount of body fat for brain function

An enzyme secreted by the body's fat tissue controls energy levels in the brain, according to new research at Washington University School of Medicine in St. Louis. The findings, in mice, underscore a role for the body's fat tissue in controlling the brain's response to food scarcity, and suggest there is an optimal amount of body fat for maximizing health and longevity.

Shin-ichiro Imai, MD, PhD, led a study showing how fat tissue affects brain function. Mice with a defect in fat tissue that stopped production of an important enzyme had low energy levels in the brain and were lethargic, especially after a period of fasting. Normal physical activity was restored by giving the mice a compound called NMN (picture above), which is produced by that enzyme.

The study appears April 23 in the journal Cell Metabolism.
"We showed that fat tissue controls brain function in a really interesting way," said senior author Shin-ichiro Imai, MD, PhD, professor of developmental biology and of medicine. "The results suggest that there is an optimal amount of fat tissue that maximizes the function of the control center of aging and longevity in the brain. We still don't know what that amount is or how it might vary by individual. But at least in mice, we know that if they don't have enough of a key enzyme produced by fat, an important part of the brain can't maintain its energy levels."
The findings may help explain the many studies that show a survival benefit to having a body mass index toward the low end of what is considered overweight.
"As we age, people who are slightly overweight tend to have fewer problems," Imai said. "No one knows why people categorized as being slightly overweight tend to have a lower mortality rate. But our study suggests that if you don't have an optimal amount of fat, you are affecting a part of the brain that is particularly important for controlling metabolism and aging."
Imai and his colleagues study how cells produce and utilize energy and how that affects aging. Past work of theirs and others demonstrated the importance of an enzyme called NAMPT in producing a vital cellular fuel called NAD. Traditionally, NAMPT is thought to be important for making this fuel inside cells. But Imai and members of his team noticed that fat tissue churned out a lot of NAMPT that ended up outside cells, circulating in the bloodstream.
"There's been a lot of controversy in the field about whether extracellular NAMPT has any function in the body," Imai said. "Some researchers have said it's just a result of leakage from dead cells. But our data indicate it is a highly active enzyme that is highly regulated."
Such fine-tuned regulation suggests secreted NAMPT is doing something important somewhere in the body. To find out what that is, the researchers raised mice that lacked the ability to produce NAMPT only in the fat tissue.
"We were not surprised to see that energy levels in the fat tissue plummeted when fat tissue lacked this key enzyme," Imai said. "Other tissues such as the liver and muscles were unaffected. But there was one distant location that was affected, and that was the hypothalamus."
The hypothalamus is a part of the brain known to have important roles in maintaining the body's physiology, including regulating body temperature, sleep cycles, heart rate, blood pressure, thirst and appetite. Mice with low NAMPT in fat tissue had low fuel levels in the hypothalamus. These mice also showed lower measures of physical activity than mice without this defect.
Their findings suggest that fat tissue communicates specifically with the hypothalamus, influencing the way the brain controls the body's physiologic set points. Indeed, past work from Imai's group also supported an important role for the hypothalamus in whole body metabolism. They showed that increasing the expression of a protein called SIRT1 in the mouse hypothalamus increased the mouse lifespan, mimicking the effects of a calorie-restricted diet.
Imai suspects that all these processes influence one another. Their past work on the hypothalamus also had shown that SIRT1 function is dependent on energy levels in cells. And the new paper links energy levels in the hypothalamus to the fat tissue's newly identified function.
After examining what happens to mice with fat tissue that doesn't make NAMPT, they performed the opposite experiment, studying mice that produced more NAMPT in fat tissue than is typical.
Mice that expressed high levels of NAMPT in the fat tissue were very physically active. Their activity levels were especially pronounced after fasting. The mice with low NAMPT in the fat tissue became even more lethargic after the fasting period. The mice with an overabundance of NAMPT in the fat tissue appeared unaffected by the period of time without food, remaining at activity levels similar to normal mice without food restriction. In fact, the mice with a lot of NAMPT produced in their fat behaved very similarly to the mice with a lot of SIRT1 in the brain.
Imai said they are now studying whether an overabundance of NAMPT in the fat increases lifespan, as they showed in the mice with an overabundance of SIRT1 in the brain.
The researchers also found they could temporarily boost the physical activity of the mice with low NAMPT in the fat tissue by injecting NMN, the compound that the enzyme NAMPT produces. Imai is investigating NMN as a possible intervention in diseases associated with aging.
Imai speculated that this NAMPT signal from the fat tissue, especially in response to fasting, may serve as a survival mechanism.
"This phenomenon makes sense in the wild," Imai said. "If you can't get food and you just sit around and wait, you won't survive. So the brain, working in conjunction with the fat tissue, has a way to kick in and let you move to survive, even when food is scarce."
This research was supported by the National Institute on Aging of the National Institutes of Health (NIH), grant numbers AG024150, AG037457 and AG047902, and by the Ellison Medical Foundation.
Journal Reference:

1. Myeong Jin Yoon, Mitsukuni Yoshida, Sean Johnson, Akiko Takikawa, Isao Usui, Kazuyuki Tobe, Takashi Nakagawa, Jun Yoshino, Shin-Ichiro Imai. SIRT1-Mediated eNAMPT Secretion from Adipose Tissue Regulates Hypothalamic NAD and Function in Mice. Cell Metabolism, 2015 DOI: 10.1016/j.cmet.2015.04.002 

Courtesy: ScienceDaily