In a mouse study, Australian researchers have mapped out what happens behind the scenes in fat tissue during intermittent fasting, showing that it triggers a cascade of dramatic changes, depending on the type of fat deposits and where they are located around the body.
Using state-of-the-art instruments, University of Sydney researchers discovered that fat around the stomach, which can accumulate into a ‘protruding tummy’ in humans, was found to go into ‘preservation mode’, adapting over time and becoming more resistant to weight loss.
The findings are published today in Cell Reports.
A research team led by Dr Mark Larance examined fat tissue types from different locations to understand their role during every-other-day fasting, where no food was consumed on alternate days.
The fat types where changes were found included visceral “belly” fat, which is fat tissue surrounding our organs including the stomach, and subcutaneous fat, which lies just under the skin and is associated with better metabolic health.
“While most people would think that all fat tissue is the same, in fact, the location makes a big difference,” said senior author Dr Larance from the Charles Perkins Centre and School of Life and Environmental Sciences at the University of Sydney.

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“Our data show both visceral and subcutaneous fat undergo dramatic changes during intermittent fasting,” said Dr Larance, who is also a Cancer Institute of NSW Future Research Fellow.
Why visceral fat can be resistant to weight loss
During fasting, fat tissue provides energy to the rest of the body by releasing fatty acid molecules.
However, the researchers found visceral fat became resistant to this release of fatty acids during fasting.
There were also signs that visceral and subcutaneous fat increased their ability to store energy as fat, likely to rapidly rebuild the fat store before the next fasting period.

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Dr Larance said it was possible that a history of repeated fasting periods triggered a preservation signalling pathway in visceral fat.
“This suggests the visceral fat can adapt to repeated fasting bouts and protect its energy store,” he said.
“This type of adaptation may be the reason why visceral fat can be resistant to weight loss after long periods of dieting.”
Dr Larance said using a mouse model was a useful analogue ahead of studies in humans.
“Mouse physiology is similar to humans, but their metabolism is much faster, allowing us to observe changes more rapidly than in human trials, and examine tissues difficult to sample in humans,” he said.
Future research in mice and humans could uncover the mechanisms by which this resistance occurs and also which types of diet and other interventions may be best at tackling belly fat.
Mapping out the inner workings of fat deposits
The research team examined more than 8500 proteins located in fat deposits, creating a catalogue of changes that occurred during intermittent fasting, using a technique called proteomics.
Proteomics — the study of all proteins — a relatively new area of study that takes its name from genomics (the study of all genes), monitors how proteins react under certain conditions, which in this case is intermittent fasting.
The results provide a rich source of data that helps to paint a more complete picture of the inner workings of fat tissue.
It was via proteomics that the research team were alerted of major cellular changes caused by intermittent fasting and, after further analysis, highlighted the visceral fat’s preservation mechanism in action.
The study was conducted using the instruments of the Sydney Mass Spectrometry in the Charles Perkins Centre, part of the University of Sydney’s Core Research Facilities.
Dr Larance says it should be noted that findings from the intermittent study may not apply to different diet regimes such as the 5:2 diet (fasting 2 days out of 7) or calorie restriction, which is common in people wanting to lose weight.
The results lay the foundation for future studies, which will dissect the molecules responsible for why visceral fat is resistant to energy release during fasting, and help determine what diet plans would be most beneficial for metabolic health.
“This sort of research has been enabled by these new instruments that allow us to ‘look beyond the streetlight’ — it’s hypothesis generating; we knew we would find something but we didn’t know what,” Dr Larance explained.
“Now that we’ve shown ‘belly fat’ in mice is resistant to this diet, the big question will be to answer why, and how do we best tackle it?”

In a new paper published by Nature Communications, The Lundquist Institute (TLI) Investigator Wei Yan, MD, PhD, and his research colleagues spell out an innovative strategy that has led to the discovery of a natural compound as a safe, effective and reversible male contraceptive agent in pre-clinical animal models. Despite tremendous efforts over the past decades, the progress in developing non-hormonal male contraceptives has been very limited.
The compound is triptonide, which can be either purified from a Chinese herb called Tripterygium Wilfordii Hook F, or produced through chemical synthesis. Single daily oral doses of triptonide induce altered sperm having minimal or no forward motility with close to 100% penetrance and consequently male infertility in 3-4 and 5-6 weeks. Once the treatment is stopped, the males become fertile again in ~4-6 weeks, and can produce healthy offspring. No discernable toxic effects were detected in either short- or long-term triptonide treatment. All of their data suggest that triptonide is a highly promising non-hormonal male contraceptive agent for men because it appears to meet all of the criteria for a viable contraceptive drug candidate, including bioavailability, efficacy, reversibility and safety. A battery of biochemical analyses suggest that triptonide targets one of the last steps during sperm assembly, leading to the production of altered sperm without vigorous motility required for fertilization.
“Thanks to decades of basic research, which inspired us to develop the idea that a compound that targets a protein critical for the last several steps of sperm assembly would lead to the production of nonfunctional sperm without causing severe depletion of testicular cells,” said Dr. Yan. “We are very excited that the new idea worked and that this compound appears to be an ideal male contraceptive. Our results using non-injurious studies on lower primates suggest triptonide will be an effective treatment for human males as well. Hopefully, we will be able to start human clinical trials soon to make the non-hormonal male contraceptive a reality.”
“Dr. Yan’s discovery represents a major leap forward in the field,” said Drs. Christina Wang and Ronald Swerdloff, who are TLI co-Principal Investigators helping lead NIH-supported advanced clinical trials on hormone-based birth control approaches. “The more contraceptive methods available, the better, as we will want a family of pharmaceutical products to safely and effectively meet the family planning needs of men and couples at different stages of their reproductive lives, with differing ethnic, cultural and religious backgrounds and economic means,” emphasized Wang and Swerdloff.

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Using the model organism Caenorhabditis elegans, researchers at the University of Cologne have developed an ‘aging clock’ that reads the biological age of an organism directly from its gene expression, the transcriptome. Bioinformatician David Meyer and geneticist Professor Dr Björn Schumacher, director of the Institute for Genome Stability in Aging and Disease at the CECAD Cluster of Excellence in Aging Research and the Center for Molecular Medicine Cologne (CMMC), describe their so-called BiT age (binarized transcriptomic aging clock) in the article ‘BiT age: A transcriptome based aging clock near the theoretical limit of accuracy’ in Aging Cell.
We are all familiar with chronological age — our age since birth. But biological age can differ from it, at times significantly. Everyone ages differently. Scientists can use aging clocks to determine an organism’s biological age. Until now, aging clocks such as Horvath’s epigenetic clock have been based on the pattern of methylations, small chemical groups that attach to DNA and change with age. Using the transcriptome, the new clock takes into consideration the set of genes that are read from DNA (messenger RNA) to make proteins for the cell.
Until now, the transcriptome was considered too complex to indicate age. Sometimes genes transcribe a particularly large amount of mRNA, sometimes less. Hence, so far it has not been possible to develop precise aging clocks based on gene activity. Meyer and Schumacher’s new approach uses a mathematical trick to eliminate the differences in gene activity. The binarized transcriptome aging clock divides genes into two groups — ‘on’ or ‘off’ — thus minimizing high variation. This makes aging predictable from the transcriptome. ‘Surprisingly, this simple procedure allows very accurate prediction of biological age, close to the theoretical limit of accuracy. Most importantly, this aging clock also works at high ages, which were previously difficult to measure because the variation in gene activity is particularly high then,’ said Meyer.
BiT age is based exclusively on approximately 1,000 different transcriptomes of C. elegans, for which the lifespan is precisely known. Model organisms such as the nematode provide a controllable view of the aging process, allowing biomarkers to be discovered and the effects of external influences such as UV radiation or nutrition on longevity to be studied.
The new aging clock allows researchers to accurately predict the pro- and anti-aging effects of gene variants and various external factors in the nematode at a young age. The aging clock also showed that genes of the immune response as well as signalling in neurons are significant for the aging process. ‘BiT age can also be applied to predict human age quickly and with very high accuracy. Measuring biological age is important to determine the influence of environment, diet or therapies on the aging process and the development of age-related diseases. This clock could therefore find wide application in aging research. Since BiT age is based purely on gene activity, it can basically be applied to any organism,’ Schumacher explained.

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Imagine seeing the world in muted shades — gray sky, gray grass. Some people with color blindness see everything this way, though most can’t see specific colors. Tinted glasses can help, but they can’t be used to correct blurry vision. And dyed contact lenses currently in development for the condition are potentially harmful and unstable. Now, in ACS Nano, researchers report infusing contact lenses with gold nanoparticles to create a safer way to see colors.
Some daily activities, such as determining if a banana is ripe, selecting matching clothes or stopping at a red light, can be difficult for those with color blindness. Most people with this genetic disorder have trouble discriminating red and green shades, and red-tinted glasses can make those colors more prominent and easier to see. However, these lenses are bulky and the lens material cannot be made to fix vision problems. Thus, researchers have shifted to the development of special tinted contact lenses. Although the prototype hot-pink dyed lenses improved red-green color perception in clinical trials, they leached dye, which led to concerns about their safety. Gold nanocomposites are nontoxic and have been used for centuries to produce “cranberry glass” because of the way they scatter light. So, Ahmed Salih, Haider Butt and colleagues wanted to see whether incorporating gold nanoparticles into contact lens material instead of dye could improve red-green contrast safely and effectively.
To make the contact lenses, the researchers evenly mixed gold nanoparticles into a hydrogel polymer, producing rose-tinted gels that filtered light within 520-580 nm, the wavelengths where red and green overlap. The most effective contact lenses were those with 40 nm-wide gold nanoparticles, because in tests, these particles did not clump or filter more color than necessary. In addition, these lenses had water-retention properties similar to those of commercial ones and were not toxic to cells growing in petri dishes in the lab. Finally, the researchers directly compared their new material to two commercially available pairs of tinted glasses, and their previously developed hot-pink dyed contact lens. The gold nanocomposite lenses were more selective in the wavelengths they blocked than the glasses. The new lenses matched the wavelength range of the dyed contact lenses, suggesting the gold nanocomposite ones would be suitable for people with red-green color issues without the potential safety concerns. The researchers say that the next step is to conduct clinical trials with human patients to assess comfort.

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At the beginning of an immune response, a molecule known to mobilize immune cells into the bloodstream, where they home in on infection sites, rapidly shifts position, a new study shows. Researchers say this indirectly amplifies the attack on foreign microbes or the body’s own tissues.
Past studies had shown that the immune system regulates the concentration of the molecule, sphingosine 1 phosphate (S1P), in order to draw cells to the right locations. The targeted cells have proteins on their surface that are sensitive to levels of this molecule, enabling them to follow the molecule’s “trail,” researchers say. S1P concentration gradients, for instance, can guide immune T cells to either stay in lymph nodes, connected glands in which these cells mature, or move into blood vessels.
For the first time, researchers at NYU Grossman School of Medicine showed in mice experiments that S1P levels in lymph nodes increase as the immune response mounts. Such activation of immune cells can cause inflammation, swelling, and/or death of targeted cells.
While past work had shown that S1P is produced by cells attached to lymph nodes, the new study found that monocytes, circulating immune cells, also produced it when mice were infected with a virus. This in turn may influence the migration of T cells, a set of white blood cells that expands rapidly in response to infection, say the study authors.
Publishing in the journal Nature online March 3, study results showed that T cells left mouse lymph nodes less than half as fast when S1P levels rose, while mostly immature cells escaped when S1P levels were not spiking.
“Our research shows a larger role for sphingosine 1 phosphate in coordinating immune defenses in response to infection and inflammation,” says study lead investigator Audrey Baeyens, PhD, a postdoctoral fellow at NYU Langone and its Skirball Institute of Biomolecular Medicine. “While further testing is needed, our findings raise the prospect of controlling levels of S1P to either boost or diminish the body’s immune response, as needed.”
Moreover, the researchers found that when lymph node levels of S1P went up, it signaled T cells to remain in lymph nodes. Such “trapped” T cells, with longer time to mature and become fully armed in the node, increase in their toxicity. These mature T cells can attack cells infected by viruses, or healthy cells as part of autoimmune diseases.
Indeed, medications that block S1P, preventing immune cells from leaving the lymph nodes, are used to curb unwanted and autoimmune inflammation related to inflammatory bowel disease, psoriasis, and multiple sclerosis, a disease for which fingolimod (Gilenya) is one of the few approved treatments.
Researchers say their findings could also explain why multiple sclerosis patients can experience severe disease relapse immediately after ceasing fingolimod treatment, as T cells held long in lymph nodes are then freed to attack the body’s nerves, a key trait of the disease.
“Now that we have a better understanding of sphingosine 1 phosphate inhibition, we can work on finding new uses for this class of medications, perhaps by manipulating the time T cells spend in the lymph nodes,” says study senior investigator Susan Schwab, PhD. Schwab is an associate professor in the Department of Pathology at NYU Langone and Skirball.
For the study, S1P levels were measured in mice bred to develop symptoms of multiple sclerosis, a disease involving severe inflammation of the brain and spine. They also measured S1P levels in mice exposed to viral genetic material to mimic the inflammation that occurs in infection.
Schwab says the team next plans to study how different S1P levels affect T cell maturation, and how these different maturation times strengthen or weaken the overall immune response to infection.

Care homes are at high risk of experiencing outbreaks of COVID-19, the disease caused by SARS-CoV-2. Older people and those affected by heart disease, respiratory disease and type 2 diabetes — all of which increase with age — are at greatest risk of severe disease and even death, making the care home population especially vulnerable.
Care homes are known to be high-risk settings for infectious diseases, owing to a combination of the underlying vulnerability of residents who are often frail and elderly, the shared living environment with multiple communal spaces, and the high number of contacts between residents, staff and visitors in an enclosed space.
In research published in eLife, a team led by scientists at the University of Cambridge and Wellcome Sanger Institute used a combination of genome sequencing and detailed epidemiological information to examine the impact of COVID-19 on care homes and to look at how the virus spreads in these settings.
SARS-CoV-2 is an RNA virus and as such its genetic code is prone to errors each time it replicates. It is currently estimated that the virus mutates at a rate of 2.5 nucleotides (the A, C, G and U of its genetic code) per month. Reading — or ‘sequencing’ — the genetic code of the virus can provide valuable information on its biology and transmission. It allows researchers to create ‘family trees’ — known as phylogenetic trees — that show how samples relate to each other.
Scientists and clinicians in Cambridge have pioneered the use of genome sequencing and epidemiological information to trace outbreaks and transmission networks in hospitals and community-based healthcare settings, helping inform infection control measures and break the chains of transmission. Since March 2020, they have been applying this method to SARS-CoV-2 as part of the COVID-19 Genomics UK (COG-UK) Consortium.
In this new study, researchers analysed samples collected from 6,600 patients between 26 February and 10 May 2020 and tested at the Public Health England (PHE) Laboratory in Cambridge. Out of all the cases, 1,167 (18%) were care home residents from 337 care homes, 193 of which were residential homes and 144 nursing homes, the majority in the East of England. The median age of care home residents was 86 years.

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While the median number of cases per care home was two, the ten care homes with the largest number of cases accounted for 164 cases. There was a slight trend for nursing homes to have more cases per home than residential homes, with a median of three cases.
Compared with non-care home residents admitted to hospital with COVID-19, hospitalised care home residents were less likely to be admitted to intensive care units (less than 7% versus 21%) and more likely to die (47% versus 20%).
The researchers also explored links between care homes and hospitals. 68% of care home residents were admitted to hospital during the study period. 57% were admitted with COVID-19, 6% of cases had suspected hospital-acquired infection, and 33% were discharged from hospital within 7 days of a positive test. These findings highlight the ample opportunities for SARS-CoV-2 transmission between hospital and care home settings.
When the researchers examined the viral sequences, they found that for several of the care homes with the highest number of cases, all of the cases clustered closely together on a phylogenetic tree with either identical genomes or just one base pair difference. This was consistent with a single outbreak spreading within the care home.
By contrast, for several other care homes, cases were distributed across the phylogenetic tree, with more widespread genetic differences, suggesting that each of these cases was independent and not related to a shared transmission source.

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“Older people, particularly those in care homes who may be frail, are at particular risk from COVID-19, so it’s essential we do all that we can to protect them,” said Dr Estée Török, an Honorary Consultant at Addenbrooke’s Hospital, Cambridge University Hospitals (CUH), and an Honorary Senior Visiting Fellow at the University of Cambridge.
“Preventing the introduction of new infections into care homes should be a key priority to limit outbreaks, alongside infection control efforts to limit transmission within care homes, including once an outbreak has been identified.”
The team found two clusters that were linked to healthcare workers. One of these involved care home residents, a carer from that home and another from an unknown care home, paramedics and people living with them. The second involved several care home residents and acute medical staff at Cambridge University Hospitals NHS Foundation Trust who cared for at least one of the residents. It was not possible to say where these clusters originated from and how the virus spread.
“Using this technique of ‘genomic surveillance’ can help institutions such as care homes and hospitals better understand the transmission networks that allow the spread of COVID-19,” added Dr William Hamilton from the University of Cambridge and CUH. “This can then inform infection control measures, helping ensure that these places are as safe as possible for residents, patients, staff and visitors.”
The absolute number of diagnosed COVID-19 cases from care home residents declined more slowly in April than for non-care home residents, increasing the proportion of cases from care homes and contributing to the slow rate of decline in total case numbers during April and early May 2020.
“Our data suggest that care home transmission was more resistant to lockdown measures than non-care home settings. This may reflect the underlying vulnerability of the care home population, and the infection control challenges of nursing multiple residents who may also share communal living spaces,” said Gerry Tonkin-Hill from the Wellcome Sanger Institute.
The team found no new viral lineages from outside the UK, which may reflect the success of travel restrictions in limiting new viral introductions into the general population during the first epidemic wave and lockdown period.
This work was funded by COG-UK, Wellcome, the Academy of Medical Sciences, the Health Foundation and the NIHR Cambridge Biomedical Research Centre.