Tag Archives: #obesity

Mice Treated with This Cytokine Lose Weight by ‘Sweating’ Fat (Medicine)

A seemingly unremarkable observation — greasy hair — showed Penn researchers how the immune system could be targeted to reverse obesity

Treating obese mice with the cytokine known as TSLP led to significant abdominal fat and weight loss compared to controls, according to new research published Thursday in Science from researchers in the Perelman School of Medicine at the University of Pennsylvania. Unexpectedly, the fat loss was notassociated with decreased food intake or faster metabolism. Instead, the researchers discovered that TSLP stimulated the immune system to release lipids through the skin’s oil-producing sebaceous glands.

“This was a completely unforeseen finding, but we’ve demonstrated that fat loss can be achieved by secreting calories from the skin in the form of energy-rich sebum,” said principal investigator Taku Kambayashi, MD, PhD,an associate professor of Pathology and Laboratory Medicine at Penn, who led the study with fourth-year medical student Ruth Choa, PhD. “We believe that we are the first group to show a non-hormonal way to induce this process, highlighting an unexpected role for the body’s immune system.”

The animal model findings, Kambayashi said, support the possibility that increasing sebum production via the immune system could be a strategy for treating obesity in people.

The Hypothesis

Thymic stromal lymphopoietin (TSLP) is a cytokine — a type of immune system protein —  involved in asthma and other allergic diseases. The Kambayashi research group has been investigating the expanded role of this cytokine to activate Type 2 immune cells and expand T regulatory cells. Since past studies have indicated that these cells can regulate energy metabolism, the researchers predicted that treating overweight mice with TSLP could stimulate an immune response, which could subsequently counteract some of the harmful effects of obesity.

“Initially, we did not think TSLP would have any effect on obesity itself. What we wanted to find out was whether it could impact insulin resistance,” Kambayashi said. “We thought that the cytokine could correct Type 2 diabetes, without actually causing the mice to lose any weight.”

The Experiment

To test the effect of TSLP on Type 2 diabetes, the researchers injected obese mice with a viral vector that would increase their bodies’ TSLP levels. After four weeks, the research team found that TSLP had not only affected their diabetes risk, but it had actually reversed the obesity in the mice, which were fed a high-fat diet. While the control group continued to gain weight, the weight of the TSLP-treated mice went from 45 grams down to a healthy 25 grams, on average, in just 28 days.

Most strikingly, the TSLP-treated mice also decreased their visceral fat mass. Visceral fat is the white fat that is stored in the abdomen around major organs, which can increase diabetes, heart disease, and stroke risk. These mice also experienced improved blood glucose and fasting insulin levels, as well as decreased risk of fatty liver disease.

Given the dramatic results, Kambayashi assumed that the TSLP was sickening the mice and reducing their appetites. However, after further testing, his group found that the TSLP-treated mice were actually eating 20 to 30 percent more, had similar energy expenditures, base metabolic rates, and activity levels, when compared to their non-treated counterparts.

The Findings

To explain the weight loss, Kambayashi recalled a small observation he had previously ignored: “When I looked at the coats of the TSLP-treated mice, I noticed that they glistened in the light. I always knew exactly which mice had been treated, because they were so much shinier than the others,” he said.

Kambayashi considered a far-fetched idea — was their greasy hair a sign that the mice were “sweating” out fat from their skin?

To test the theory, the researchers shaved the TSLP-treated mice and the controls and then extracted oils from their fur. They found that Kambayashi’s hypothesis was correct: The shiny fur contained sebum-specific lipids. Sebum is a calorically-dense substance produced by sebocytes (highly specialized epithelial cells) in the sebaceous glands and helps to form the skin barrier. This confirmed that the release of oil through the skin was responsible for the TSLP-induced fat loss.

The Conclusions

To examine whether TSLP could potentially play a role in the control of oil secretion in humans, the researchers then examined TSLPand a panel of 18 sebaceous gland-associated genes in a publicly-available dataset. This revealed that TSLPexpression is significantly and positively correlated with sebaceous gland gene expression in healthy human skin.

The study authors write that, in humans, shifting sebum release into “high gear” could feasibly lead to the “sweating of fat” and weight loss. Kambayashi’s group plans further study to test this hypothesis.

“I don’t think we naturally control our weight by regulating sebum production, but we may be able to highjack the process and increase sebum production to cause fat loss. This could lead to novel therapeutic interventions that reverse obesity and lipid disorders,” Kambayashi said.

This research was supported by grants from the National Institutes of Health (R01-HL111501, R01-10 AI121250, R01-AR070116, T32-HL07439), the Doris Duke Charitable Foundation, and the University of Pennsylvania Medical Scientist Training Program.

Penn researchers who contributed to this work include: Junichiro Tohyama, Shogo Wada, Hu Meng, Jian Hu, Mariko Okumura, Tanner F. Robertson, Ruth-Anne Langan Pai, Arben Nace, Christian Hopkins, Elizabeth A. Jacobsen, Malay Haldar, Garret A. FitzGerald, Edward M. Behrens, Andy J. Minn, Patrick Seale, George Cotsarelis, Brian Kim, John T. Seykora, Mingyao Li, and Zoltan Arany.

Reference: Thymic stromal lymphopoietin induces adipose loss through sebum hypersecretion, Science (2021). DOI: 10.1126/science.abd2893

Provided by Perelman School of Medicine at the University of Pennsylvania

Obesity Increases Survival in Advanced Prostate Cancer (Medicine)

Obese patients with a form of advanced prostate cancer survive longer than overweight and normal weight patients, new research has found.

The study, presented today at the European Association of Urology congress, EAU21, followed more than 1500 patients over three years. Patients classed as obese – with a BMI over 30 – had a ten percent higher survival rate than thinner patients over 36 months.

Although obesity is usually associated with an increased risk of death from many cancers and some other chronic diseases, there is some evidence in a few cancers of a survival advantage for patients with high body mass index. This phenomenon is known as the ‘obesity paradox’.

Nicola Fossati, Alberto Martini and colleagues at San Raffaele University in Italy wanted to test whether the ‘obesity paradox’ held true for patients with metastatic castration resistant prostate cancer – an advanced form of the disease that no longer responds to testosterone lowering treatments.

They looked at survival rates in 1,577 patients involved in three different clinical trials, with an average age of 69 and average BMI of 28. They found that BMI was a protective factor in both overall and cancer-specific survival, with 4% higher overall survival probability and 29% cancer-specific survival probability. Even when they adjusted for higher doses of chemotherapy given to larger patients, the team found the protective effect remained. Over 36 months, around 30% of obese patients survived compared to 20% of overweight and normal weight individuals.

Dr Nicola Fossati, a urologist at San Raffaele University says: “Looking at patients with metastasis of prostate cancer, we found that obese patients are living longer. This means that BMI could be used to predict survival in these patients.

“This obesity paradox has been seen in some other cancers, possibly due to the relationship between tissue fat and cancer genomes, and more research is needed in this area. It’s also possible that improved survival may be due to the interaction of chemotherapy with other drugs. Obese patients in this older age group tend to be taking medication for other conditions and we do not fully understand how these medicines interconnect.

“Nevertheless, we would not recommend weight gain to anyone with this or another disease. Obesity is a risk factor for many cancers and other diseases and patients should always aim for a healthy BMI of 18 to 24.”

Professor Peter Albers, from Düsseldorf University, who chairs the EAU Scientific Congress Office, said: “There are many possible explanations for the association of body weight with positive outcome in metastatic cancers. It might be that patients with higher BMI are able to tolerate the toxicity of the treatments and their side effects better; in prostate cancer it might be due to the protective impact of hormones found in tissue fat; and it is known that healthy men with slightly higher BMI have a higher overall life expectancy compared to very slim ones.

“However, at the moment, these are just hypotheses. Further research is needed to identify the biological mechanism behind these different outcomes. Until that mechanism is proven, we can’t recommend any change to treatment for patients with advanced prostate cancer.”

This science news has been confirmed by us from European Association of Urology

Provided by European Association of Urology

Scientists Discover Gene Mutations That Protect Against Obesity (Biology)

Scientists from the Regeneron Genetics Center (RGC) have discovered rare genetic mutations in the GPR75 gene that are associated with protection against obesity. 

As part of the research that led to the finding, published in Science, RGC scientists analyzed deidentified genetic and associated health data from 645,000 volunteers from the United Kingdom, United States and Mexico, including participants in Geisinger’s MyCode Community Health Initiative

It is estimated that more than one billion people will be suffering from severe obesity (body mass index [BMI] of 35 or higher) by 2030. Working with collaborators, RGC scientists found that individuals who have at least one inactive copy of the GPR75 gene have lower BMI and, on average, tend to weigh about 12 pounds less and face a 54% lower risk of obesity than those without the mutation. Protective mutations were found in about one of every 3,000 people sequenced. 

“This is a potentially game-changing discovery that could improve the lives and health of millions of people dealing with obesity, for whom lasting interventions have often been elusive,” said Christopher D. Still, D.O., director for the Geisinger Obesity Research Institute at Geisinger Medical Center. “While the behavioral and environmental ties to obesity are well understood, the discovery of GPR75 helps us put the puzzle pieces together to better understand the influence of genetics. Further studies and evaluation are needed to determine if reducing weight in this manner can also lower the risk of conditions commonly associated with high BMI, such as heart disease, diabetes, high blood pressure and fatty liver disease.”

Regeneron scientists, collaborating with scientists at New York Medical College, replicated their finding in mice that were genetically engineered using Regeneron’s VelociGene® technology to lack copies of the GPR75 gene. Such mice gained 44% less weight than mice without the mutation when both groups were fed a high-fat diet. Regeneron scientists are pursuing multiple therapeutic pathways – such as antibody, small molecule and gene silencing approaches – based on this newly discovered genetic target. 

“Discovering protective genetic superpowers, such as in GPR75, provides hope in combatting global health challenges as complex and prevalent as obesity,” said George D. Yancopoulos, M.D., Ph.D., co-founder, president and chief scientific officer at Regeneron. “Discovery of protective mutations – many of which have been made by the Regeneron Genetics Center in its eight-year history – will allow us to unlock the full potential of genetic medicine by instructing on where to deploy cutting-edge approaches like gene-editing, gene-silencing and viral vector technologies.”

Reference: Parsa Akbari et al., “Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity”, Science  02 Jul 2021: Vol. 373, Issue 6550, eabf8683 DOI: https://doi.org/10.1126/science.abf8683

Provided by Geisinger

Fecal Transplant Plus Fibre Supplements Improve Insulin Sensitivity in Severely Obese Patients (Medicine)

Research provides further evidence the microbiome can benefit patients’ health, says researcher Karen Madsen.

A transplant of healthy gut microbes followed by fibre supplements benefits patients with severe obesity and metabolic syndrome, according to University of Alberta clinical trial findings published today in Nature Medicine.

Patients who were given a single-dose oral fecal microbial transplant followed by a daily fibre supplement were found to have better insulin sensitivity and higher levels of beneficial microbes in their gut at the end of the six-week trial. Improved insulin sensitivity allows the body to use glucose more effectively, reducing blood sugar.

“They were much more metabolically healthy,” said principal investigator Karen Madsen, professor of medicine in the Faculty of Medicine & Dentistry and director of the Centre of Excellence for Gastrointestinal Inflammation and Immunity Research

“These patients were on the best known medications (for metabolic syndrome) and we could improve them further, which shows us there is an avenue for improvement by targeting these different pathways in the microbiome.”

Sixty-one patients with a body mass index of 40 or higher completed the double-blind, randomized trial. Recruited from the bariatric surgery waitlist in Edmonton, all had metabolic syndrome, a condition that includes insulin resistance, high blood glucose, high blood pressure and other complications. It can eventually lead to diabetes. 

The overlooked organ

The microbiome is all of the bugs—micro-organisms, bacteria, viruses, protozoa and fungi—found in the gastrointestinal tract. People with various diseases are known to have altered microbial contents. It is not fully understood whether microbiome changes cause disease or whether disease causes changes in the gut, but it is likely a bit of both, Madsen said. It is known that replacing unhealthy bacteria with healthy bacteria can lead to improved health.

Fecal transplants, which contain microbes from healthy stool donors, are currently used extensively for treating Clostridium difficile, or C. difficile, bacterial infections, and research is underway to test their usefulness in treating other illnesses such as inflammatory bowel disease, mental health and metabolic disorders. 

“We know that the gut microbiome affects all of these processes—inflammation, metabolism, immune function,” said Madsen, who is a member of the Women and Children’s Health Research Institute and is one of the University of Alberta leads for the national Microbiome Research Core (IMPACTT).

“The potential for improving human health through the microbiome is immense,” Madsen said. “We are only scratching the surface at the moment.”

The right kind of fibre 

This is the first study to show that oral delivery of fecal transplantation is effective in patients with obesity-related metabolic syndrome. 

A previous study done in Europe on a small number of male patients with obesity and metabolic syndrome had shown promising results, but the transplants in that study were given through an invasive endoscopy (a tube down the throat) and the patients had milder disease.

The fecal microbial transplants in this study were from four lean, healthy donors, and were taken by mouth in a single dose of about 20 capsules prepared in a U of A lab. The capsules have no taste or odour. 

The fibre supplements following the transplant were key to the success, Madsen said. 

“When you transplant beneficial microbes, you need to feed them to keep them around,” Madsen explained. “If you give a new microbe and you don’t feed it, if you continue to eat a diet of processed foods and no fibre, then that microbe will likely die.”

Our bodies do not naturally produce the enzymes needed to break down fibre, but that’s what healthy bacteria in the microbiome need to live, thus the supplements. The team experimented with fermentable fibre (the kind found in beans, which produce gas) and non-fermentable fibre (essentially cellulose, found in whole grains). 

“Non-fermentable fibre can change gut motility—how fast things move through—as well as acting as a bulking and binding agent that can change levels of bile acids, which could help explain our results,” Madsen explained. 

Proof of concept

Madsen said the next step will be to do a longer study with more participants in multiple centres to learn how the transplant/fibre combination works and to monitor for changes in medication requirements, weight loss and other indicators. If results continue to show benefit, she said the pills could be available as a potential therapy within five years. 

While scientists continue to narrow down which bacteria are the most beneficial for us, Madsen recommends we support the health of our own gut microbiome by eating fewer processed foods and more foods that contain fibre, such as whole grains, fruits and vegetables. 

Funding for the trial was provided by the Weston Family Foundation, the University of Alberta Clinician Investigator Program and the Canadian Institutes for Health Research.

Featured image: A clinical trial led by medicine professor Karen Madsen showed that a single oral fecal transplant followed by fibre supplements improved insulin sensitivity in severely obese patients. Improved insulin sensitivity allows the body to use glucose more effectively, reducing blood sugar. (Photo: Faculty of Medicine & Dentistry)

Reference: Mocanu, V., Zhang, Z., Deehan, E.C. et al. Fecal microbial transplantation and fiber supplementation in patients with severe obesity and metabolic syndrome: a randomized double-blind, placebo-controlled phase 2 trial. Nat Med (2021). https://doi.org/10.1038/s41591-021-01399-2

Provided by University of Alberta

Can Regulating A Novel Brain Circuit Help Control Obesity? (Neuroscience)

Like a good story, feeding has a beginning, a middle and an end. It begins with appetite prompting the search for food, continues with eating the food and it ends when satiation hits and the consumption of food is stopped. At Baylor College of Medicine, Dr. Qi WuDr. Yong Han and their colleagues have uncovered new aspects of the last part of this story that relate to the little-known neural circuits and neurotransmitters involved in ending food consumption.

The team discovered a novel circuit that connects a unique subset of dopamine-producing neurons with downstream neurons in the hindbrain (lower brainstem) and potently suppresses food intake by triggering satiation in mice. They also found that the FDA-approved drug methylphenidate (MPH) mediates its noticeable weight loss effect by activating this particular circuit, opening the possibility that regulating this circuit might help people control weight. The study appears in the journal Sciences Advances.

“Many people struggle with weight control, eating more than what the body needs, which adds extra pounds that can lead to obesity and higher risk of serious conditions such as heart disease, stroke and type 2 diabetes,” said Han, a postdoctoral associate in pediatrics-nutrition in the Wu lab and the first author of this study. “Our lab is interested in improving our understanding of what goes on in the brain during feeding with the hope that our findings might one day help people better control their weight.”

New insights into brain regulation of the satiation response

“The current study is about a circuit in the brain that helps to precisely regulate the size of the food portion that is consumed,” said Wu, assistant professor in pediatrics-nutrition and the corresponding author of the study. “It is not about how eating begins but about how it ends. It’s about the satiation response, which is as important as appetite.”

Using several advanced techniques to study neural function, including cell-specific circuitry mapping, optogenetics and real-time recordings of brain activity, the researchers discovered a novel neural circuit that connects a unique group of dopamine-producing neurons called DA-VTA with downstream target neurons known as DRD1-LPBN and regulates food consumption in mice.

The team examined the activities of the two sets of neurons while the mice were eating. They observed that the activity of these DA-VTA neurons increased immediately before the animals stopped eating. When the researchers genetically inhibited these neurons, the animals prolonged their feeding, drastically increasing the portion size. This suggests that inhibiting the circuit prevented the satiation response. They also found that enhancing the activity of the DRD1-LPBN neurons, which receive signals from the DA-VTA neurons, robustly generated the response of meal termination.

The researchers also found that the novel circuit mediated the weight loss effect that is associated with taking the drug MPH, which is approved for mitigation of attention deficit hyperactivity disorder.

“Other brain circuits have been proposed to regulate feeding, but the one we discovered is the first to be fully described to regulate portion size via dopamine signaling,” Han said. “Our new study shows that a circuit connecting neurons that produce dopamine, a chemical messenger previously known for the regulation of motivation and pleasure, has a new role in the control of feeding through dynamically regulating the satiety response.”

“Our finding that MPH suppresses feeding and reduces body weight in laboratory mice by strengthening the dopamine-supported novel circuit we discovered, suggests a potential off-label application of a class of MPH and derivatives in tackling obesity,” Wu said. “This also has implications for the future development of circuitry-based precision medicine that can deliver weight-reducing results with higher safety and effectiveness.”.

Guobin Xia, Yanlin He, Yang He, Monica Farias and Yong Xu, all at Baylor College of Medicine, also contributed to this work.

This project was supported by funding from a Shared Instrumentation grant from the NIH (S10 599 OD016167), the NIH Digestive Diseases Center PHS grant P30 DK056338, NIH grants (R01DK109194, R56DK109194), the Pew Charitable Trust award (0026188), American Diabetes Association awards (#7-13-JF-61), Baylor Collaborative Faculty Research Investment Program grants and USDA/CRIS grants (3092-5-001-059). Further support was provided by the Faculty Start-up grants from USDA/ARS NIH grants (R01DK093587, R01DK101379, and R01DK117281), USDA/CRIS grants (3092-5-001-059), American Heart Association awards (17GRNT32960003), American Diabetes Association (1-17-PDF-138), the NIH Centers of Biomedical Research Excellence (COBRE) grant P20 GM135002, a Pew Scholarship of Biomedical Sciences and a Kavli Scholarship.

Reference: Yong Han, Guobin Xia, Yanlin He et al., “A hindbrain dopaminergic neural circuit prevents weight gain by reinforcing food satiation”, Science Advances  26 May 2021: Vol. 7, no. 22, eabf8719 DOI: 10.1126/sciadv.abf8719

Provided by Baylor College of Medicine

Weight-loss Maintainers Sit Less Than Weight-stable People With Obesity (Physiology)

People who are successful at weight-loss maintenance spend less time sitting during the week and weekends compared to weight-stable individuals with obesity, according to a paper published online in Obesity, The Obesity Society’s flagship journal. This is the first study to examine time spent in various sitting activities among weight-loss maintainers.

Prior findings from 2006 in the National Weight Control Registry indicated that weight-loss maintainers watched significantly less television than controls, but other sitting activities were not examined. In the current study, weight-loss maintainers did not significantly differ from controls in reported weekly sitting time spent watching television, but did differ in time spent in non-work-related time using a computer or video game.

Differences between the current study and National Weight Control Registry findings could reflect changes over the past 15 years in available electronic devices, including the rise in availability of computers and video games. Weight-loss maintainers and controls also did not appreciably differ in time spent sitting while reading or studying, traveling; or talking, texting and socializing. These could be considered more mentally active forms of sedentary behavior.

“The findings hopefully will prompt future weight maintenance intervention research testing the effects of and optimal approaches for reducing sedentary behavior, including non-work-related computer and video game usage. Future research should include objective measures of sedentary behavior and activity,” said Suzanne Phelan, Department of Kinesiology and Public Health and The Center for Health Research, California Polytechnic State University, in San Luis Obispo. Phelan is the corresponding author of the study.

Participants in the study included 4,305 weight-loss maintainers from WW (formerly Weight Watchers) who had maintained >9.1 kg of weight loss (24.7 kg on average) for 3.3 years and had an average current BMI of 27.6 kg/m2. The group of weight-stable individuals with obesity had an average BMI of 38.9 kg/m2. To gather data, the Multicontext Sitting Time and Paffenbarger physical activity questionnaires were administered.

Results revealed that weight-loss maintainers versus weight-stable individuals with obesity spent three hours less per day sitting during the week (10.9 versus 13.9) and weekends (9.7 versus 12.6). Weight-loss maintainers compared with controls also spent one hour less per day in non-work-related sitting using a computer or playing a video game during the week (1.4 versus 2.3) and weekends (1.5 versus 2.5). There were no meaningful differences between weight-loss maintainers and weight-stable individuals with obesity in the number of television sets and sedentary-promoting devices in the home (15.8 versus 14.8). Weight-loss maintainers expended significantly more calories per week in physical activity (1,835 versus 785).

“These findings are important for understanding behaviors that may enhance weight loss maintenance, and one of those may be to reduce sitting time and other modes of sedentary behavior. However, this study also showed that physical activity was associated with improved weight-loss maintenance. Thus, this study does not imply that simply standing more rather than sitting will contribute to weight-loss maintenance, but may suggest that less sitting that results in more movement is what is key to weight loss maintenance. Hence, sit less and move more,” said John M. Jakicic, PhD, FACSM, FTOS, Distinguished Professor, and Director of the Healthy Lifestyle Institute and the Physical Activity and Weight Management Research Center at the University of Pittsburgh in Pennsylvania. Jakicic was not associated with the research.

Other authors of the study include James Roake, Noemi Alarcon and Sarah Keadle of the Department of Kinesiology and Public Health and The Center for Health Research, California Polytechnic State University, in San Luis Obispo. Chad Rethorst of Texas A&M Agrilife in Dallas, Texas and Gary Foster of WW International, Inc. of New York and the Center for Weight and Eating Disorders, Perelman School of Medicine, University of Pennsylvania, in Philadelphia also co-authored the study.

The paper, titled “Sitting Time, Type, and Context Among Long-Term Weight-Loss Maintainers“, will be published in the June 2021 print issue.

This research was supported by a grant from WW International, Inc.

Phelan reports receiving a research grant from WW International, Inc. Foster is an employee and shareholders of WW. At the time of the study, Rethorst was an employee and shareholder of WW. The remaining authors declared no conflicts of interest.

Provided by The Obesity Society

Obesity Protects Against Death in Severe Bacterial Infection (Medicine)

For many diseases, overweight and obesity are risk factors. But now a study shows that a higher BMI may be linked to higher survival rates in patients hospitalized for severe bacterial infections.

Scientists at Sahlgrenska Academy, University of Gothenburg, and Skaraborg Hospital in Skövde carried out the research, and their study has now been published in the journal PLOS ONE. The data were collected before the COVID-19 pandemic.

The population-based study involved observations, over a nine-month period, of all 2,196 individual adults receiving care for suspected severe bacterial infection at Skaraborg Hospital in Skövde. The researchers followed the patients in this study population over time, during and after their hospital stay.

The results show that the raised chances of survival were associated with a higher body mass index (BMI) in both the short and long term, at 28 days and one year after hospitalization respectively. The differences in survival rates were clear. In the normal-weight group, 26 percent were dead within a year. The corresponding figures in the groups with higher BMI were 9–17 percent.

Unlike other diseases

Occasional surveys of limited patient groups have previously shown similar results. The new findings clarify and confirm the “obesity survival paradox”: that overweight and obesity afford protection against severe bacterial infections.

Åsa Alsiö Photo: Elin Lindström

Åsa Alsiö, adjunct senior lecturer in infectious diseases at Sahlgrenska Academy and senior consultant in infectious diseases at Skövde, is the study’s first and corresponding author.

“In the context of most other diseases, overweight and obesity are disadvantageous. This applies to several types of cancer, cardiovascular disease and, in particular, COVID-19, in which a higher BMI is associated with higher mortality. Paradoxically, it’s the other way round here.

“What we don’t know,” Alsiö continues, “is how being overweight can benefit the patient with a bacterial infection, or whether it’s connected with functions in the immune system and how they’re regulated. More knowledge is needed about how being overweight affects the immune system. One patient category it could be studied in is individuals undergoing bariatric surgery.”

BMI a key variable

Gunnar Jacobsson, Sahlgrenska Academy and senior consultant in infectious diseases at Skaraborg Hospital in Skövde, is the senior author of the study:

Gunnar Jacobsson Photo: Privat

“The COVID-19 pandemic has highlighted vulnerable patient groups, and overweight people have been hit hard. Maybe experience and handling of care for patients with severe bacterial infections can be used to improve the prognosis of COVID-19 and overweight. Globally, obesity is increasing at an alarming rate. More knowledge is needed to shed light on how body weight affects the body’s defenses against infection, so that treatment can be individualized,” Jacobsson says.

The researchers think there is a need for more studies, at the population level, of how BMI affects treatment outcomes in various infectious diseases and what connections with regulation of the immune system may exist.

Title: Alsiö Å, Nasic S, Ljungström L, Jacobsson G (2021) Impact of obesity on outcome of severe bacterial infections. PLoS ONE 16(5): e0251887. https://doi.org/10.1371/journal.pone.0251887

Provided by University of Gothenburg

HKU Researchers Identify Promising New Biologics For Obesity-related Diseases (Medicine)

The research teams at the University of Hong Kong led by Professor Xuechen LI from the Research Division for Chemistry and Department of Chemistry, and Professor Yu WANG from the Department of Pharmacology and Pharmacy, reported a synthetic biotherapeutics with promising anti-tumour, insulin sensitising and hepatoprotective activities in the Journal of the American Chemical Society.

Obesity is a global pandemic associated with a significantly reduced life expectancy, it also increases the risk of type 2 diabetes, hypertension, coronary heart disease, stroke, chronic kidney disease and cancer. Adiponectin, as a protein hormone and adipokine, regulates glucose levels and improve lipid metabolism, and is a major player in the pathogenesis of obesity, insulin resistance and metabolic syndrome. Obese patients have low adiponectin levels, a condition known as hypoadiponectinemia, which contributes to increase risks of cardiovascular, metabolic diseases as well as aggressive development of malignancies with poor prognoses. Adiponectin supplementation is a long-sought-after strategy for the prevention and treatment of cancer and metabolic diseases, especially in obese patients. However, the adiponectin application in therapy has been hampered by the difficult production of human adiponectin.

The teams have been working on the development of synthetic compounds which can mimic the bioactivity of adiponectin over the past seven years. Finally, they developed an efficient synthetic approach to produce the adiponectin-derived glycopeptides that exhibit potent anti-tumour, insulin-sensitising and metabolic activities in various mouse models. The products hold greater potentials for clinical application in obesity and related medical complications, such as type 2 diabetes, hypertension, coronary heart disease, stroke, chronic kidney disease and cancer.

Professor Li and Professor Wang believe that this finding opens the door to explore the opportunity of using the synthetic glycopeptide as a potential adiponectin downsized mimic supplementary in clinical treatment. The apparent advantage of these synthetic glycopeptides is that they can be readily produced by chemical process. The two teams are continuing to apply for research grants which can support them to further evaluate the potential of these agents in preclinical studies for drug development.

The research paper: https://pubs.acs.org/doi/10.1021/jacs.1c02382

Featured image : The two HKU research teams. (From left to right) Mr Yuanxin LI (Department of Pharmacology and Pharmacy), Professor Yu WANG (Department of Pharmacology and Pharmacy), Dr Yiwei ZHANG (Department of Pharmacology and Pharmacy), Mr Hongxiang WU (Research Division for Chemistry and Department of Chemistry) and Professor Xuechen LI (Research Division for Chemistry and Department of Chemistry). © HKU

Provided by University of Hong Kong

Research Reveals Potential Treatment To Prevent Obesity-driven Liver Damage (Medicine)

Team led by experts at Cincinnati Children’s reports success- in mice-at controlling a subgroup of immune system cells that trigger non-alcoholic fatty liver disease (NAFLD)

One of the especially dangerous health risks of being extremely overweight occurs when an obese person begins to accumulate fat in their liver.

This condition–non-alcoholic fatty liver disease (NAFLD)–is the world’s most common chronic liver disease and is the primary underlying cause for liver transplants in children and adults. Without such transplants, which are available to only a small percentage of patients, NAFLD over time can be fatal. In fact, (excluding alcohol-related liver damage) more than 30,000 people a year die from NAFLD.

For years, the primary way to treat NAFLD has been through the use of various weight control methods: diet programs, exercise regimens, medications of limited benefit, bariatric surgery, and more. But once people develop progressive NAFLD, simply losing weight is not enough.

Now, after years of studying the numerous mechanisms involved with obesity and NAFLD, a team of 20 scientists at Cincinnati Children’s reports taking a significant step forward. Their findings were published online May 17, 2021, in Cell Metabolism.

Introducing ihTh17 cells

The research team reports that excessive fat deposition in the liver due to obesity can alter the microenvironment of the liver in a way that attracts a highly specific population of immune T cells to the liver. These “inflammatory hepatic CXCR3+Th17 cells” or “ihTh17” cells go on to trigger excess inflammation and life-threatening liver damage.

By running a series of experiments using human tissues and cells and multiple lines of genetically modified mice, the team found that obesity itself triggers activity along a molecular “pathway” that starts with excess expression of the CXCL10 and CXCR3 genes. This abnormal activity attracts more and more ihTh17 cells to the liver. The consequence being a scorched earth inflammatory feedback loop that recruits additional immune cells and progressively damages liver function.

After tracing the ihTh17 cell liver recruitment pathway, the team set out to find a way to break the unhealthy cycle of inflammation. They found success with mice bred to lack expression of the gene Pkm2 in their T cells, which appears to be crucial to continued activity along the CXCR3 pathway.

When these modified mice were given obesity-inducing diets, they still got fat. But they suffered notably less liver damage than non-modified mice.

Next, the researchers tested human tissues collected from people with NAFLD. They confirmed that many of the key genes and molecular activities occurring in the mice also could be detected in the human liver cells.

“Our results demonstrate for the first time that ihTh17 cells represent an important component of the complex world of NAFLD pathogenesis,” say corresponding author Senad Divanovic, PhD, a member of the Division of Immunobiology at Cincinnati and first author Maria Moreno-Fernandez, PhD, a postdoctoral fellow in the Divanovic laboratory.

Learning more about how to regulate ihTh17 cells’ function and their interaction with the liver cells and the immune system could lead to new therapies to reduce the harm caused by NAFLD.

Next steps

But will the treatment approach used in mice also help people? Human gene editing is not likely to be an acceptable option for this condition anytime soon. However, some drugs are known to be capable of blocking Pkm2 activity, Divanovic says.

Those drugs still require more in-depth laboratory evaluation. Ultimately, a promising compound also would need to be tested in multi-year clinical trials. But now, for the first time in years, the team has a promising lead to explore.

“If we can modulate the unwanted inflammatory responses associated with NAFLD in a targeted way we may be able to ameliorate the liver damage and improve the survival and health of people with NAFLD,” Divanovic says.

About the study

These findings reflect the latest insights from scientists, surgeons and clinicians at Cincinnati Children’s who have devoted many years to obesity research. Their previous work has increased understanding of how obesity changes metabolic activity, immune system function, heart health and more. Several of the co-authors on this publication previously helped establishing bariatric surgery as a safe option for obese children that also helps reverse type 2 diabetes.

In addition to Divanovic, co-authors from 15 research divisions and services at Cincinnati Children’s contributed to this study. They include Maria E. Moreno-Fernandez (n.e Fields) (lead author- Division of Immunobiology); Daniel Giles (now at Janssen); Jarren Oates (Division of Immunobiology), Calvin Chan (Division of Immunobiology), Michelle Damen (Division of Immunobiology), Jessica Doll (Division of Immunobiology), Traci Stankiewicz (Division of Immunobiology), Xiaoting Chen (CAGE), Kashish Chetal (Division of Biomedical Informatics), Rebekah Karns (Division of Gastroenterology, Hepatology and Nutrition), Matthew Weirauch (CAGE), Lindsey Romick-Rosendale (NMR Metabolomics Core), Stavra Xanthakos (Division of Gastroenterology, Hepatology and Nutrition), Rachel Sheridan (now at Dayton Children’s), Sara Szabo (Division of Pathology and Laboratory Medicine), Amy Shah (Division of Endocrinology), Michael Helmrath (CuSTOM), Hitesh Deshmukh (Division of Neonatology and Pulmonary Biology), and Nathan Salomonis (Division of Biomedical Informatics). Co-authors also include Thomas Inge (now at Children’s Hospital Colorado).

Funding for this work includes grants from the National Institutes of Health R01DK099222, R01DK099222-02S1, T32AI118697, T32GM063483-14, R01HL142708-01 and P30 DK078392 of the Digestive Disease Research Core Center; the Department of Defense W81XWH2010392; the American Diabetes Association 1-18-IBS-100 and 1-19-PMF-019; the American Heart Association 17POST33650045; and internal funding support from Cincinnati Children’s and the University of Cincinnati.

Featured image: Obesity driven steatotic liver microenvironment through the activation of CXCR3 axis gives rise to a distinct population of inflammatory hepatic Th17 (ihTh17) cell subset, which preferentially utilizes the glycolytic pathway and PKM2 activity to fuel tissue inflammation and promote NAFLD progression. © Cincinnati Children’s

Reference: Maria E. Moreno-Fernandez, Daniel A. Giles, Jarren R. Oates, Calvin C. Chan, Michelle S.M.A. Damen, Jessica R. Doll, Traci E. Stankiewicz, Xiaoting Chen, Kashish Chetal, Rebekah Karns, Matthew T. Weirauch, Lindsey Romick-Rosendale, Stavra A. Xanthakos, Rachel Sheridan, Sara Szabo, Amy S. Shah, Michael A. Helmrath, Thomas H. Inge, Hitesh Deshmukh, Nathan Salomonis, Senad Divanovic, PKM2-dependent metabolic skewing of hepatic Th17 cells regulates pathogenesis of non-alcoholic fatty liver disease, Cell Metabolism, 2021, , ISSN 1550-4131, https://doi.org/10.1016/j.cmet.2021.04.018. (https://www.sciencedirect.com/science/article/pii/S1550413121002163)

Provided by Cincinnati Children’s Hospital and Medical Center