Keep up with your weight loss goals with daily weighing

According to research presented in the American Heart Association’s 2018 scientific meeting, daily weighing may help with weight loss goals. People who don’t weigh themselves at all or rarely were less likely to lose weight than those who weighed themselves often,

Researchers examined the self-weighing patterns of 1,042 adults (78 percent male, 90 percent white, average age 47) and whether there were differences in weight change by these self-weighing patterns over 12 months. They analyzed remotely transmitted self-weighing data from Health eHeart, an ongoing prospective e-cohort study. The participants weighed themselves at home as they normally would, without interventions, guidance or weight-loss incentives from researchers.

Researchers identified several categories of self-weighing adults, from those that weighed themselves daily or almost daily to adults who never used at-home scales.

They found that people who never weighed themselves or only weighed once a week did not lose weight in the following year. Those that weighed themselves six to seven times a week had a significant weight loss (1.7 percent) in 12 months.

Citation: Daily weighing may be key to losing weight
American Heart Association Meeting  Poster Presentation Sa2394 – Session: NR.APS.01
Yaguang Zheng, Ph.D., M.S.N., R.N., University of Pittsburgh School of Nursing, Pittsburgh, PA

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Late night snack with cottage cheese has no major adverse metabolic effects

Associate Professor of Nutrition, Food and Exercise Sciences Michael Ormsbee and former Florida state university graduate student Samantha Leyh found that consuming 30 grams of protein about 30 minutes before bed appears to have a positive effect on muscle quality, metabolism, and overall health. They compared protein from whole food (cottage cheese) versus liquid protein shake and placebo. In their results they showed no difference between whole food and liquid protein shake in terms of appetite and metabolic changes. Research suggests that no adverse impact of pre-sleep protein on metabolic activity. Research findings are published in the British Journal of Nutrition.

Study participants active young women in their early 20s ate samples of cottage cheese 30 to 60 minutes before bedtime. Researchers specifically wanted to see if this food may have an impact on the metabolic rate and muscle recovery.

“Until now, we presumed that whole foods would act similarly to the data on supplemental protein, but we had no real evidence,” Ormsbee said. “This is important because it adds to the body of literature that indicates that whole foods work just as well as protein supplementation, and it gives people options for presleep nutrition that go beyond powders and shaker bottles.”

Leyh, who is now a research dietitian with the Air Force, said the results serve as a foundation for future research on precise metabolic responses to whole food consumption.

Ormsbee said that his research team will start examining more presleep food options and longer-term studies to learn more about the optimal food choices that can aid individuals in recovery from exercise, repair and regeneration of muscle and overall health.

Citation:Leyh, Samantha M., Brandon D. Willingham, Daniel A. Baur, Lynn B. Panton, and Michael J. Ormsbee. “Pre-sleep Protein in Casein Supplement or Whole-food Form Has No Impact on Resting Energy Expenditure or Hunger in Women.” British Journal of Nutrition120, no. 9 (2018): 988-94. doi:10.1017/s0007114518002416.

Amino acids link gut microbiome to obesity

Researchers at Lund University in Sweden have discovered a new link between gut bacteria and obesity. They found that certain amino acids in our blood can be connected to both obesity and the composition of the gut microbiome.

Increasing number of research studies indicate that our gut microbiome does play an important role in our health. It affects our metabolism and can be linked to obesity, cardiovascular disease and type 2 diabetes.

Previous studies have shown that people with these diseases have varying occurrence of different metabolites, i.e. small molecules or metabolic residues, in the bloodstream. The aim of the new study was therefore to identify metabolites in the blood that can be linked to obesity (high body mass index, BMI) and to investigate whether these obesity-related metabolites affect the composition of the bacterial flora in stool samples.

The researchers analysed blood plasma and stool samples from 674 participants in the Malmö Offspring Study. They found 19 different metabolites that could be linked to the person’s BMI; glutamate and so-called BCAA (branched-chain and aromatic amino acids) had the strongest connection to obesity. They also found that the obesity-related metabolites were linked to four different intestinal bacteria (Blautia, Dorea and Ruminococcus in the Lachnospiraceae family, and SHA98).

“The differences in BMI were largely explained by the differences in the levels of glutamate and branched-chain and aromatic amino acids. This indicates that the metabolites and gut bacteria interact, rather than being independent of each other”, says Marju Orho-Melander, professor of genetic epidemiology at Lund University.

By far the strongest risk factor for obesity in the study, glutamate, has been associated with obesity in previous studies, and BCAA has been used to predict the future onset of type 2 diabetes and cardiovascular disease.

“This means that future studies should focus more on how the composition of gut bacteria can be modified to reduce the risk of obesity and associated metabolic diseases and cardiovascular disease”, says Marju Orho-Melander. “To get there, we first need to understand what a healthy normal gut flora looks like, and what factors impact the bacterial composition. This requires large population studies, like the Malmö Offspring Study, as well as intervention studies”, she concludes.

Citation: Ottosson, Filip, Louise Brunkwall, Ulrika Ericson, Peter M. Nilsson, Peter Almgren, Céline Fernandez, Olle Melander, and Marju Orho-Melander. “Connection between BMI related plasma metabolite profile and gut microbiota.” The Journal of Clinical Endocrinology & Metabolism, 2018. doi:10.1210/jc.2017-02114.

Adapted from press release by the Lund University.

Animal studies show that naturally occurring peptide catestatin has potential as anti-obesity and type 2 diabetes treatment

Research by team from University of California San Diego School of Medicine shows that treating obese mice with catestatin (CST), a peptide naturally occurring in the body, showed significant improvement in glucose and insulin tolerance and reduced body weight.

In a study published in journal Diabetes, researchers identified catestatins’s role in the recruitment and function of macrophages in the liver as well as regulation of obesity-induced liver inflammation and insulin resistance.

“We have shown that an endogenous peptide, catestatin, can directly suppress glucose production from hepatocytes and can indirectly suppress lipid accumulation in liver as well as macrophage-mediated inflammation in obese mice,” said Sushil K. Mahata, PhD, professor of medicine at UC San Diego School of Medicine. “The net results are improved glucose tolerance and insulin sensitivity. Therefore, this peptide has immense potential for an anti-obesity reagent as well as a novel drug to treat type 2 diabetes.”

Treating obese mice with catestatin inhibited the recruitment of monocyte-derived macrophages to the liver and decreased inflammation, suggesting catestatin is an anti-inflammatory peptide. Catestatin treatment also lowered blood sugar and insulin levels to normal, and reduced fatty liver. Administering catestatin had no effect on insulin or glucose tolerance in control lean mice, showing that the effect of catestatin is restricted to obese animals. This difference may be explained by the reduced levels of normal catestatin in obese mice compared to the lean control animals. To confirm the importance of naturally occurring catestatin, the authors studied mice that lacked catestatin. These mice ate more and were heavier but lost weight when treated with catestatin. The researchers theorize that naturally occurring catestatin may help maintain body weight by suppressing hunger and enhancing glucose tolerance.

“The improved glucose and insulin sensitivity with catestatin treatment may be partly explained by the anti-inflammatory effects of catestatin on the liver,” said Mahata. “We have identified a novel pathway for suppression of liver glucose production that could be used to compensate for the loss of naturally occurring catestatin or to bolster its impact. But further studies are needed to uncover how catestatin suppresses liver inflammation to improve metabolism.”

Citation: Ying, Wei, Sumana Mahata, Gautam K. Bandyopadhyay, Zhenqi Zhou, Joshua Wollam, Jessica Vu, Rafael Mayoral, Nai-Wen Chi, Nicholas J.g. Webster, Angelo Corti, and Sushil K. Mahata. “Catestatin Inhibits Obesity-Induced Macrophage Infiltration and Inflammation in the Liver and Suppresses Hepatic Glucose Production Leading to Improved Insulin Sensitivity.” Diabetes, 2018. doi: 10.2337/db17-0788.

Funding:  Department of Veterans Affairs, American Heart Association, National Natural Science Foundation of China, Noland Scholarship.

Adapted from press release by University of California San Diego School of Medicine.

Obesity genes: role of foraging gene in fruit fly

A University of Toronto study on fruit flies has uncovered a gene that could play a key role in obesity in humans. The paper published online this month in Genetics examines a “foraging gene” humans share in common with the flies, which plays multiple roles and is found in similar places, such as the nervous system, in the muscle and in fat.

“What our study does is nails the gene for being very important for the traits of moving, feeding and fat storage,” says University Professor Marla Sokolowski of the Department of Ecology & Evolutionary Biology in U of T’s Faculty of Arts & Science.

In nature, fruit flies called “Rovers” with high amounts of the gene tend to move a lot, eat very little and stay lean, while flies with low amounts of for called “Sitters” are the opposite. The same could apply to obesity in humans.

“So you could imagine if you are a fly, preferences for sugar, the tendency to store a lot of fat and the tendency to move less could all be contributing to the likelihood of being more obese if you have low levels of this gene, or to be leaner if you have higher levels.”

Such similarities between species are known as orthologs, meaning they are genes that evolved from a common ancestor eons ago.

The study involved a technique called recombineering to manipulate DNA at the molecular level, so as to remove and then reinsert the gene in various doses to see the effects on behavior and metabolism.

“To be able to take a gene of this large size and complexity and put it back in the fly so that it works is almost at the edge of what is possible,” Sokolowski says it’s particularly interesting that one gene should have multiple roles in feeding and obesity in the body, a characteristic known as pleiotropy.

The next question would be how exactly it plays multiple roles. “Lots of genes have multiple roles, but the idea here is that this gene may be involved in the coordination of roles in traits important for feeding and obesity.”

 “We don’t know much about pleiotropy, or how it happens, or how it’s regulated at the level of the molecules. So this sets the groundwork to be able to look at that in detail.”

Citation: Allen, Aaron M., Ina Anreiter, Megan C. Neville, and Marla B. Sokolowski. “Feeding-Related Traits Are Affected by Dosage of the foraging Gene in Drosophila melanogaster.” Genetics 205, no. 2 (2016): 761-73.
doi:10.1534/genetics.116.197939.
Research funding: Natural Sciences and Engineering Council of Canada, Canadian Institutes for Health Research.
Adapted from press release by the University of Toronto.

Obesity related Epigenetic changes in DNA

Obesity has been linked to “letter” changes at many different sites in the genome, yet these differences do not fully explain the variation in people’s body mass index (BMI) or why some overweight people develop health complications while others don’t. A large study from Boston Children’s Hospital, the University of Edinburgh, the Harvard School of Public Health, the Framingham Heart Study and the National Heart, Lung, and Blood Institute (NHLBI) provides more insight, linking obesity with epigenetic modifications to DNA that in turn are tied to an increased risk of weight-related health problems such as coronary artery disease.

The study is one of the largest to date to examine the link between BMI, obesity-related disease and DNA methylation  a type of epigenetic modification that influences whether genes are turned on or off. Findings were published in PLoS Medicine.

“Even though we’ve genetically sequenced more and more people at greater and greater breadth and depth, we haven’t completely explained who develops obesity and why,” says Michael Mendelson, MD, ScM, a pediatric cardiologist with the Preventive Cardiology Program at Boston Children’s Hospital, who shared first authorship on the paper with Riccardo Marioni of the University of Edinburgh. “We found that obesity is related to widespread changes in DNA methylation. Unlike your DNA sequence, these regulatory modifications change over time and can influence your risk of disease in later life.”

The researchers studied blood samples from 7,800 adults from the Framingham Heart Study, the Lothian Birth Cohort and three other population studies. They systematically looked for markers of DNA methylation at more than 400,000 sites in the genome. They then looked to see if these markers differed according to BMI in a predictable pattern.

Their analysis identified strong associations between BMI and DNA methylation at 83 locations in 62 different genes. Methylation at these sites was, in turn, associated with differences in the expression of genes involved in energy balance and lipid metabolism.

When Mendelson and colleagues scored people in the study for how many methylation changes they had, they found that the more changes, the greater their BMI. The methylation score captured 18 percent of the variation in BMI when tested in a separate population. For each standard deviation increase in the score, the odds ratio for obesity was 2.8 times higher.

The researchers then applied a statistical technique called Mendelian randomization, which provides supportive evidence that a detected association is causal. They concluded that 16 of the 83 identified sites in the genome were differently methylated as a result of obesity, a finding that held true across people of different ethnicities.

Difference in methylation at one gene, SREBF1, appeared to be causative of obesity and was clearly linked with unhealthy blood lipid profiles, glycemic traits (a risk factor for diabetes) and coronary artery disease. It encodes a known regulator of lipid metabolism and could be a target for a drug treatment, the researchers say.

“Taken together, these results suggest that epigenetic modifications may help identify therapeutic targets to prevent or treat obesity-related disease in the population,” says Mendelson, who is also a research fellow in the Population Sciences Branch of the NHLBI. “The next step is to understand how we can modify epigenetic modifications to prevent the development of cardiometabolic disease.”
Since the study was done in blood cells, it also suggests that with further study, methylation markers could be easily accessible biomarkers to guide therapy bringing a “precision medicine” approach to preventive cardiology, says Mendelson.

“We’ve known for a long time that people who are overweight or obese are more likely to develop metabolic risk factors like diabetes, lipid abnormalities and hypertension,” adds study coauthor Daniel Levy, MD. He is director of the Framingham Heart Study, which is supported by the NHLBI. “This study may help us understand the molecular mechanism linking obesity to metabolic risk, and that knowledge may pave the way for new approaches to prevent even more dire complications such as cardiovascular disease.”

Citation: Michael M. Mendelson, Riccardo E. Marioni, Roby Joehanes, Chunyu Liu, Åsa K. Hedman, Stella Aslibekyan, Ellen W. Demerath, Weihua Guan, Degui Zhi, Chen Yao, Tianxiao Huan, Christine Willinger, Brian Chen, Paul Courchesne, Michael Multhaup, Marguerite R. Irvin, Ariella Cohain, Eric E. Schadt, Megan L. Grove, Jan Bressler, Kari North, Johan Sundström, Stefan Gustafsson, Sonia Shah, Allan F. McRae, Sarah E. Harris, Jude Gibson, Paul Redmond, Janie Corley, Lee Murphy, John M. Starr, Erica Kleinbrink, Leonard Lipovich, Peter M. Visscher, Naomi R. Wray, Ronald M. Krauss, Daniele Fallin, Andrew Feinberg, Devin M. Absher, Myriam Fornage, James S. Pankow, Lars Lind, Caroline Fox, Erik Ingelsson, Donna K. Arnett, Eric Boerwinkle, Liming Liang, Daniel Levy and Ian J. Deary. “Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardio metabolic Disease: A Mendelian Randomization Approach.”
DOI: 10.1371/journal.pmed.1002215

Research funding: National Heart, Lung, and Blood Institute of the NIH, Tommy Kaplan Fund (Department of Cardiology, Boston Children’s Hospital), UK Biotechnology and Biological Sciences Research Council, UK Royal Society, Chief Scientist Office of the Scottish Government, Age UK, Wellcome Trust Institutional Strategic Support Fund, UK Economic and Social Research Council, UK Medical Research Council, Australian National Health and Medical Research Council.

Adapted from press release by Boston Children’s Hospital.

Vitamin E requirements increased in people suffering from metabolic syndrome

New research has shown that people with metabolic syndrome need significantly more vitamin E – which could be a serious public health concern, in light of the millions of people who have this condition that’s often related to obesity. A study published in the American Journal of Clinical Nutrition also made it clear that conventional tests to measure vitamin E levels in the blood may have limited accuracy compared to tests made in research laboratories, to the point that conventional tests can actually mask an underlying problem.

Vitamin E supplements. Credit: John Liu / Oregon State University.

Vitamin E – one of the more difficult micronutrients to obtain by dietary means – is an antioxidant important for cell protection. It also affects gene expression, immune function, aids in the repair of wounds and the damage of atherosclerosis, is important for vision and neurologic function, and largely prevents fat from going rancid.

Nutrition surveys have estimated that 92 percent of men and 96 percent of women in the United States fail to get an adequate daily intake of vitamin E in their diet. It is found at high levels in almonds, wheat germ, various seeds and oils, and at much lower levels in some vegetables and salad greens, such as spinach and kale.

This study was done by researchers at the Linus Pauling Institute at Oregon State University and the Human Nutrition Program at The Ohio State University, as a double-blind, crossover clinical trial focusing on vitamin E levels in people with metabolic syndrome. “The research showed that people with metabolic syndrome need about 30-50 percent more vitamin E than those who are generally healthy,” said Maret Traber, a professor in the OSU College of Public Health and Human Sciences, and Ava Helen Pauling Professor in the Linus Pauling Institute.

“In previous work, we showed that people with metabolic syndrome had a lower bioavailability of vitamin E. Our current work uses a novel approach to measure how much vitamin E the body needs. This study clearly demonstrates that people with metabolic syndrome need a higher intake of this vitamin.”

More than 30 percent of the American public are obese, and more than 25 percent of the adults in the United States meet the criteria for metabolic syndrome, putting them at significantly increased the risk for cardiovascular disease and type-2 diabetes primary causes of death in the developed world.

That syndrome is defined by diagnosis of three or more of several conditions, including abdominal obesity, elevated lipids, high blood pressure, pro-inflammatory state, a pro-thrombotic state and insulin resistance or impaired glucose tolerance. This research, for the first time, also clearly outlined a flaw with conventional approaches to measuring vitamin E.

By “labeling” vitamin E with deuterium, a stable isotope of hydrogen, scientists were able to measure the amount of the micronutrient that was eliminated by the body, compared to the intake. The advanced research laboratory tests, which are not available to the general public, showed that people with metabolic syndrome retained 30-50 percent more vitamin E than healthy people – showing that they needed it. When the body doesn’t need vitamin E, the excess is excreted.

But in the group with metabolic syndrome, even as their tissues were taking up and retaining the needed vitamin E, their blood levels by conventional measurement appeared about the same as those of a normal, healthy person.

“We’ve discovered that vitamin E levels often look normal in the blood, because this micronutrient is attracted to high cholesterol and fat,” Traber said. “So vitamin E can stay at higher levels in the circulatory system and give the illusion of adequate levels, even as tissues are deficient.

“This basically means that conventional vitamin E blood tests as they are now being done are useless.”

The findings support the conclusion that people with metabolic syndrome have higher levels of oxidative and inflammatory stress, scientists said in their conclusion, and require more antioxidants such as vitamins E as a result.

Citation: Maret G Traber, Eunice Mah, Scott W Leonard, Gerd Bobe, and Richard S Bruno. “Metabolic syndrome increases dietary α-tocopherol requirements as assessed using urinary and plasma vitamin E catabolites: a double-blind, crossover clinical trial.” The American Journal of Clinical Nutrition 2017 pp: ajcn138495
DOI: 10.3945/ajcn.116.138495
Research funding: National Institutes of Health, National Dairy Council, and DSM Nutrition.
Adapted from press release by Oregon State University.

Research shows red cabbage microgreens reduce weight gain and lower cholesterol in mice fed on high-fat diet

Microgreens are sprouting up everywhere from upscale restaurants to home gardens. They help spruce up old recipes with intense flavors and colors and are packed with nutrients. Now research has shown that for mice on a high-fat diet, red cabbage microgreens helped lower their risk factors for developing cardiovascular disease and reduce their weight gain. The report appears in ACS’ Journal of Agricultural and Food Chemistry.

In an animal study, red cabbage microgreens helped lower “bad” cholesterol. Credit: American Chemical Society

Microgreens are tender, immature plants and herbs that take only a week or two to grow before they’re ready for harvesting. A growing body of research suggests that microgreens could offer more health benefits than their mature counterparts. And since previous studies have shown that full-grown red cabbage can help guard against excessive cholesterol, Thomas T.Y. Wang and colleagues wanted to see if red cabbage microgreens might have a similar or even greater effect than their larger counterparts.

To test their hypothesis, the researchers used mice that were a modelled for obesity. These animals also tend to develop high cholesterol and other risk factors for cardiovascular disease. The team divided 60 of these mice into different diet groups. They received food low in fat or high in fat, and with or without either red cabbage microgreens or mature red cabbage. Both the microgreens and mature cabbage diets reduced weight gain and levels of liver cholesterol in the mice on high-fat diets. The study showed that microgreens intake lowered LDL cholesterol, liver triglyceride, and inflammatory cytokine levels in the animals. 

Citation: Huang, Haiqiu, Xiaojing Jiang, Zhenlei Xiao, Lu Yu, Quynhchi Pham, Jianghao Sun, Pei Chen, Wallace Yokoyama, Liangli Lucy Yu, Yaguang Sunny Luo, and Thomas T. Y. Wang. “Red cabbage microgreen lower circulating LDL, liver cholesterol and inflammatory cytokines in mice fed a high fat diet.” Journal of Agricultural and Food Chemistry (2016).
DOI: 10.1021/acs.jafc.6b03805
Research funding: U.S. Department of Agriculture.
Adapted from press release by The American Chemical Society.

New approach to treating Obesity with fat burning molecule ABX300

A small molecule ABX300 could provide valuable help in combating the global epidemic of obesity. When it was fed to obese mice, the animals’ metabolism sped up and their excess weight was shed. It is doing so by recruiting the help of a body’s own genes in countering the effects of a high-fat diet. The research team conducting the study believes their findings may provide a new unexplored therapeutic approach to fighting excessive weight gain in cases where diets or exercise have no effect. The study was led by Julien Santo, Celia Lopez-Herrera and Cécile Apolit of a French biotechnology company, and is published in Springer Nature’s International Journal of Obesity.

A high-fat diet may contribute to obesity in some individuals. Treatment in such situations has focused on behavioral changes, which is highly challenging to achieve for the general population on a long term basis. This study introduces the concept of recruiting the help of our genes in countering the effects of a high-fat diet, instead of focusing on reducing the intake of high-fat food.
Researchers know that the structure of some genes that help to produce certain proteins can actually change when someone constantly eats too much high-fat food. In the process, the person can become overweight or obese, or develop other lifestyle-related metabolic disorders such as diabetes or heart problems. In many cases, the same gene can produce two or more alternate proteins, based on how the translation from DNA (gene) to proteins is processed. One of these genes is LMNA, which plays a role in the development of different metabolic disorders. The LMNA RNA, which is the genetic material resulting from a process called DNA transcription, is modified by three SR proteins called SRSFI, SRSF5, and SRSF6. In this process called splicing, the genetic material encoded in the RNA is basically diced or shifted around and therefore alters the resulting proteins.

The research team found that a small molecule ABX300 is able to change the way one particular SR protein, SRSFI, works in the bodies of mice that gained excessive weight after being fed a high-fat diet. SRSFI determines which of the gene products of opposing effects could be produced from a single LMNA gene. One gene product promotes fat storage, the other opposes it. This study showed that blocking SRSFI with a compound promotes gene expression of the protein that burns calories and prevents fat gain or induces fat loss when mice are on a high-fat diet. It did not have any effect on lean mice of normal weight.

According to the research team, this approach alters the animals’ metabolic rate or energy expenditure. It means that it can speed up the metabolism of obese animals and that their bodies start to function at a higher energy level shedding the excess weight. In the process, their bodies started to burn much more fat, as especially fatty acids serve as much-needed sources of energy.

“The results of this animal study show that this molecule can abrogate or do away with the effect of a high-fat diet,” says Santo.

“Dietary management and exercise are not always successful as an intervention for obesity, underscoring the need for efficient medication to treat metabolic disorders,” adds Lopez-Herrera, who believes that this treatment represents an as yet unexplored approach to treating obesity.

According to Apolit, this compound did not seem to have any adverse effects, so more research in animals and eventual research in humans is needed. If the studies are positive, this may be a new way to treat obesity.

Citation: Santo J, Lopez-Herrera C, Apolit C, Bareche Y, Lapasset L, et. al. “Pharmacological modulation of LMNA SRSF1-dependent splicing abrogates diet-induced obesity in mice”. International Journal of Obesity 2016.
DOI: 10.1038/ijo.2016.220
Adapted from press release by Springer.

Understanding signaling pathway that creates brown fat to help in fight against obesity and diabetes

A signaling pathway in fat cells may one day provide the key to better treatments for obesity, according to new research by scientists at the Perelman School of Medicine at the University of Pennsylvania. They reported their findings in Genes & Development.

This image shows adipose tissue, with fat droplets in green
and blood vessels in red. Credit: The laboratory of
Zoltan Arany, MD, PhD, Perelman School of Medicine,
 University of Pennsylvania
Ordinary fat cells, also called white adipocytes, stuff themselves with fat molecules to store up energy, and their overloading leads to obesity and related conditions, including diabetes. Brown adipocytes, which are prevalent in children as “baby fat,” but much less so in adults, do virtually the opposite: they burn energy rapidly to generate heat and thereby protect the body from cold as well as obesity and diabetes. The signaling pathway discovered by the Penn scientists activates a “browning program” in white adipocytes, making them more like energy-burning brown adipocytes.
“It’s conceivable that one would be able to target this pathway with a drug, to push white fat to become brown fat and thereby treat obesity,” said the study’s senior author Zoltan P. Arany, MD, Ph.D., an associate professor of Cardiovascular Medicine. About 36 percent of American adults are considered obese and nearly 10 percent have type 2 diabetes.

Arany and colleagues found that the browning program in white adipocytes is normally suppressed by a protein called FLCN. It performs this function in cooperation with a major cellular signaling hub, a protein complex known as mTOR. The FLCN-mTOR interaction keeps the browning program switched off by preventing a protein called TFE3 from entering the cell nucleus.

The scientists showed that deleting the FLCN gene in the white adipocytes of mice allows TFE3 to migrate into the nucleus, where it binds to DNA and activates a key regulator of cellular metabolism called PGC-1β. It then turns on the set of genes for the browning program.

In the mice in which FLCN was deleted, white adipocytes became visibly browner as they produced more mitochondria–tiny, oxygen reactors that supply chemical energy within cells and convert energy to heat in brown adipocytes. In several other ways too, including their altered cellular structures, mitochondria’s higher capacity for consuming oxygen, and their distinctive pattern of gene expression, the cells became more like brown adipocytes.

Arany and his team showed that they could reproduce this browning effect merely by forcing the overexpression of PGC-1β in the white adipocytes of mice. “In principle, a drug that boosts the activity of PGC-1β or some of its target genes might serve as a therapeutic activator of the browning program to curb obesity and treat or prevent diabetes,” Arany said.

Aside from its potential medical relevance, the discovery is an important advance in understanding cell biology. “Cellular metabolism is regulated by major signaling pathways and with this study, we’re linking two of these major pathways, the mTOR, and the PGC-1 pathways,” Arany said. “The connection between them hasn’t been well understood, but here we’re clarifying it significantly.”

Arany and his team plan further studies of the pathway and its relation to other mTOR signaling pathways.

Citation:“The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue”. Shogo Wada, Michael Neinast, Cholsoon Jang, Yasir H. Ibrahim, Gina Lee, Apoorva Babu, Jian Li, Atsushi Hoshino, Glenn C. Rowe, James Rhee, José A. Martina, Rosa Puertollano, John Blenis, Michael Morley, Joseph A. Baur, Patrick Seale and Zoltan Arany. Genes & development 2016.
DOI: 10.1101/gad.287953.116
Research funding: National Institutes of Health.
Adapted from press release by Perelman School of Medicine at the University of Pennsylvania.