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Gut microbes respond differently to foods with similar nutrition labels

Source: Cell Press
Date: 06/12/2019
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Foods that look the same on nutrition labels can have vastly different effects on our microbiomes, report researchers in a paper publishing June 12 in the journal Cell Host & Microbe. The researchers’ observations of participants’ diets and stool samples over the course of 17 days suggested that the correlation between what we eat and what’s happening with our gut microbes might not be as straightforward as we thought. This adds an increased level of complexity to research focused on improving health by manipulating the microbiome.

“Nutrition labels are human-centric,” says senior author Dan Knights (@KnightsDan), of the Department of Computer Science and Engineering and the BioTechnology Institute at the University of Minnesota. “They don’t provide much information about how the microbiome is going to change from day to day or person to person.”

In the study, the investigators enrolled 34 participants to record everything they ate for 17 days. Stool samples were collected daily, and shotgun metagenomic sequencing was performed. This allowed the researchers to see at very high resolution how different people’s microbiomes, as well as the enzymes and metabolic functions that they influence, were changing from day to day in response to what they ate. It provided a resource for analyzing the relationships between dietary changes and how the microbiome changes over time.

“We expected that by doing this dense sampling–where you could see what people were eating every single day and what’s happening to their microbiome–we would be able to correlate dietary nutrients with specific strains of microbes, as well as account for the differences in microbiomes between people,” Knights says. “But what we found were not the strong associations we expected. We had to scratch our heads and come up with a new approach for measuring and comparing the different foods.”

What the researchers observed was a much closer correspondence between changes in the diet and the microbiome when they considered how foods were related to each other rather than only their nutritional content. For example, two different types of leafy greens like spinach and kale may have a similar influence on the microbiome, whereas another type of vegetable like carrots or tomatoes may have a very different impact, even if the conventional nutrient profiles are similar. The researchers developed a tree structure to relate foods to each other and share statistical information across closely related foods.

Two people in the study consumed nothing but Soylent, a meal replacement drink that is popular with people who work in technology. Although it was a very small sample, data from these participants showed variation in the microbiome from day to day, suggesting that a monotonous diet doesn’t necessarily lead to a stable microbiome.

“The microbiome has been linked to a broad range of human conditions, including metabolic disorders, autoimmune diseases, and infections, so there is strong motivation to manipulate the microbiome with diet as a way to influence health,” Knights concludes. “This study suggests that it’s more complicated than just looking at dietary components like fiber and sugar. Much more research is needed before we can understand how the full range of nutrients in food affects how the microbiome responds to what we eat.”

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This work was supported by General Mills Inc.

Cell Host & Microbe, Johnson et al.: “Daily longitudinal sampling reveals personalized diet-microbiome associations.” https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(19)30250-1

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Clinical trial shows alternate-day fasting a safe alternative to caloric restriction

Source: Cell Press
Date: 08/27/2019
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In recent years there has been a surge in studies looking at the biologic effects of different kinds of fasting diets in both animal models and humans. These diets include continuous calorie restriction, intermittent fasting, and alternate-day fasting (ADF). Now the largest study of its kind to look at the effects of strict ADF in healthy people has shown a number of health benefits. The participants alternated 36 hours of zero-calorie intake with 12 hours of unlimited eating. The findings are reported August 27 in the journal Cell Metabolism.

“Strict ADF is one of the most extreme diet interventions, and it has not been sufficiently investigated within randomized controlled trials,” says Frank Madeo, a professor of the Institute of Molecular Biosciences at Karl-Franzens University of Graz in Austria. “In this study, we aimed to explore a broad range of parameters, from physiological to molecular measures. If ADF and other dietary interventions differ in their physiological and molecular effects, complex studies are needed in humans that compare different diets.”

In this randomized controlled trial, 60 participants were enrolled for four weeks and randomized to either an ADF or an ad libitum control group, the latter of which could eat as much as they wanted. Participants in both groups were all of normal weight and were healthy. To ensure that the people in the ADF group did not take in any calories during fast days, they underwent continuous glucose monitoring. They were also asked to fill in diaries documenting their fasting days. Periodically, the participants had to go to a research facility, where they were instructed on whether to follow ADF or their usual diet, but other than that they lived their normal, everyday lives.

Additionally, the researchers studied a group of 30 people who had already practiced more than six months of strict ADF previous to the study enrollment. They compared them to normal, healthy controls who had no fasting experience. For this ADF cohort, the main focus was to examine the long-term safety of the intervention.

“We found that on average, during the 12 hours when they could eat normally, the participants in the ADF group compensated for some of the calories lost from the fasting, but not all,” says Harald Sourij, a professor at the Medical University of Graz. “Overall, they reached a mean calorie restriction of about 35% and lost an average of 3.5 kg [7.7 lb] during four weeks of ADF.”

The investigators found several biological effects in the ADF group:

* The participants had fluctuating downregulation of amino acids, in particular the amino acid methionine. Amino acid restriction has been shown to cause lifespan extension in rodents.

  • They had continuous upregulation of ketone bodies, even on nonfasting days. This has been shown to promote health in various contexts.
  • They had reduced levels of sICAM-1, a marker linked to age-associated disease and inflammation.
  • They had lowered levels of triiodothyronine without impaired thyroid gland function. Previously, lowered levels of this hormone have been linked to longevity in humans.
  • They had lowered levels of cholesterol.
  • They had a reduction of lipotoxic android trunk fat mass–commonly known as belly fat.

“Why exactly calorie restriction and fasting induce so many beneficial effects is not fully clear yet,” says Thomas Pieber, head of endocrinology at the Medical University of Graz. “The elegant thing about strict ADF is that it doesn’t require participants to count their meals and calories: they just don’t eat anything for one day.”

The investigators point to other benefits that ADF may have, compared with continuous calorie restriction. Previous studies have suggested calorie-restrictive diets can result in malnutrition and a decrease in immune function. In contrast, even after six months of ADF, the immune function in the participants appeared to be stable.

“The reason might be due to evolutionary biology,” Madeo explains. “Our physiology is familiar with periods of starvation followed by food excesses. It might also be that continuous low-calorie intake hinders the induction of the age-protective autophagy program, which is switched on during fasting breaks.”

Despite the benefits, the researchers say they do not recommend ADF as a general nutrition scheme for everybody. “We feel that it is a good regime for some months for obese people to cut weight, or it might even be a useful clinical intervention in diseases driven by inflammation,” Madeo says. “However, further research is needed before it can be applied in daily practice. Additionally, we advise people not to fast if they have a viral infection, because the immune system probably requires immediate energy to fight viruses. Hence, it is important to consult a doctor before any harsh dietary regime is undertaken.”

In the future, the researchers plan to study the effects of strict ADF in different groups of people including people with obesity and diabetes. They also plan to compare ADF to other dietary interventions and to further explore the molecular mechanisms in animal models.

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The research was primarily funded by the Austrian Science Fund; the Austrian Federal Ministry of Education, Science and Research; the University of Graz, and the field of excellence program BioHealth. Additional funding and declarations of interests can be found in the study.

Cell Metabolism, Stekovic, Hofer, and Tripolt et al.: “Alternate day fasting improves physiological and molecular markers of aging in healthy, non-obese humans.” https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30429-2

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Researchers alter mouse gut microbiomes by feeding good bacteria their preferred fibers

Source: Cell Press
Date: 09/19/2019
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Humans choose food based on the way it looks, smells, and tastes. But the microbes in our guts use a different classification system–one that is based on the molecular components that make up different fibers. In a study published September 19 in the journal Cell, investigators found particular components of dietary fiber that encourage growth and metabolic action of beneficial microbes in the mouse gut.

The research aims to develop ways to identify compounds that can enhance the representation of health-promoting members of the gut microbial community. The goal is to identify sustainable, affordable dietary fiber sources for incorporation into next-generation, more nutritious food products.

“Fiber is understood to be beneficial. But fiber is actually a very complicated mixture of many different components,” says senior author Jeffrey Gordon, a microbiologist at the Washington University School of Medicine in St. Louis. “Moreover, fibers from different plant sources that are processed in different ways during food manufacturing have different constituents. Unfortunately, we lack detailed knowledge of these differences and their biological significance. We do know that modern Western diets have low levels of fiber; this lack of fiber has been linked to loss of important members of the gut community and deleterious health effects.”

The researchers started by testing 34 food-grade fiber preparations, many purified from byproducts of food manufacturing such as peels from fruits and vegetables that are thrown out during production of processed foods and drinks. They used mice initially raised under sterile conditions and then colonized with human gut microbes. The animals were fed a high-fat, low-fiber diet representative of diets typically consumed in the United States, with or without different types of supplemental fibers. The goal was to identify those fibers that were best at boosting the levels of key fiber-degrading bacterial species and promoting the expression of beneficial metabolic enzymes in the microbiome.

Since the mice had been colonized with a defined collection of human gut bacteria with sequenced genomes, the researchers knew all the genes that were present in their model human gut microbial community. This allowed them to perform a comprehensive, high-resolution proteomics study of all bacterial proteins whose expression changed in response to the different fiber types they tested. Combining these results with genetic screens, they were able to identify particular fiber sources, their bioactive molecular components, and the bacterial genes that increased for different Bacteroides species when they encountered different fibers. They focused on Bacteroides because members of this group of bacterial species contain genes responsible for metabolizing dietary fiber that are not present in the human genome.

For the second phase of the study, the investigators wanted to determine how different members of the microbial community interact with each other as they dine on dietary fiber. First author Michael Patnode, a postdoctoral fellow in Gordon’s lab, developed fluorescently labeled artificial food particles with different types of bound carbohydrates from different fibers. Collections of these nutrient-containing particles were fed to mice colonized with defined microbial communities containing different combinations of Bacteroides species.

“We were excited to see how these ‘biosensors’ could be used to assess the processing of particular fiber components by particular bacterial species,” Patnode says. By feeding these particles to mice that either carried or did not carry a dominant fiber-consuming species, the authors found that subordinate species were waiting in line to step up and consume the fiber.

“We had suspected there might be competition going on among the different strains and that some would be stronger competitors than others,” Patnode says. Proteomics analyses and genetic screens confirmed that there was a hierarchy of fiber consumption among the species present in this model bacterial community.

Gordon explains that “it’s important to understand how the presence of a particular organism affects the dining behavior of other organisms–in this case, with regard to different fibers. If we are going to develop microbiota-directed foods aimed at providing benefits to human health, it’s important to find ways to determine which food staples will be the best source of nutrients and how the microbiota will respond.”

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This work was supported by the National Institutes of Health, Mondelez International, and the U.S. Department of Energy. Gordon is a co-founder of Matatu, Inc., a company characterizing the role of diet-by-microbiota interactions in animal health. Elements of this report are the subject of patent applications that are currently being submitted.

Cell, Patnode et al.: “Interspecies competition impacts targeted manipulation of human gut bacteria by fiber-derived glycans” https://www.cell.com/cell/fulltext/S0092-8674(19)30899-2

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Pilot study finds time-restricted eating has benefits for people at risk for diabetes

Source: Cell Press
Date: 12/05/2019
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Previous studies have looked at employing time-restricted eating (TRE), a form of intermittent fasting, as a way to lose weight and improve health measures such as blood sugar and blood pressure in mice and healthy people. But in a study publishing December 5 in the journal Cell Metabolism, researchers for the first time looked at the effects of TRE in people who had been diagnosed with metabolic syndrome and therefore were at a higher risk of diabetes, heart disease, and stroke. The investigators found that when participants restricted their eating to 10 hours or less over a period of 12 weeks, they lost weight and some symptoms of metabolic syndrome improved.

“There has been a lot of discussion about intermittent fasting and what time window people should eat within to get the benefits of this kind of diet,” says co-corresponding author Satchidananda Panda, a Professor at the Salk Institute. “Based on what we’ve observed in mice, a 10-hour time window seems to convey these benefits. At the same time, it’s not so restrictive that people can’t follow it long-term.”

Metabolic syndrome is characterized by having three or more of five specific risk factors: high fasting blood sugar, high blood pressure, high triglyceride levels, low HDL (“good”) cholesterol, and abdominal obesity. People with metabolic syndrome are at greatly increased risk of developing more severe health problems, including diabetes, heart disease, and stroke.

“As a preventive cardiologist, I try to work with my patients and encourage them to make lifestyle changes, but it is very hard to get them to make lasting and meaningful changes,” says co-corresponding author Pam Taub, a cardiologist and Associate Professor of Medicine at the University of California San Diego School of Medicine. “When someone has been diagnosed with metabolic syndrome, this is a critical window for intervention. Once people become diabetic or are on multiple medications such as insulin, it’s very hard to reverse the disease process.”

In the study, 19 individuals with metabolic syndrome were recruited to participate in a program of TRE for three months. They were told they could decide what time to eat and how much to eat as long as all food consumption occurred within a 10-hour window. Most of the people in the study were obese and 84% were taking at least one medication, like a statin or antihypertensive.

At the end of the 12 weeks, the participants had an average of a 3% reduction in their weight and body mass index (BMI) and a 3% reduction in abdominal/visceral fat. Many also had reductions in cholesterol and blood pressure and improvements in fasting glucose.

Participants in the study used an app created by Panda called myCircadianClock (mCC) to log the times they ate and also to track their sleep. They also wore activity monitors that measured their sleeping and waking patterns and a glucose monitor that continuously tracked their glucose levels.

“We told people that they could choose when they ate their meals, as long as they remained within the 10-hour window,” Panda says. “We found that universally, they chose to eat breakfast later, about two hours after waking, and to eat dinner earlier, about three hours before going to bed.” He notes that in addition to the improvements seen in body weight and measures of metabolic syndrome, 70% of the participants also reported an increase in sleep satisfaction or in the amount they slept.

Taub says that the participants, about half of whom were already her patients, also reported generally having more energy, and some were able to have their medications lowered or stopped after completing the study. Overall, they told her that the plan was easier to follow than counting calories or embarking on an exercise program. More than two-thirds of participants continued with TRE for up to a year after the study was over, at least part of the time, she says.

Based on this pilot study, Taub and Panda have already begun a randomized, controlled clinical trial funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to confirm the benefits of TRE in people with metabolic syndrome. They plan to recruit more than 100 participants–half for each arm. They also intend to conduct additional research to look at other physiological responses to TRE, including effects on the mitochondria in skeletal muscle and changes in liver function.

For anyone considering trying TRE, Taub recommends they first consult with a physician. This is especially important for anyone with metabolic syndrome who is already taking medication, she notes. “Any time someone is losing weight, they need to check with their doctor about whether their medications need to be adjusted,” she says. “For instance, if a patient is on blood pressure medications and they lose a significant amount of weight their blood pressure medication needs to be lowered.”

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This study was funded by a University of California San Diego Public Health Pilot Grant, an American College of Cardiology (ACC)/Merck Research Fellowship Award, a Larry L. Hillblom Foundation Postdoctoral Fellowship, a Salk Women in Science Fellowship, the Department of Homeland Security, the Department of Defense, the Leona M. and Harry B. Helmsley Charitable Trust, the Robert Wood Johnson Foundation, and the National Institutes of Health.

Cell Metabolism, Wilkinson et al.: “Ten-hour time-restricted eating reduces weight, blood pressure, and atherogenic lipids in patients with metabolic syndrome” https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30611-4

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Food Safety during COVID-19: What People with Cancer Should Know

Source: Memorial Sloan Kettering
Date: 04/21/2020
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During the COVID-19 pandemic, we’ve been told to wash our hands frequently, sanitize surfaces, and not touch our faces. On top of that, conflicting reports are circulating online about how to safely handle the food that we’re bringing into our homes.

The challenges of safely buying groceries and getting takeout may be even greater for people with cancer and cancer survivors, who often have weakened immune systems. This makes it harder for their bodies to fight off infections, including COVID-19. It’s important that people with cancer closely follow steps to protect themselves while still getting proper nutrition.

Memorial Sloan Kettering clinical dietitian Cara Anselmo offers guidance for people with cancer and their families on how to carefully get and prepare food during the COVID-19 pandemic.

What safety measures should you take while grocery shopping?

If you are in active treatment for cancer or you have a weakened immune system because of a cancer history or other medical conditions, it’s better to have someone else in your household or a neighbor or friend go to the store for you, or use a delivery service. That’s the most important way you can avoid exposure to COVID-19 or other infectious germs.

But if you do have to go to the store, here are some important tips:

  • Take a grocery list. Before you go, figure out exactly what you need so you can get in and get out fast. This also helps minimize the number of shopping trips.
  • Bring sanitizing wipes to disinfect the handle of the shopping cart or basket.
  • Don’t browse with your hands. When you are at the store, avoid touching food or other products that you don’t intend to buy.
  • Cover your face with a scarf or cloth mask. (In early April, the Centers for Disease Control and Prevention recommended that all Americans wear a face covering to protect themselves from COVID-19.) If you need to adjust your mask, be careful not to touch the part that touches your face.
  • Check to see if your store has special hours for people who are immunocompromised and read the store’s policies on how many shoppers are allowed inside at once. While you are in the store, be careful to maintain a proper distance of six feet from others.

Do you need to disinfect your groceries after bringing them into your home?

At this time, experts are not aware of COVID-19 being spread by food or food packaging. But it’s still important to carefully wash your hands before and after grocery shopping. You should also wash your hands after putting your groceries away.

If you are concerned about the surfaces of packages, you can use disinfectant products to wipe them off. Fresh fruits and vegetables should be carefully washed with running water. Never use Lysol or bleach on fruits and vegetables, since the chemicals could be ingested.

How can you safely get takeout or food delivery from restaurants?

A lot of the advice for grocery shopping is the same for getting takeout or delivery: You should wash your hands before and after touching bags and food packages from restaurants, and before eating.

If you are picking up takeout, make sure you maintain safe distances. If you are getting delivery, pay in advance and ask the delivery person to leave the food outside your door to minimize person-to-person contact.

With either takeout or delivery, you should always transfer food to your own plates and dishes.

People whose immune systems are compromised by cancer or cancer treatment should be careful about eating certain foods from restaurants. This includes things like prepared salads, cut fruit, and deli meats. This is important to avoid food poisoning and not specifically because of COVID-19.

Do you have tips for healthy eating during the COVID-19 pandemic?

If you can’t get fresh produce, frozen or canned fruits and vegetables can be just as healthy. If you normally buy organic foods and you are not able to get them, don’t worry. Organic foods are not necessarily healthier or safer than conventional foods.

In this time of stress and uncertainty, it’s especially important to practice mindful eating. That means you should only eat when you’re hungry. Don’t eat so much that you feel too full. Do the best you can to include plenty of fruits and vegetables, but give yourself permission to eat what tastes good and feels good in your body. There’s no such thing as a perfect diet.

Some dietary supplements are claiming that they improve your immune function and offer protection against COVID-19. What do we know about these products?

Some of these products may be dangerous and potentially even life-threatening. The government has issued warning letters to many companies making these claims about their products.

There have been claims that some familiar supplements, including vitamin C and zinc, may “boost” your immune system. Some studies show that these supplements stimulate the immune system, but the evidence is inconclusive. They can also lead to unwanted effects.

Make sure you talk to your doctor, nurse, or registered dietitian before taking any supplements. Some of these products may also interfere with cancer treatment.

The best way to keep your immune system strong is to eat a balanced diet, limit alcohol, stay hydrated, manage stress, stay as physically active as you can, and get enough sleep.

During this difficult time, many people may be struggling to put food on the table. What are some good resources for MSK patients and their families?

MSK’s Food to Overcome Outcome Disparities program connects patients with a variety of emergency food resources. This includes a food pantry that MSK operates for patients and their families. If you would like more information, you can discuss it with your MSK care team or call MSK’s nutrition office at 212-639-7312.

New York City is offering three free meals per day for both children and adults, with pickup at more than 400 sites. People who are age 60 and older and need assistance can also get home-delivered meals. 

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Artificial sweeteners combined with carbs may be more harmful than those sweeteners alone

Source: Cell Press
Date: 03/03/2020
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The influence of artificial sweeteners on the brain and ultimately metabolism has been hotly debated in recent years. Some studies have found adverse effects on blood sugar and insulin levels, while others have not. In a study publishing March 3 in the journal Cell Metabolism, researchers say the discrepancies in these studies may be due to how the sweeteners are consumed–or, more specifically, what they are consumed with.

Investigators report that the artificial sweetener sucralose seems to have no negative impact on its own, but when it is consumed with a carbohydrate, it induces deleterious changes in insulin sensitivity and decreases the brain’s response to sweet taste as measured by fMRI.

“When we set out to do this study, the question that was driving us was whether or not repeated consumption of an artificial sweetener would lead to a degrading of the predictive ability of sweet taste,” says senior author Dana Small, a neuroscientist who is a professor of psychiatry and the director of the Modern Diet and Physiology Research Center at Yale University. “This would be important because sweet-taste perception might lose the ability to regulate metabolic responses that prepare the body for metabolizing glucose or carbohydrates in general.”

The trial enrolled 45 volunteers between the ages of 20 and 45 who didn’t normally consume low-calorie sweeteners. All of them were of healthy weight and had no metabolic dysfunction. Other than consuming seven beverages in the lab over a two-week period, they didn’t make any changes to their diet or other habits. The investigators conducted studies on the volunteers before, during, and after the testing period, including performing fMRI scans to look at changes in the brain in response to sweet tastes, as well as other tastes like salty and sour. They also measured taste perception and did an oral glucose tolerance test to look at insulin sensitivity.

The sweeteners were consumed as fruit-flavored beverages with added sucralose, or with table sugar for comparison. In what was intended to be a control group: some of the volunteers had the carbohydrate maltodextrin added to their sucralose drinks. The researchers chose maltodextrin, a non-sweet carbohydrate, to control for the calories of sugar without adding more sweet taste to the beverage. Surprisingly, it was this control group that showed changes in the brain’s response to sweet taste and the body’s insulin sensitivity and glucose metabolism. Given the surprising result, the researchers added a second control group, in which the participants drank beverages with maltodextrin alone. They found no evidence that consuming maltodextrin-containing beverages over the seven-day period alters insulin sensitivity and glucose metabolism.

“Perhaps the effect resulted from the gut generating inaccurate messages to send to the brain about the number of calories present,” Small says. “The gut would be sensitive to the sucralose and the maltodextrin and signal that twice as many calories are available than are actually present. Over time, these incorrect messages could produce negative effects by altering the way the brain and body respond to sweet taste.”

She notes that a subset of the previous studies of artificial sweeteners have involved mixing the sweeteners with plain yogurt, adding carbohydrates from the yogurt and leading to the same effects seen here as with the maltodextrin. This could explain why previous findings about artificial sweeteners have been in conflict with each other.

Small says that her team began doing similar studies in adolescents, but they ended the trial early when they saw that two of the kids who were getting the sucralose-carbohydrate combination had their fasting insulin skyrocket.

“Previous studies in rats have shown that changes in the ability to use sweet taste to guide behavior can lead to metabolic dysfunction and weight gain over time. We think this is due to the consumption of artificial sweeteners with energy,” she notes.

Future studies will look at whether other artificial sweeteners, as well as more natural sweeteners like stevia, have the same effects as sucralose. Small expects that many of them will. “It’s hard to say, because we still don’t fully understand the mechanism,” she concludes. “That’s also something we hope to study further, especially in mice.”

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This work was supported by the National Institutes of Health.

Cell Metabolism, Dalenberg et al.: “Short-term consumption of sucralose with, but not without, carbohydrate impairs neural and metabolic sensitivity to sugar” https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30057-7

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Inactivity in obese mice linked to a decreased motivation to move

Source: Cell Press
Date: 12/29/16
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Starting a regular program at the gym is a common New Year’s resolution, but it’s one that most people are unable to stick with for very long. Now a study done in mice is providing clues about one of the reasons why it may be hard for so many people to stick with an exercise program. The investigators found that in obese mice, physical inactivity results from altered dopamine receptors rather than excess body weight. The report appears in Cell Metabolism on December 29.

“We know that physical activity is linked to overall good health, but not much is known about why people or animals with obesity are less active,” says the study’s senior author Alexxai V. Kravitz, an investigator in the Diabetes, Endocrinology, and Obesity Branch at the National Institute of Diabetes and Digestive and Kidney Diseases–part of the National Institutes of Health. “There’s a common belief that obese animals don’t move as much because carrying extra body weight is physically disabling. But our findings suggest that assumption doesn’t explain the whole story.”

Kravitz has a background in studying Parkinson’s disease, and when he began conducting obesity research a few years ago, he was struck by similarities in behavior between obese mice and Parkinsonian mice. Based on that observation, he hypothesized that the reason the mice were inactive was due to dysfunction in their dopamine systems.

“Other studies have connected dopamine signaling defects to obesity, but most of them have looked at reward processing–how animals feel when they eat different foods,” Kravitz says. “We looked at something simpler: dopamine is critical for movement, and obesity is associated with a lack of movement. Can problems with dopamine signaling alone explain the inactivity?”

In the study, mice were fed either a standard or a high-fat diet for 18 weeks. Beginning in the second week, the mice on the unhealthy diet had higher body weight. By the fourth week, these mice spent less time moving and got around much more slowly when they did move. Surprisingly, the mice on high-fat diet moved less before they gained the majority of the weight, suggesting that the excess weight alone was not responsible for the reduced movements.

The investigators looked at six different components in the dopamine signaling pathway and found that the obese, inactive mice had deficits in the D2 dopamine receptor. “There are probably other factors involved as well, but the deficit in D2 is sufficient to explain the lack of activity,” says Danielle Friend, first author and former NIDDK postdoctoral fellow.

The team also studied the connection between inactivity and weight gain, to determine if it was causative. By studying lean mice that were engineered to have the same defect in the D2 receptor, they found that those mice did not gain weight more readily on a high-fat diet, despite their lack of inactivity, suggesting that weight gain was compounded once the mice start moving less.

“In many cases, willpower is invoked as a way to modify behavior,” Kravitz says. “But if we don’t understand the underlying physical basis for that behavior, it’s difficult to say that willpower alone can solve it.”

He adds that if we begin to decipher the physiological causes for why people with obesity are less active, it may also help reduce some of the stigma that they face. Future research will focus on how unhealthy eating affects dopamine signaling. The researchers also plan to look at how quickly the mice recover to normal activity levels once they begin eating a healthy diet and losing weight.

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Diabetic mice on fasting-mimicking diet repair insulin-producing pancreas cells

Source: Cell Press
Date: 02/23/17
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Research in mice and human cells suggests that a fasting-mimicking diet may reprogram pancreas cells that are unable to produce insulin and enable them to repair themselves and start making it. The work, published February 23 in Cell, provides an alternative approach to replacing damaged insulin-producing beta cells.

“Our conclusion is that by pushing the mice into an extreme state and then bringing them back–by starving them and then feeding them again–the cells in the pancreas are triggered to use some kind of developmental reprogramming that rebuilds the part of the organ that’s no longer functioning,” says senior author Valter Longo of the University of Southern California School of Gerontology and Director of the USC Longevity Institute.

Longo originally developed the fasting-mimicking diet as a way to reduce stress and protect from toxicity in people undergoing chemotherapy. It involves consuming a very limited number of high-fat calories for five days and then returning to a normal diet. Measurement of four biomarkers associated with a water-only diet suggested that the diet has the same physiological effects on the body as more extreme fasting.

Studies since then have suggested that the diet may be a way to “reboot” the body by inducing it to slow down aging and regenerating new cells. Researchers have found that the expression of three key genes drops during the fasting-mimicking diet. These genes–IGF1, TOR, and PKA–are associated with stress and aging.

In the latest study, the researchers hypothesize that the downregulation of these three genes reprograms the cells so that they return to an embryonic-like state, in which they have the potential to give rise to a number of different cell types. “During starvation, the cells go into standby mode,” Longo says. “Then, when you begin refeeding the mice, you see these embryonic-like cells begin to give rise to beta cells.”

The researchers used two different mouse models of diabetes to study the effects of the diet. One was mice with a gene mutation that causes insulin resistance and loss of insulin secretion. The other was mice that were treated with a chemical to destroy their beta cells. Both models were given three cycles of the diet.

“Medically, these findings have the potential to be very important because we’ve shown–at least in mouse models–that you can use diet to reverse the symptoms of diabetes,” Longo says. “Scientifically, the findings are perhaps even more important because we’ve shown that you can use diet to reprogram cells without having to make any genetic alterations.” In addition to looking at mouse models of diabetes, the researchers also showed that exposure of human pancreatic islet cells–both from healthy donors and from patients with Type 1 diabetes–to fasting-mimicking diet in a dish stimulated insulin production.

Much research is needed before the findings can be validated in humans, but Longo says these clinical trials are already being planned. In Science Translational Medicine (DOI: 10.1126/scitranslmed.aai8700) on February 15, his team published a related, randomized Phase II study in 100 people that showed that when humans were exposed to three rounds of the fasting-mimicking diet, their IGF1 levels decreased and their fasting glucose levels improved, among other findings.

Longo says the findings also have implications for diseases beyond diabetes. “We want to start looking system by system to see how widely acting this process is on different types of cells,” he says. “The amazing thing is that this system has probably always been there. Now that we’ve discovered it, we can find ways to work with it and utilize it for benefits to human health.”