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Why When You Eat Might Be as Important as What You Eat

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Fasting and eating schedule
Adapted from Wilkinson MJ, Cell Metab, 2019

About 1 in 3 American adults have metabolic syndrome, a group of early warning signs for increased risk of type 2 diabetes, heart disease, and stroke. To help avoid such health problems, these folks are often advised to pay close attention to the amount and type of foods they eat. And now it seems there may be something else to watch: how food intake is spaced over a 24-hour period.

In a three-month pilot study, NIH-funded researchers found that when individuals with metabolic syndrome consumed all of their usual daily diet within 10 hours—rather than a more customary span of about 14 hours—their early warning signs improved. Not only was a longer stretch of daily fasting associated with moderate weight loss, in some cases, it was also tied to lower blood pressure, lower blood glucose levels, and other improvements in metabolic syndrome.

The study, published in Cell Metabolism, is the result of a joint effort by Satchidananda Panda, Salk Institute for Biological Sciences, La Jolla, CA, and Pam R. Taub, University of California, San Diego [1]. It was inspired by Panda’s earlier mouse studies involving an emerging dietary intervention, called time-restricted eating (TRE), which attempts to establish a consistent daily cycle of feeding and fasting to create more stable rhythms for the body’s own biological clock [2, 3].

But would observations in mice hold true for humans? To find out, Panda joined forces with Taub, a cardiologist and physician-scientist. The researchers enlisted 19 men and women with metabolic syndrome, defined as having three or more of five specific risk factors: high fasting blood glucose, high blood pressure, high triglyceride levels, low “good” cholesterol, and/or extra abdominal fat. Most participants were obese and taking at least one medication to help manage their metabolic risk factors.

In the study, participants followed one rule: eat anything that you want, just do so over a 10-hour period of your own choosing. So, for the next three months, these folks logged their eating times and tracked their sleep using a special phone app created by the research team. They also wore activity and glucose monitors.

By the pilot study’s end, participants following the 10-hour limitation had lost on average 3 percent of their weight and about 3 percent of their abdominal fat. They also lowered their cholesterol and blood pressure. Although this study did not find 10-hour TRE significantly reduced blood glucose levels in all participants, those with elevated fasting blood glucose did have improvement. In addition, participants reported other lifestyle improvements, including better sleep.

The participants generally saw their metabolic health improve without skipping meals. Most chose to delay breakfast, waiting about two hours after they got up in the morning. They also ate dinner earlier, about three hours before going to bed—and then did no late night snacking.

After the study, more than two-thirds reported that they stuck with the 10-hour eating plan at least part-time for up to a year. Some participants were able to cut back or stop taking cholesterol and/or blood-pressure-lowering medications.

Following up on the findings of this small study, Taub will launch a larger NIH-supported clinical trial involving 100 people with metabolic syndrome. Panda is now exploring in greater detail the underlying biology of the metabolic benefits observed in the mice following TRE.

For people looking to improve their metabolic health, it’s a good idea to consult with a doctor before making significant changes to one’s eating habits. But the initial data from this study indicate that, in addition to exercising and limiting portion size, it might also pay to watch the clock.

References:

[1] Ten-hour time-restricted eating reduces weight, blood pressure, and atherogenic lipids in patients with metabolic syndrome. Wilkinson MJ, Manoogian ENC, Zadourian A, Lo H, Fakhouri S, Shoghi A, Wang X, Fleisher JG, Panda S, Taub PR. Cell Metab. 2019 Jan 7; 31: 1-13. Epub 2019 Dec 5.

[2] Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. Hatori M, Vollmers C, Zarrinpar A, DiTacchio L, Bushong EA, Gill S, Leblanc M, Chaix A, Joens M, Fitzpatrick JA, Ellisman MH, Panda S. Cell Metab. 2012 Jun 6;15(6):848-60.

[3] Time-restricted feeding is a preventative and therapeutic intervention against diverse nutritional challenges. Chaix A, Zarrinpar A, Miu P, Panda S. Cell Metab. 2014 Dec 2;20(6):991-1005.

Links:

Metabolic Syndrome (National Heart, Lung, and Blood Institute/NIH)

Obesity (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)

Body Weight Planner (NIDDK/NIH)

Satchidananda Panda (Salk Institute for Biological Sciences, La Jolla, CA)

Taub Research Group (University of California, San Diego)

NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases


Targeting the Microbiome to Treat Malnutrition

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Caption: A Bangladeshi mother and child in the Nutritional Rehabilitation Unit.
Credit: International Centre for Diarrhoeal Disease Research, Bangladesh

A few years ago, researchers discovered that abnormalities in microbial communities, or microbiomes, in the intestine appear to contribute to childhood malnutrition. Now comes word that this discovery is being translated into action, with a new study showing that foods formulated to repair the “gut microbiome” may help malnourished kids rebuild their health [1].

In a month-long clinical trial in Bangladesh, 63 children received either regular foods to treat malnutrition or alternative formulations for needed calories and nutrition that also encouraged growth of beneficial microbes in the intestines. The kids who ate the microbiome-friendly diets showed improvements in their microbiome, which helps to extract and metabolize nutrients in our food to help the body grow. They also had significant improvements in key blood proteins associated with bone growth, brain development, immunity, and metabolism; those who ate standard therapeutic food did not experience the same benefit.

Globally, malnutrition affects an estimated 238 million children under the age 5, stunting their normal growth, compromising their health, and limiting their mental development [2]. Malnutrition can arise not only from a shortage of food but from dietary imbalances that don’t satisfy the body’s need for essential nutrients. Far too often, especially in impoverished areas, the condition can turn extremely severe and deadly. And the long term effects on intellectual development can limit the ability of a country’s citizens to lift themselves out of poverty.

Jeffrey Gordon, Washington University School of Medicine in St. Louis, and his NIH-supported research team have spent decades studying what constitutes a normal microbiome and how changes can affect health and disease. Their seminal studies have revealed that severely malnourished kids have “immature” microbiomes that don’t develop in the intestine like the microbial communities seen in well nourished, healthy children of the same age.

Gordon and team have also found that this microbial immaturity doesn’t resolve when kids consume the usual supplemental foods [3]. In another study, they turned to mice raised under sterile conditions and with no microbes of their own to demonstrate this cause and effect. The researchers colonized the intestines of the germ-free mice with microbes from malnourished children, and the rodents developed similar abnormalities in weight gain, bone growth, and metabolism [4].

All of this evidence raised a vital question: Could the right combination of foods “mature” the microbiome and help to steer malnourished children toward a healthier state?

To get the answer, Gordon and his colleagues at the International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh, led by Tahmeed Ahmed, first had to formulate the right, microbiome-friendly food supplements, and that led to some interesting science. They carefully characterized over time the immature microbiomes found in Bangladeshi children treated for severe malnutrition. This allowed them to test their new method for analyzing how individual microbial species fluctuate over time and in relationship to one another in the intestine [5]. The team then paired up these data with measurements of a set of more than 1,300 blood proteins from the children that provide “readouts” of their biological state.

Their investigation identified a network of 15 bacterial species that consistently interact in the gut microbiomes of Bangladeshi children. This network became their means to characterize sensitively and accurately the development of a child’s microbiome and/or its relative state of repair.

Next, they turned to mice colonized with the same collections of microbes found in the intestines of the Bangladeshi children. Gordon’s team then tinkered with the animals’ diets in search of ingredients commonly consumed by young children in Bangladesh that also appeared to encourage a healthier, more mature microbiome. They did similar studies in young pigs, whose digestive and immune systems more closely resemble humans.

The Gordon team settled on three candidate microbiome-friendly formulations. Two included chickpea flour, soy flour, peanut flour, and banana at different concentrations; one of these two also included milk powder. The third combined chickpea flour and soy flour. All three contained similar amounts of protein, fat, and calories.

The researchers then launched a randomized, controlled clinical trial with children from a year to 18 months old with moderate acute malnutrition. These young children were enrolled into one of four treatment groups, each including 14 to 17 kids. Three groups received one of the newly formulated foods. The fourth group received standard rice-and-lentil-based meals.

The children received these supplemental meals twice a day for four weeks at the International Centre for Diarrhoeal Disease Research followed by two-weeks of observation. Mothers were encouraged throughout the study to continue breastfeeding their children.

The formulation containing chickpea, soy, peanut, and banana, but no milk powder, stood out above the rest in the study. Children taking this supplement showed a dramatic shift toward a healthier state as measured by those more than 1,300 blood proteins. Their gut microbiomes also resembled those of healthy children their age.

Their new findings published in the journal Science offer the first evidence that a therapeutic food, developed to support the growth and development of a healthy microbiome, might come with added benefits for children suffering from malnutrition. Importantly, the researchers took great care to design the supplements with foods that are readily available, affordable, culturally acceptable, and palatable for young children in Bangladesh.

A month isn’t nearly long enough to see how the new foods would help children grow and recover over time. So, the researchers are now conducting a much larger study of their leading supplement in children with histories of malnutrition, to explore its longer-term health effects for them and their microbiomes. The hope is that these new foods and others adapted for use around the world soon will help many more kids grow up to be healthy adults.

References:

[1] Effects of microbiota-directed foods in gnotobiotic animals and undernourished children. Gehrig JL, Venkatesh S, Chang HW, Hibberd MC, Kung VL, Cheng J, Chen RY, Subramanian S, Cowardin CA, Meier MF, O’Donnell D, Talcott M, Spears LD, Semenkovich CF, Henrissat B, Giannone RJ, Hettich RL, Ilkayeva O, Muehlbauer M, Newgard CB, Sawyer C, Head RD, Rodionov DA, Arzamasov AA, Leyn SA, Osterman AL, Hossain MI, Islam M, Choudhury N, Sarker SA, Huq S, Mahmud I, Mostafa I, Mahfuz M, Barratt MJ, Ahmed T, Gordon JI. Science. 2019 Jul 12;365(6449).

[2] Childhood Malnutrition. World Health Organization

[3] Persistent gut microbiota immaturity in malnourished Bangladeshi children. Subramanian S, Huq S, Yatsunenko T, Haque R, Mahfuz M, Alam MA, Benezra A, DeStefano J, Meier MF, Muegge BD, Barratt MJ, VanArendonk LG, Zhang Q, Province MA, Petri WA Jr, Ahmed T, Gordon JI. Nature. 2014 Jun 19;510(7505):417-21.

[4] Gut bacteria that prevent growth impairments transmitted by microbiota from malnourished children. Blanton LV, Charbonneau MR, Salih T, Barratt MJ, Venkatesh S, Ilkaveya O, Subramanian S, Manary MJ, Trehan I, Jorgensen JM, Fan YM, Henrissat B, Leyn SA, Rodionov DA, Osterman AL, Maleta KM, Newgard CB, Ashorn P, Dewey KG, Gordon JI. Science. 2016 Feb 19;351(6275).

[5] A sparse covarying unit that describes healthy and impaired human gut microbiota development. Raman AS, Gehrig JL, Venkatesh S, Chang HW, Hibberd MC, Subramanian S, Kang G, Bessong PO, Lima AAM, Kosek MN, Petri WA Jr, Rodionov DA, Arzamasov AA, Leyn SA, Osterman AL, Huq S, Mostafa I, Islam M, Mahfuz M, Haque R, Ahmed T, Barratt MJ, Gordon JI. Science. 2019 Jul 12;365(6449).

Links:

Childhood Nutrition Facts (Centers for Disease Control and Prevention)

Gordon Lab (Washington University School of Medicine in St. Louis)

NIH Human Microbiome Project

International Centre for Diarrhoeal Disease Research (Dhaka, Bangladesh)

NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of General Medical Sciences; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Center for Advancing Translational Sciences; National Cancer Institute


Ultra-Processed Diet Leads to Extra Calories, Weight Gain

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Dietary Weight Gain and Loss
Credit: Hall et al., Cell Metabolism, 2019

If you’ve ever tried to lose a few pounds or just stay at a healthy weight, you’ve likely encountered a dizzying array of diets, each with passionate proponents: low carb, low fat, keto, paleo, vegan, Mediterranean, and so on. Yet most nutrition experts agree on one thing: it’s best to steer clear of ultra-processed foods. Now, there’s some solid scientific evidence to back up that advice.

In the first randomized, controlled study to compare the effects of ultra-processed with unprocessed foods, NIH researchers found healthy adults gained about a pound per week when they were given a daily diet high in ultra-processed foods, which often contain ingredients such as hydrogenated fats, high fructose corn syrup, flavoring agents, emulsifiers, and preservatives. In contrast, when those same people ate unprocessed whole foods, they lost weight.

Intriguingly, the weight differences on the two diets occurred even though both kinds of foods had been carefully matched from a nutritional standpoint, including calorie density, fiber, fat, sugar, and salt. For example, breakfast for the ultra-processed group might consist of a bagel with cream cheese and turkey bacon, while the unprocessed group might be offered oatmeal with bananas, walnuts, and skim milk.

The explanation for the differences appears to lie in the fact that study participants were free to eat as little or as much food as they wished at mealtimes and to snack between meals. It turns out that when folks were on the ultra-processed diet they ate significantly more—about 500 extra calories per day on average—than when they were on the unprocessed diet. And, as you probably know, more calories without more exercise usually leads to more weight!

This might not seem new to you. After all, it has been tempting for some time to suggest a connection between the rise of packaged, ultra-processed foods and America’s growing waistlines. But as plausible as it might seem that such foods may encourage overeating, perhaps because of their high salt, sugar, and fat content, correlation is not causation and controlled studies of what people actually eat are tough to do. As a result, definitive evidence directly tying ultra-processed foods to weight gain has been lacking.

To explore the possible connection in the study now reported in Cell Metabolism, researchers at NIH’s National Institute of Diabetes and Digestive and Kidney Diseases took advantage of the Metabolic Clinical Research Unit at the NIH Clinical Center, Bethesda, MD. The unit is specially equipped to study issues involving diet and metabolism.

The researchers asked 20 healthy men and women of stable weight to stay at the center for 28 days. Each volunteer was randomly assigned to eat either an ultra-processed or unprocessed diet for two consecutive weeks. At that point, they switched to the other diet for another two weeks.

Both diets consisted of three daily meals, and volunteers were given permission to eat as much food as they liked. Importantly, a team of dieticians had carefully designed the ultra-processed and unprocessed meals such that they were well matched for total calories, calorie density, macronutrients, fiber, sugars, and salt.

At lunch, for example, one of the study’s processed meals consisted of quesadillas, refried beans, and diet lemonade. An unprocessed lunch consisted of a spinach salad with chicken breast, apple slices, bulgur, and sunflower seeds with a side of grapes.

The main difference between each diet was the proportion of calories derived from ultra-processed versus unprocessed foods as defined by the NOVA diet classification system. This system categorizes food based on the nature, extent, and purpose of food processing, rather than its nutrient content.

Each week, researchers measured the energy expenditure, weight, and changes in body composition of all volunteers. After two weeks on the ultra-processed diet, volunteers gained about two pounds on average. That’s compared to a loss of about two pounds for those on the unprocessed diet.

Metabolic testing showed that people expended more energy on the ultra-processed diet. However, that wasn’t enough to offset the increased consumption of calories. As a result, participants gained pounds and body fat. The study does have some limitations, such as slight differences in the protein content of the two diets. and the researchers plan to address such issues in their future work.

During this relatively brief study, the researchers did not observe other telltale changes associated with poor metabolic health, such as a rise in blood glucose levels or fat in the liver. While a couple of pounds might not sound like much, the extra calories and weight associated with an ultra-processed diet would, over time, add up.

So, it appears that a good place to start in reaching or maintaining a healthy weight is to follow the advice shared by all those otherwise conflicting diet plans: work to eliminate or at least reduce ultra-processed foods in your diet in favor of a balanced variety of unprocessed, nutrient-packed foods.

Reference:

[1] Ultra-processed diets cause excess calorie intake and weight gain: An inpatient randomized controlled trial of ad libitum food intake. Hall KD et al. Cell Metab. 2019 May 16.

Links:

Obesity (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)

Healthy Eating Plan (National Heart, Lung, and Blood Institute/NIH)

Body Weight Planner (NIDDK/NIH)

Kevin D. Hall (NIDDK/NIH)

Metabolic Clinical Research Unit (NIDDK/NIH)

NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases


‘Exercise Hormone’ Tied to Bone-Strengthening Benefits

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Exercise
Credit: gettyimages/kali9

There’s no doubt that exercise is good for us—strengthening our muscles, helping us maintain a healthy weight, maybe even boosting our moods and memories. There’s also been intriguing evidence that exercise may help build strong bones.

Now, an NIH-funded study is shedding light on the mechanism behind exercise’s bone-strengthening benefits [1]. The new work—which may lead to new approaches for treating osteoporosis, a disease that increases the risk of bone fracture—centers on a hormone called irisin that is secreted by muscles during exercise.

In a series of mouse experiments, the researchers found that irisin works directly on a common type of bone cell, stimulating the cells to produce a protein that encourages bones to thin. However, this chain of molecular events ultimately takes a turn for the better and reverses bone loss.

Bruce Spiegelman’s lab at the Dana-Farber Cancer Institute and Harvard University Medical School, Boston, first discovered the irisin hormone in 2012 [2]. In the years since, evidence has accumulated suggesting a connection between irisin and many of the benefits that come with regular workouts. For example, delivering low doses of irisin—sometimes called “the exercise hormone”—increase bone density and strength in mice.

But how does irisin act on bones? The answer hasn’t been at all clear. A major reason is the protein receptor on our cells that binds and responds to irisin wasn’t known.

In the new study reported in the journal Cell, Spiegelman’s team has now identified irisin’s protein receptor, called αVβ5 integrin. Those receptors are present on the surface of osteocytes, the most common cell type found in mature bone tissue.

The researchers went on to show that irisin helps osteocytes to live longer. It also leads the bone cells to begin secreting a protein called sclerostin, known for its role in preparing bones for remodeling and rebuilding by first breaking them down. Interestingly, previous studies also showed sclerostin levels increase in response to the mechanical stresses that come with exercise.

To further explore the role of irisin in mouse studies, the researchers gave the animals the hormone for six days. And indeed, after the treatment, the animals showed higher levels of sclerostin in their blood.

The findings suggest that irisin could form the basis of a new treatment for osteoporosis, a condition responsible for almost nine million fractures around the world each year. While it might seem strange that a treatment intended to strengthen bone would first encourage them to break down, this may be similar to the steps you have to follow when fixing up a house that has weakened timbers. And Spiegelman notes that there’s precedent for such a phenomenon in bone remodeling—treatment for osteoporosis, parathyroid hormone, also works by thinning bones before they are rebuilt.

That said, it’s not yet clear how best to target irisin for strengthening bone. In fact, locking in on the target could be a little complicated. The Speigelman lab found, for example, that mice prone to osteoporosis following the removal of their ovaries were paradoxically protected from weakening bones by the inability to produce irisin.

This new study fits right in with other promising NIH-funded efforts to explore the benefits of exercise. One that I’m particularly excited about is the Molecular Transducers of Physical Activity Consortium (MoTrPAC), which aims to develop a comprehensive map of the molecular changes that arise with physical activity, leading to a range of benefits for body and mind.

Indeed, the therapeutic potential for irisin doesn’t end with bone. In healthy people, irisin circulates throughout the body. In addition to being produced in muscle, its protein precursor is produced in the heart and brain.

The hormone also has been shown to transform energy-storing white fat into calorie-burning brown fat. In the new study, Spiegelman’s team confirms that this effect on fat also depends on the very same integrin receptors present in bone. So, these new findings will no doubt accelerate additional study in Speigelman’s lab and others to explore the many other benefits of irisin—and of exercise—including its potential to improve our moods, memory, and metabolism.

References:

[1] Irisin Mediates Effects on Bone and Fat via αV Integrin Receptors. Kim H, Wrann CD, Jedrychowski M, Vidoni S, Kitase Y, Nagano K, Zhou C, Chou J, Parkman VA, Novick SJ, Strutzenberg TS, Pascal BD, Le PT, Brooks DJ, Roche AM, Gerber KK, Mattheis L, Chen W, Tu H, Bouxsein ML, Griffin PR, Baron R, Rosen CJ, Bonewald LF, Spiegelman BM. Cell. 2018 Dec 13;175(7):1756-1768. 

[2] A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbach KA, Boström EA, Choi JH, Long JZ, Kajimura S, Zingaretti MC, Vind BF, Tu H, Cinti S, Højlund K, Gygi SP, Spiegelman BM. Nature. 2012 Jan 11;481(7382):463-8.

Links:

Osteoporosis (NIH)

Guide to Physical Activity (National Heart, Lung, and Blood Institute/NIH)

Spiegelman Lab (Dana-Farber Cancer Institute, Boston)

Molecular Transducers of Physical Activity in Humans (Common Fund/NIH)

Video: MoTrPAC (Common Fund)

NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; National Institute on Aging; National Institute of Neurological Disorders and Stroke


Has an Alternative to Table Sugar Contributed to the C. Diff. Epidemic?

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Ice cream sundae

Thinkstock/piyaphat50

Most of us know how hard it is to resist the creamy sweetness of ice cream. But it might surprise you to learn that, over the past 15 years or so, some makers of ice cream and many other processed foods—from pasta to ground beef products—have changed their recipes to swap out some of the table sugar (sucrose) with a sweetening/texturizing ingredient called trehalose that depresses the freezing point of food. Both sucrose and trehalose are “disaccharides.” Though they have different chemical linkages, both get broken down into glucose in the body. Now, comes word that this switch may be an important piece of a major medical puzzle: why Clostridium difficile (C. diff) has emerged as a leading cause of hospital-acquired infections.

A new study in the journal Nature indicates that trehalose-laden food may have helped fuel the recent epidemic spread of C. diff., which is a microbe that can cause life-threatening gastrointestinal distress, especially in older patients getting antibiotics and antacid medicines [1, 2]. In laboratory experiments, an NIH-funded team found that the two strains of C. diff. most likely to make people sick possess an unusual ability to thrive on trehalose, even at very low levels. And that’s not all: a diet containing trehalose significantly increased the severity of symptoms in a mouse model of C. diff. infection.


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