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A Study Finds That People With Low BMI Aren’t More Active

Source: Cell Press
Date: 8/27/2022
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The majority of obesity research to date has concentrated on examining people with high body mass indexes (BMI), but a Chinese research team is using a different strategy. In a study that was published in the journal Cell Metabolism, the researchers focused on those with very low BMIs. Contrary to the belief that they have a metabolism that makes them inherently more active, their data show that these individuals are really much less active than those with a BMI in the usual range. They also consume less food than those with a normal BMI.

“We expected to find that these people are really active and to have high activity metabolic rates matched by high food intakes,” says corresponding author John Speakman, a professor at the Shenzhen Institutes of Advanced Technology in China and the University of Aberdeen in the UK. “It turns out that something rather different is going on. They had lower food intakes and lower activity, as well as surprisingly higher-than-expected resting metabolic rates linked to elevated levels of their thyroid hormones.”

150 participants who were “healthy underweight” (with a BMI below 18.5) and 173 people with normal BMIs (range 21.5 to 25) were recruited by the researchers. They screened out individuals with eating problems, those who claimed to have purposefully restricted their eating, and those who were HIV-positive. Additionally, they disqualified those who had lost weight recently that may have been caused by an illness or who were using any form of medicine. Only 4 out of 150 people claimed to “exercise in a driven way,” but they did not exclude them.The participants were observed for two weeks. Their food intake was determined using the doubly-labeled water method, an isotope-based approach that gauges energy expenditure by comparing the turnover rates of hydrogen and oxygen in body water as a function of carbon dioxide production. Their physical activity was tracked using an accelerometry-based motion detector.

The investigators found that compared with a control group that had normal BMIs, the healthy underweight individuals consumed 12% less food. They were also considerably less active, by 23%. At the same time, these individuals had higher resting metabolic rates, including elevated resting energy expenditure and elevated thyroid activity.

“Although these very lean people had low levels of activity, their markers of heart health, including cholesterol and blood pressure, were very good,” says first author Sumei Hu, currently at the Beijing Technology and Business University. “This suggests that low body fat may trump physical activity when it comes to downstream consequences.”

The investigators acknowledge some limitations of this research, including the fact that although they measured food intake, they didn’t measure what the participants were actually eating or their feelings of satiation or satiety.

The team is now expanding its research, including studies that include these measures. They also plan to look at genetic differences between normal weight and healthy underweight individuals. Preliminary analysis suggests single nucleotide polymorphisms in certain genes that might play a role. When these genetic changes were replicated in mice, the animals had some aspects of the phenotype that was observed in human subjects.

“The next stage is to understand more about the phenotype itself and understand the mechanisms that generate it more clearly,” says Speakman.

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Researchers call for a focus on fitness over weight loss for obesity-related health conditions

Source: Cell Press
Date: 9/20/2021
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The prevalence of obesity around the world has tripled over the past 40 years, and, along with that rise, dieting and attempts to lose weight also have soared. But according to a review article publishing September 20 in the journal iScience, when it comes to getting healthy and reducing mortality risk, increasing physical activity and improving fitness appear to be superior to weight loss. The authors say that employing a weight-neutral approach to the treatment of obesity-related health conditions also reduces the health risks associated with yo-yo dieting.

“We would like people to know that fat can be fit, and that fit and healthy bodies come in all shapes and sizes,” says co-author Glenn Gaesser of the College of Health Solutions at Arizona State University. “We realize that in a weight-obsessed culture, it may be challenging for programs that are not focused on weight loss to gain traction. We’re not necessarily against weight loss; we just think that it shouldn’t be the primary criterion for judging the success of a lifestyle intervention program.”

“This is especially important when you consider the physiological realities of obesity,” says co-author Siddhartha Angadi of the School of Education and Human Development at the University of Virginia. “Body weight is a highly heritable trait, and weight loss is associated with substantial metabolic alterations that ultimately thwart weight loss maintenance.”

Obesity is associated with a number of health conditions, including cardiovascular disease, diabetes, cancer, and problems with the bones and joints. But weight cycling, commonly called yo-yo dieting, is also associated with health problems, including muscle loss, fatty liver disease, and diabetes. The authors say that by focusing on fitness rather than weight loss, people can gain the benefits of exercise while avoiding the risks associated with weight cycling.

Current public health guidelines recommend that adults accumulate 150-300 minutes per week of moderate-intensity physical activity (the intensity equivalent to walking at casual-to-brisk pace) or 75-150 minutes per week of vigorous-intensity physical activity (the intensity equivalent to jogging or running). “But it’s important to note that the benefits of exercise are dose dependent, with the biggest benefits coming from just moving out of the couch-potato zone to doing at least some moderate-intensity activity,” Gaesser says. “It’s also important to emphasize that physical activity can be accumulated throughout the day. For example, multiple short walks during the day (even as short as two to ten minutes each) are just as beneficial as one long walk for health benefits.”

In the review, the authors cite recent research focused on the magnitude of mortality risk reduction associated with weight loss compared to that associated with an increase in physical activity or cardiorespiratory fitness. The risk reduction associated with increasing fitness and physical activity was consistently greater than that associated with intentional weight loss. They also looked at the magnitude of reduction in the risk markers of cardiovascular disease that are associated with either weight loss or increased physical activity. They used meta-analyses from several studies done over a range of time periods and across a broad geographical area. “Science has generally supported the main points proposed in Big Fat Lies, a book on this topic that I first published in 1996,” Gaesser notes.

The researchers acknowledge limitations in the existing body of research, including the fact that this field is heavily reliant on epidemiological studies that do not definitively establish cause and effect, and note that only large, randomized, controlled clinical trials can fully examine the outcomes of using a fitness-focused approach to optimize cardiometabolic mortality risk in people who are obese. “Collectively, however, these epidemiological studies demonstrate strong and consistent associations, and this is why meta-analyses can be useful,” Angadi says. “In the case of physical activity and fitness, the epidemiological evidence is supported by a large body of experimental studies and randomized controlled trials that have established plausible mechanisms for the consistent findings in epidemiological studies.”

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Feeding C-section newborns their mother’s poop may help build healthy microbiota: study

Source: Cell Press
Date: 10/1/2020
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Infants delivered by cesarean section have an increased risk of developing asthma and allergies as babies and toddlers, probably because they don’t get exposed to the microbiota in the mother’s vagina and perineum during birth, negatively impacting how their immune systems develop. While a few studies have looked at whether swabbing a newborn’s skin with vaginal fluid immediately after birth reduces this risk, a paper published October 1 in the journal Cell offers a more drastic way to expose newborns to their mother’s microbiota: by diluting a small amount of their mother’s feces in breast milk and feeding it to them just after birth. The researchers report that the proof-of-concept procedure appears to be safe and at three months resulted in the newborns having a microbial makeup that looks more similar to babies born vaginally than to those born by C-section.

“From a clinical point of view, this transfer of microbial material is happening during a vaginal delivery,” says co-senior author Sture Andersson, of the Pediatric Research Center at the University of Helsinki and Helsinki University Hospital in Finland. “This is a gift the mother gives to her baby.”

At birth, the immune system is undeveloped, but once a baby begins living in the outside world, their immune system matures in response to microbial exposure. Although every person’s microbiota is individualized, the overall patterns of which bacteria types colonize the gut are different in babies born vaginally and those born by C-section. These variations appear to make a difference in how the immune system learns to respond to outside stimuli, including potential allergens.

The mothers who took part in the study were recruited with leaflets placed in doctors’ waiting rooms. About 30 women contacted the researchers to learn more, and 17 agreed to participate. Ten of them were found to have contraindications, such as a recent course of antibiotics or a potentially dangerous microbe, and ultimately seven mothers who were scheduled to have C-sections were enrolled.

The babies were given the fecal microbiota transplants (FMTs) shortly after birth. The mothers’ fecal samples were collected three weeks beforehand. The babies stayed in the hospital for two days after the transplant to make sure there were no complications. The babies’ own fecal microbiota was tested at birth (the meconium) and again at two days, one week, two weeks, three weeks, and three months. The babies also had blood work done two days after birth.

The investigators found that by three months of age, the microbiotas of the babies who received the FMTs were similar to those of babies born vaginally. They were different from those of babies born by C-section, as well as from their mothers’ microbiotas. As a baseline for these comparisons, the researchers used data collected previously at the same hospital, as well as global datasets.

“This was not designed as a safety study, but we found it to be effective and supporting the concept of vertical transfer from mother to baby,” says co-senior author Willem de Vos, of the Human Microbiome Research Program at the University of Helsinki and the Laboratory of Microbiology at Wageningen University in the Netherlands. “However, it’s very important to tell people that this is not something they should try on their own. The samples have to be tested for safety and suitability.”

Andersson notes that despite how unpalatable this research may seem to most people, the mothers who agreed to participate in the study were very motivated. One woman who was having twins was told the FMT could be giving to one baby, with the other one used as a sort of control. She declined, stating that she didn’t want one of her babies to have an unfair advantage by receiving the transplant.

In future work, the researchers plan to study the development of the immune systems in C-section babies who receive FMTs and compare it to those who don’t. Unlike the current study, which was observational, the future studies will have a control group and will be blinded to the mothers.

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Embedding Diabetes Care in the Latino Community

Source: Brigham and Women's Hospital
Date: 5/24/2023
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Brigham and Women’s Hospital has adopted a new approach to providing diabetes care for Latino (LatinX) and Hispanic patients that involves embedding diabetes specialists in community clinics and offering culturally appropriate services to help patients control their disease and related complications.

The new model for care is spearheaded by A. Enrique Caballero, MD, director of Latino Diabetes Health in the Division of Endocrinology, Diabetes and Hypertension. His work developing comprehensive models of diabetes care for the Latino/Hispanic community has earned widespread recognition since he founded the Latino Diabetes Initiative at the Harvard-affiliated Joslin Diabetes Center (JDC) in 2002. Recently, for example, he received the American Diabetes Association’s Outstanding Educator in Diabetes Award for his work with the Latino population and his leading role in professional education.

“Despite meaningful advances in diabetes care, we are falling short in helping many patients achieve treatment targets,” Dr. Caballero says. “This burden is particularly taxing among Latino and Hispanic populations and leads to increased risk of complications and comorbidities.”

Delivering Diabetes Care Closer to Home

Dr. Caballero transitioned from the JDC to the Brigham in 2018 and decided to establish his practice at the Brigham’s Southern Jamaica Plain Health Center, which is in a culturally diverse neighborhood with many Spanish speakers. There, he sees patients during routine appointments with their Brigham primary care providers and supplies targeted education, outreach services, and research opportunities that would otherwise be difficult or impossible for patients to access.

His presence in the clinic gives Dr. Caballero the opportunity to guide the clinic’s primary care providers on how to better assess and treat patients with diabetes. It also supports a multidisciplinary, collaborative approach that allows him to stay closer to patients’ other health needs and improve the management of chronic diseases like diabetes.

“Ninety percent of diabetes care is delivered by primary care providers, and many health systems require patients to travel to a main campus for specialty care,” Dr. Caballero says. “The Brigham has made a commitment to reducing health disparities among underserved populations by bringing that care closer to home and involving the entire care team, including primary care providers, nurses, dieticians, social workers, educators, pharmacists, and population health specialists.”

Care at Dr. Caballero’s clinic also feels closer to home for Latino patients because all providers on staff are fluent Spanish speakers. Furthermore, Dr. Caballero conducts all his patient encounters in Spanish, which leads to enhanced provider-patient concordance, better engagement, more authentic conversations, and more productive interactions. Patient education materials are linguistically and culturally appropriate to help patients better understand and comply with treatment and lifestyle recommendations.

Patient Management Plans Consider Social Determinants of Health

To further reduce diabetes care inequalities in the Latino community, Dr. Caballero’s initiative combines the latest evidence-based strategies for diabetes care with a focus on social determinants of health (SDOH). He says this area has been long neglected in diabetes care.

“Traditionally, the physician’s role has been to make a diagnosis, recommend a treatment, and send the patient along their way,” Dr. Caballero says. “We are moving beyond that approach by talking with patients about the financial, societal, cultural, emotional, and family support factors that influence their behavior so we can be more effective in helping them reach their treatment goals.”

For example, while healthier eating is a first-line recommendation for diabetes patients, many underserved patients are food insecure and struggle to afford or access healthy food (especially if they live in a food desert, where residents have limited access to affordable, nutritious food providers). A doctor’s recommendation to exercise more may be unattainable for those who can’t afford a gym membership or find welcoming fitness facilities. Compliance with medication protocols may prove difficult for patients who lack adequate insurance coverage.

To address these SDOH issues, members of the clinic’s multidisciplinary team talk to patients about free and reduced-cost nutrition, exercise, and medication assistance programs.

“While the science of caring for diabetes patients with new technologies and new medications continues to move forward, it is not the whole solution,” Dr. Caballero says. “We also need to focus on the art of caring for diabetes patients by addressing their social, cultural, emotional, and economic concerns. Everyone at the Brigham is committed to working against health disparities and doing the best possible job of acknowledging these social determinants of health.”

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Can a Fatty Acid Supplement Benefit People With Obesity and Prediabetes?

Source: Brigham and Women's Hospital
Date: 10/4/2022
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Obesity is a vast and growing health problem that negatively affects many systems in the body. It also increases the risk of diabetes, fatty liver disease, and cardiovascular disease, among other conditions.

Investigators at Brigham and Women’s Hospital are now looking at novel ways to boost the natural mechanisms that the body uses to counteract the development of obesity and its related complications. An upcoming clinical trial will explore whether dietary supplementation with palmitoleic acid (POA)—a monounsaturated fatty acid that is released by fat tissue during the metabolic process and part of the modern diet—can enhance key health measures in individuals who are obese and prediabetic.

In the lab, POA appears to reduce the accumulation of fat in the liver, improve the body’s sensitivity to glucose, and decrease inflammation in the vascular vessels.

“POA is a molecule that is part of the body’s own rescue system,” says physician-scientist Mehmet Furkan Burak, MD, an endocrinologist at the Brigham and instructor at Harvard Medical School, and a basic scientist in the Department of Molecular Metabolism within the Harvard T.H. Chan School of Public Health. “From an endocrinology standpoint, we want to see if we can mimic the body’s own rescue mechanism to tackle obesity-related problems.”

Harnessing the Body’s Natural Mechanisms

Researchers have known that when it comes to dietary fat, quality is more important than quantity for maintaining good metabolic health. This is where the idea of “healthy fats” comes from. But studies looking at supplementing the diet with so-called healthy fats like fish oil have had mixed results. One reason is that these oils contain a mixture of fatty acids, some of which may be beneficial and others of which are neutral or even detrimental.

POA is a key component of macadamia nut oil, which has been studied for its potential benefits. But in addition to high levels of POA, this oil also contains significant levels of palmitic acid, another fatty acid, which counteracts POA’s beneficial effects. A technique that allows the purification and separation of clinical-grade POA from other fatty acids is one thing that has made this new trial possible.

The discovery that POA could be a good candidate for boosting the body’s metabolism of fat came from laboratory studies by the Harvard T.H. Chan School of Public Health team, led by Gökhan S. Hotamisligil, MD, PhD (published in Cell in 2008). That research found that POA is an adipose tissue-derived lipid hormone that strongly stimulates muscle insulin action and suppresses fat accumulation in the liver.

Later work in mice revealed that POA could have beneficial health effects in disease models. “This molecule goes to the muscle and improves insulin sensitivity. It goes to immune cells and makes them less inflammatory. It also decreases fat formation,” Dr. Burak says. “If we supply it from the outside in patients, can it lead to the same therapeutic improvements?”

A Unique, Placebo-controlled Trial Involving POA

Dr. Burak’s trial, which is expected to begin recruiting patients in November 2022, will be the first to look at supplementation with POA in people who are obese and prediabetic. The investigators plan to screen 120 individuals to ensure a distribution of individuals across the spectrum of glucose tolerance, ultimately enrolling 40 in the trial. Half of the participants will receive POA, with the other half receiving a placebo.

The primary measure of the trial will be POA’s effects on insulin sensitivity. The patients will also receive liver MRIs and DEXA scans. A key factor enabling this study is the ability to measure insulin sensitivity with the hyperinsulinemic euglycemic clamp test. “This high-end technique is the gold standard for testing insulin sensitivity. It’s not a calculation using a surrogate but is really the quantitative measurement,” Dr. Burak says. “Very few centers in the world can do this test.”

There will also be a lab component to this study in collaboration with Pau Sancho-Isabel Graupera of the Hospital Clínic de Barcelona. This research will investigate the molecular mechanisms of POA treatment on human liver organoids.

“If this trial proves successful, there are many implications for treating obesity-related complications,” Dr. Burak concludes.

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SOME OBESITY-LINKED DISEASES MAY BE RELATED TO CHOLESTEROL

Source: Brigham and Women's Hospital
Date: 1/25/2021
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Obesity is linked to an increased risk of many diseases, but much remains unknown about the molecular mechanisms underlying this connection. In a new study from Brigham and Women’s Hospital and Harvard Medical School, investigators have found an unexpected role for cholesterol and its effects on the immune system in driving some of these obesity-linked diseases — in particular, with conditions characterized by autoimmunity.

The association turns out to be mediated by interleukin-17 (IL-17), a cytokine that provides important protection against infections. When produced in excess, however, IL-17 is associated with autoimmune-related diseases including psoriasis, rheumatoid arthritis and multiple sclerosis.

“We know that IL-17 is linked with these diseases, and we know that IL-17 is increased in people who are obese,” said Brigham immunologist Lydia Lynch, PhD, senior author of the study published in Nature Immunology. “But the connection to cholesterol was surprising, because these diseases are not typically associated with high cholesterol.”

Discovering Unexpected Links

Dr. Lynch’s lab studies the effects of obesity and diet on the functions of immune cells. Her previous work found that obesity doesn’t affect every type of immune cell in the same way. “It’s not that obesity impairs all immune cells,” she said. “Instead, it skews them toward being IL-17 producers and therefore less cytotoxic, as it impairs natural killer cells and other cells that are associated with recognizing and fighting infections and cancer.”

In the current work, the researchers found the cells that produce high levels of IL-17 have lipid droplets inside of them, which is not typical of immune cells. Furthermore, mice that were fed a high-fat diet had higher IL-17 production. Alternatively, levels of IL-17 could be reduced by blocking lipid uptake in the mice.

When the team took a closer look at the type of lipids inside the cells, they discovered that in addition to triglycerides and fatty acids, which were expected, the cells contained cholesterol droplets. “It appeared that cholesterol was particularly associated with these IL-17-producing cells, suggesting a possible link between high cholesterol and IL-17-related diseases like psoriasis,” Dr. Lynch explained.

Combination of Obesity and Type 2 Diabetes Increases Risks

Dr. Lynch pointed out that one important aspect to note about the connections between obesity and disease is that the effects of obesity on the immune system are not the same in every individual. Other factors are involved as well.

For example, people who have obesity but do not have type 2 diabetes or other hallmarks of metabolic syndrome do not necessarily carry the same risks as those who have obesity and metabolic syndrome. Their immune system is less affected by obesity.

“It’s not just obesity on its own that affects disease risk, and it’s not just type 2 diabetes on its own either,” she said. “It’s the combination of obesity and type 2 diabetes that seems to have the worst effect on the immune system.”

Implications for Future Research

Although cholesterol appears to be associated with increased IL-17, the approach of treating high cholesterol to lower disease risk may not be so straightforward.

“We know that weight loss is associated with reduced IL-17, so lowering cholesterol through diet is probably beneficial,” Dr. Lynch said. “However, our early work has suggested that it may not be that simple. That’s because lowering cholesterol seems to cause these cells to start making their own lipids and cholesterol if they can’t take them up from the environment.”

She added, however, that much more work is needed before this connection can be fully understood.

Findings from this research have implications beyond autoimmune disorders. Previous work in Dr. Lynch’s lab focused on the role of the immune system in relation to obesity and cancer — specifically, how the cellular environment in people with obesity impairs immunosurveillance. This earlier research, which has suggested that metabolic reprogramming of natural killer cells may improve cancer outcomes in people with obesity, also has implications for immunosurveillance more broadly, including the connections between obesity and infectious diseases like COVID-19.

Research like Dr. Lynch’s is also helping to fuel treatment at the Brigham’s Center for Weight Management and Wellness, which offers medical, endoscopic and surgical weight management services and interventions. Caroline Apovian, MD, co-director of the center and a physician within the Brigham’s Division of Endocrinology, Diabetes and Hypertension says that research like this is instrumental in helping to understand what mechanisms cause patients with obesity to develop certain diseases.

“The more we understand about the triggers for certain obesity-linked disease’s, the better equipped we are to help our patients and adapt our treatment approaches.”

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Mitochondria may metabolize ADP differently in aging muscle, despite exercise resistance

Source: Cell Press
Date: 03/13/2018
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Most adults reach their peak levels of muscle mass in their late 30s or early 40s. Even for those who exercise regularly, strength and function start to decline after that point. For those who don’t exercise, the drops can be dramatic. Now, a study of twenty men published March 13 in the journal Cell Reports provides new clues about the cellular mechanisms of aging muscles, showing a key role for how mitochondria, the powerhouses of the cell, process ADP, which provides energy to cells.

ADP, or adenosine diphosphate, plays a role in how our cells release and store energy. But previous lab models that have looked at the mechanisms of aging in human cells have not included ADP. When ADP is metabolized in the mitochondria, it stimulates cellular respiration and decreases reactive oxidative species (ROS; also known as free radicals). Higher ROS levels are linked to damage in different components of the cell, a process also called oxidative stress.

In the study, the investigators developed an in vitro system employing individual muscle fibers taken from muscle biopsies. The fibers were put into a system in which mitochondrial function and respiration could be measured across a range of ADP concentrations that are relevant to those found in the human body. “The way people normally measure ROS is in a system that has ADP removed,” says senior author Graham Holloway, an associate professor at the University of Guelph in Ontario. “But biologically, we always have ADP in the system. We started to think that maybe how we get ADP into the mitochondria is important for aging.”

In the first part of the paper, the researchers compared muscle from ten healthy men in their 20s with muscle from ten healthy men in their early 70s. They found that there was an 8- to 10-fold decrease in ADP sensitivity, and therefore, when ADP was added to the system, there was a 2- to 3-fold higher rate of ROS emission in the muscle taken from the older men. ROS levels were determined by measuring emissions of hydrogen peroxide, a byproduct of activity in the cell.

The findings suggested that mitochondrial ADP sensitivity was somehow impaired in the muscles of the older men and that increased levels of ROS were contributing to sarcopenia, or the degenerative loss of muscle mass. “The magnitude of change was quite striking to us,” Holloway explains. “For humans, it’s remarkable to have such a big difference.”

In the second part, the older men undertook a program of supervised resistance training, which included leg presses and upper-body exercises. But, after 12 weeks, there were no changes in the levels of hydrogen peroxide emitted, suggesting no improvements in age-associated cellular stress.

“This doesn’t mean there’s no hope for building strength in aging muscle,” Holloway says. “I actually think that endurance training would be potentially beneficial, because we know with that kind of training you get increases in mitochondrial content.” Endurance training includes aerobic exercise like cycling and swimming. “Moving forward, we plan to look at other types of exercise, to see if it can improve the dynamic response of mitochondria to ADP,” he adds.

Other future work will use rodent models to delve into the cause-and-effect relationships of the molecular mechanisms of ADP metabolism. The investigators also plan to extend their studies to looking at different types of exercise in aging women. Early research in healthy young people has indicated that there are differences in sensitivity to ADP between men and women.