Brain's 'appetite control center' different in people who are overweight or living with obesity

Cambridge scientists have shown that the hypothalamus, a key region of the brain involved in controlling appetite, is different in the brains of people who are overweight and people with obesity when compared to people who are a healthy weight.

The researchers say their findings add further evidence to the relevance of brain structure to weight and food consumption.

Current estimations suggest that over 1.9 billion people worldwide are either overweight or obese. In the UK, according to the Office for Health Improvement & Disparities, almost two-thirds of adults are overweight or living with obesity. This increases an individual's risk of developing a number of health problems, including type 2 diabetes, heart disease and stroke, cancer and poorer mental health.

A large number of factors influence how much we eat and the types of food we eat, including our genetics, hormone regulation, and the environment in which we live. What happens in our brains to tell us that we are hungry or full is not entirely clear, though studies have shown that the hypothalamus, a small region of the brain about the size of an almond, plays an important role.

Dr Stephanie Brown from the Department of Psychiatry and Lucy Cavendish College, University of Cambridge, said: "Although we know the hypothalamus is important for determining how much we eat, we actually have very little direct information about this brain region in living humans. That's because it is very small and hard to make out on traditional MRI brain scans."

The majority of evidence for the role of the hypothalamus in appetite regulation comes from animal studies. These show that there are complex interacting pathways within the hypothalamus, with different cell populations acting together to tell us when we are hungry or full.

To get around this, Dr Brown and colleagues used an algorithm developed using machine learning to analyse MRI brain scans taken from 1,351 young adults across a range of BMI scores, looking for differences in the hypothalamus when comparing individuals who are underweight, healthy weight, overweight and living with obesity.

In a study published today in Neuroimage: Clinical, the team found that the overall volume of the hypothalamus was significantly larger in the overweight and obese groups of young adults. In fact, the team found a significant relationship between volume of the hypothalamus and body-mass index (BMI).

These volume differences were most apparent in those sub-regions of the hypothalamus that control appetite through the release of hormones to balance hunger and fullness.

While the precise significance of the finding is unclear -- including whether the structural changes are a cause or a consequence of the changes in body weight -- one possibility is that the change relates to inflammation. Previous animal studies have shown that a high fat diet can cause inflammation of the hypothalamus, which in turn prompts insulin resistance and obesity. In mice, just three days of a fat-rich diet is enough to cause this inflammation. Other studies have shown that this inflammation can raise the threshold at which animals are full -- in other words, they have to eat more food than usual to feel full.

Dr Brown, the study's first author, added: "If what we see in mice is the case in people, then eating a high-fat diet could trigger inflammation of our appetite control centre. Over time, this would change our ability to tell when we've eaten enough and to how our body processes blood sugar, leading us to put on weight."

Inflammation may explain why the hypothalamus is larger in these individuals, the team say. One suggestion is that the body reacts to inflammation by increasing the size of the brain's specialist immune cells, known as glia.

Professor Paul Fletcher, the study's senior author, from the Department of Psychiatry and Clare College, Cambridge, said: "The last two decades have given us important insights about appetite control and how it may be altered in obesity. Metabolic researchers at Cambridge have played a leading role in this.

"Our hope is that by taking this new approach to analysing brain scans in large datasets, we can further extend this work into humans, ultimately relating these subtle structural brain findings to changes in appetite and eating and generating a more comprehensive understanding of obesity."

The team say more research is needed to confirm whether increased volume in the hypothalamus is a result of being overweight or whether people with larger hypothalami are predisposed to eat more in the first place. It is also possible that these two factors interact with each other causing a feedback loop.

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One third of normal-weight individuals are obese, according to study based on body fat percentage

Researchers from the School of Public Health at TAU's Faculty of Medicine examined the anthropometric data of about 3,000 Israeli women and men and concluded that body fat percentage is a much more reliable indicator of an individual's overall health and cardiometabolic risk than the BMI index, widely used in clinics today. The researchers suggest that body fat percentage should become the gold standard in this respect and recommend equipping clinics all over Israel with suitable devices.

The study -- the largest of its kind ever conducted in Israel -- was led by Prof. Yftach Gepner and PhD student Yair Lahav, in collaboration with Aviv Kfir. It and was based on data from the Yair Lahav Nutrition Center in Tel Aviv. The paper was published in Frontiers in Nutrition.

Prof. Gepner: "Israel is a leader in childhood obesity and more than 60% of the country's adults are defined as overweight. The prevailing index in this respect is BMI, based on weight and height measures, which is considered a standard indicator of an individual's general health. However, despite the obvious intuitive connection between excess weight and obesity, the actual measure for obesity is the body's fat content, with the maximum normal values set at 25% for males and 35% for females. Higher fat content is defined as obesity and can cause a range of potentially life-threatening cardiometabolic diseases: heart disease, diabetes, fatty liver, kidney dysfunction, and more. The disparity between the two indexes has generated a phenomenon called 'the paradox of obesity with normal weight' -- higher than normal body fat percentage in normal-weight individuals. In this study we examined the prevalence of this phenomenon in Israel's adult population."

The researchers analyzed the anthropometric data of 3,000 Israeli women and men, accumulated over several years: BMI scores; DXA scans (using X-rays to measure body composition, including fat content); and cardiometabolic blood markers. About one third of the participants, 1,000 individuals, were found to be within the normal weight range. Of these, 38.5% of the women and 26.5% of the men were identified as 'obese with normal weight' -- having excess fat content despite their normal weight. Matching body fat percentage with blood markers for each of these individuals, the study found a significant correlation between 'obesity with normal weight' and high levels of sugar, fat, and cholesterol -- major risk factors for a range of cardiometabolic diseases. At the same time, 30% of the men and 10% of the women identified as overweight were found to have a normal body fat percentage.

Prof. Gepner: "Our findings were somewhat alarming, indicating that obesity with normal weight is much more common in Israel than we had assumed. Moreover, these individuals, being within the norm according to the prevailing BMI index, usually pass 'under the radar'. Unlike people who are identified as overweight, they receive no treatment or instructions for changing their nutrition or lifestyle -- which places them at an even greater risk for cardiometabolic diseases."

Based on their findings, the researchers concluded that body fat percentage is a more reliable indicator of an individual's general health than BMI. Consequently, they suggest that body fat percentage should become the prevailing standard of health, and recommend some convenient and accessible tools for this purpose: skinfold measurements that estimate body fat based on the thickness of the fat layer under the skin; and a user-friendly device measuring the body's electrical conductivity, already used in many fitness centers.

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Excess weight, obesity more deadly than previously believed

Excess weight or obesity boosts risk of death by anywhere from 22% to 91% -- significantly more than previously believed -- while the mortality risk of being slightly underweight has likely been overestimated, according to new CU Boulder research.

The findings, published Feb. 9 in the journal Population Studies, counter prevailing wisdom that excess weight boosts mortality risk only in extreme cases.

The statistical analysis of nearly 18,000 people also shines a light on the pitfalls of using body mass index (BMI) to study health outcomes, providing evidence that the go-to metric can potentially bias findings. After accounting for those biases, it estimates that about 1 in 6 U.S. deaths are related to excess weight or obesity.

"Existing studies have likely underestimated the mortality consequences of living in a country where cheap, unhealthy food has grown increasingly accessible, and sedentary lifestyles have become the norm," said author Ryan Masters, associate professor of sociology at CU Boulder.

"This study and others are beginning to expose the true toll of this public health crisis."

Challenging the obesity paradox

While numerous studies show that heart disease, high blood pressure and diabetes (which are often associated with being overweight) elevate mortality risk, very few have shown that groups with higher BMIs have higher mortality rates.

Instead, in what some call the "obesity paradox," most studies show a U-shaped curve: Those in the "overweight" category (BMI 25-30) surprisingly have the lowest mortality risk. Those in the "obese" category (30-35) have little or no increased risk over the so-called "healthy" category (18.5-25). And both the "underweight" (less than 18.5) and extremely obese (35 and higher) are at increased risk of death.

"The conventional wisdom is that elevated BMI generally does not raise mortality risk until you get to very high levels, and that there are actually some survival benefits to being overweight," said Masters, a social demographer who has spent his career studying mortality trends. "I have been suspicious of these claims."

He noted that BMI, which doctors and scientists often use as a health measure, is based on weight and height only and doesn't account for differences in body composition or how long a person has been overweight.

"It's a reflection of stature at a point in time. That's it," said Masters, noting that Tom Cruise (at 5 feet 7 inches and an extremely muscular 201 pounds at one point), had a BMI of 31.5, famously putting him in the category of "obese." "It isn't fully capturing all of the nuances and different sizes and shapes the body comes in."

To see what happened when those nuances were considered, Masters mined the National Health and Nutrition Examination Survey (NHANES) from 1988 to 2015, looking at data from 17,784 people, including 4,468 deaths.

He discovered that a full 20% of the sample characterized as "healthy" weight had been in the overweight or obese category in the decade prior. When set apart, this group had a substantially worse health profile than those in the category whose weight had been stable.

Masters pointed out that a lifetime carrying excess weight can lead to illnesses that, paradoxically, lead to rapid weight loss. If BMI data is captured during this time, it can skew study results.

"I would argue that we have been artificially inflating the mortality risk in the low-BMI category by including those who had been high BMI and had just lost weight recently," he said.

Meanwhile, 37% of those characterized as overweight and 60% of those with obese BMI had been at lower BMIs in the decade prior. Notably, those who had only recently gained weight had better health profiles.

"The health and mortality consequences of high BMI are not like a light switch," said Masters. "There's an expanding body of work suggesting that the consequences are duration-dependent."

By including people who had spent most of their life at low-BMI weight in the high-BMI categories, previous studies have inadvertently made high BMI look less risky than it is, he said.

When he looked at differences in fat distribution within BMI categories, he also found that variations made a huge difference in reported health outcomes.

Exposing a public health problem

Collectively, the findings confirm that studies have been "significantly affected" by BMI-related bias.

When re-crunching the numbers without these biases, he found not a U-shape but a straight upward line, with those with low BMI (18.5-22.5) having the lowest mortality risk.

Contrary to previous research, the study found no significant mortality risk increases for the "underweight" category.

While previous research estimated 2 to 3% of U.S. adult deaths were due to high BMI, his study pegs the toll at eight times that.

Masters said he hopes the research will alert scientists to be "extremely cautious" when making conclusions based on BMI. But he also hopes the work will draw attention to what he sees not as a problem for individuals alone to solve but rather a public health crisis fueled by an unhealthy or "obesogenic" environment in the U.S.

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Vitamin D benefits and metabolism may depend on body weight

Researchers from Brigham and Women's Hospital, a founding member of the Mass General Brigham healthcare system, have found new evidence that vitamin D may be metabolized differently in people with an elevated body mass index (BMI). The study, appearing in JAMA Network Open, is a new analysis of data from the VITAL trial, a large nationwide clinical trial led by Brigham researchers that investigated whether taking vitamin D or marine omega-3 supplements could reduce the risk of developing cancer, heart disease, or stroke.

"The analysis of the original VITAL data found that vitamin D supplementation correlated with positive effects on several health outcomes, but only among people with a BMI under 25," said first author Deirdre K. Tobias, ScD, an associate epidemiologist in Brigham's Division of Preventive Medicine. "There seems to be something different happening with vitamin D metabolism at higher body weights, and this study may help explain diminished outcomes of supplementation for individuals with an elevated BMI."

Vitamin D is an essential nutrient involved in many biological processes, most notably helping our body absorb minerals, such as calcium and magnesium. While some of the vitamin D we need is made in the body from sunlight, vitamin D deficiencies are often treated with supplementation. Evidence from laboratory studies, epidemiologic research and clinical research has also suggested that vitamin D may play a role in the incidence and progression of cancer and cardiovascular disease, and it was this evidence that prompted the original VITAL trial.

The VITAL trial was a randomized, double-blind, placebo-controlled trial in 25,871 U.S. participants, which included men over the age of 50 and women over the age of 55. All participants were free of cancer and cardiovascular disease at the time of enrollment. While the trial found little benefit of vitamin D supplementation for preventing cancer, heart attack, or stroke in the overall cohort, there was a statistical correlation between BMI and cancer incidence, cancer mortality, and autoimmune disease incidence. Other studies suggest similar results for type 2 diabetes.

The new study aimed to investigate this correlation. The researchers analyzed data from 16,515 participants from the original trial who provided blood samples at baseline (before randomization to vitamin D), as well as 2,742 with a follow-up blood sample taken after two years. The researchers measured the levels of total and free vitamin D, as well as many other novel biomarkers for vitamin D, such as its metabolites, calcium, and parathyroid hormone, which helps the body utilize vitamin D.

"Most studies like this focus on the total vitamin D blood level," said senior author JoAnn E. Manson, MD, DrPH, chief of the Division of Preventive Medicine at the Brigham and principal investigator of VITAL. "The fact that we were able to look at this expanded profile of vitamin D metabolites and novel biomarkers gave us unique insights into vitamin D availability and activity, and whether vitamin D metabolism might be disrupted in some people but not in others."

The researchers found that vitamin D supplementation increased most of the biomarkers associated with vitamin D metabolism in people, regardless of their weight. However, these increases were significantly smaller in people with elevated BMIs.

"We observed striking differences after two years, indicating a blunted response to vitamin D supplementation with higher BMI," Tobias said. "This may have implications clinically and potentially explain some of the observed differences in the effectiveness of vitamin D supplementation by obesity status."

"This study sheds light on why we're seeing 30-40 percent reductions in cancer deaths, autoimmune diseases, and other outcomes with vitamin D supplementation among those with lower BMIs but minimal benefit in those with higher BMIs, suggesting it may be possible to achieve benefits across the population with more personalized dosing of vitamin D," said Manson. "These nuances make it clear that there's more to the vitamin D story."

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High BMI causes depression – and both physical and social factors play a role

A largescale new study provides further evidence that being overweight causes depression and lowers wellbeing and indicates both social and physical factors may play a role in the effect.

With one in four adults estimated to be obese in the UK, and growing numbers of children affected, obesity is a global health challenge. While the dangers of being obese on physical health is well known, researchers are now discovering that being overweight can also have a significant impact on mental health.

The new study, published in Human Molecular Genetics, sought to investigate why a body of evidence now indicates that higher BMI causes depression. The team used genetic analysis, known as Mendelian Randomisation, to examine whether the causal link is the result of psychosocial pathways, such as societal influences and social stigma, or physical pathways, such as metabolic conditions linked to higher BMI. Such conditions include high blood pressure, type 2 diabetes and cardiovascular disease.

In research led by the University of Exeter and funded by the Academy of Medical Sciences, the team examined genetic data from more than 145,000 participants from the UK Biobank with detailed mental health data available. In a multifaceted study, the researchers analysed genetic variants linked to higher BMI, as well as outcomes from a clinically-relevant mental health questionnaire designed to assess levels of depression, anxiety and wellbeing.

To examine which pathways may be active in causing depression in people with higher BMI, the team also interrogated two sets of previously discovered genetic variants. One set of genes makes people fatter, yet metabolically healthier, meaning they were less likely to develop conditions linked to higher BMI, such as high blood pressure and type 2 diabetes. The second set of genes analysed make people fatter and metabolically unhealthy, or more prone to such conditions. The team found little difference between the two sets of genetic variants, indicating that both physical and social factors play a role in higher rates of depression and poorer wellbeing.

Lead author Jess O'Loughlin, at the University of Exeter Medical School, said: "Obesity and depression are both major global health challenges, and our study provides the most robust evidence to date that higher BMI causes depression. Understanding whether physical or social factors are responsible for this relationship can help inform effective strategies to improve mental health and wellbeing. Our research suggests that being fatter leads to a higher risk of depression, regardless of the role of metabolic health. This suggests that both physical health and social factors, such as social stigma, both play a role in the relationship between obesity and depression."

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A complex link between body mass index and Alzheimer's

Though obesity in midlife is linked to an increased risk for Alzheimer's disease, new research suggests that a high body mass index later in life doesn't necessarily translate to greater chances of developing the brain disease.

In the study, researchers compared data from two groups of people who had been diagnosed with mild cognitive impairment -- half whose disease progressed to Alzheimer's in 24 months and half whose condition did not worsen.

The researchers zeroed in on two risk factors: body mass index (BMI) and a cluster of genetic variants associated with higher risk for Alzheimer's disease.

Their analysis showed that a higher genetic risk combined with a lower BMI was associated with a higher likelihood for progression to Alzheimer's, and that the association was strongest in men.

The finding does not suggest people should consider gaining weight in their later years as a preventive effort -- instead, researchers speculate that lower BMI in these patients was likely a consequence of neurodegeneration, the progressive damage to the brain that is a hallmark of Alzheimer's. Brain regions affected by Alzheimer's are also involved in controlling eating behaviors and weight regulation.

"We don't want people to think they can eat everything they want because of this lower BMI association," said senior study author Jasmeet Hayes, assistant professor of psychology at The Ohio State University.

"We know that maintaining a healthy weight and having a healthy diet are extremely important to keeping inflammation and oxidative stress down -- that's a risk factor that is modifiable, and it's something you can do to help improve your life and prevent neurodegenerative processes as much as possible," she said. "If you start to notice rapid weight loss in an older individual, that could actually be a reflection of a potential neurodegenerative disease process."

The study was published online recently in the Journals of Gerontology: Series A.

Previous research has found a link between obesity and negative cognitive outcomes, but in older adults closer to the age at which Alzheimer's disease is diagnosed, the results have been mixed, Hayes said. And though a variant to the gene known as APOE4 is the strongest single genetic risk factor for Alzheimer's, it explains only about 10 to 15% of overall risk, she said.

Hayes has focused her research program on looking at multiple risk factors at the same time to see how they might interact to influence risk -- and to identify health behaviors that may help reduce the risk.

"We're trying to add more and more factors. That is my goal, to one day build a more precise and better model of the different combinations of risk factors," said Hayes, also an investigator in Ohio State's Chronic Brain Injury Initiative. "Genetic risk is important, but it really explains only a small part of Alzheimer's disease, so we're really interested in looking at other factors that we can control."

For this study, the research team obtained data from the Alzheimer's Disease Neuroimaging Initiative, compiling a sample of 104 people for whom BMI and polygenic risk scores were available. Fifty-two individuals whose mild cognitive impairment (MCI) had progressed to Alzheimer's in 24 months were matched against demographically similar people whose MCI diagnosis did not change over two years. Their average age was 73.

Statistical analysis showed that individuals with mild cognitive impairment who had both a lower BMI and higher genetic risk for Alzheimer's were more likely to progress to Alzheimer's disease within 24 months compared to people with a higher BMI.

"We think there's interaction between the genetics and lower BMI, and having both of these risk factors causes more degeneration in certain brain regions to increase the likelihood of developing Alzheimer's disease," said Jena Moody, a graduate student in psychology at Ohio State and first author of the paper.

The effect of the BMI-genetic risk interaction was significant even after taking into account the presence of beta-amyloid and tau proteins in the patients' cerebrospinal fluid -- the core biomarkers of Alzheimer's disease.

The relationship between low BMI and high genetic risk and progression to Alzheimer's was stronger in males than in females, but a larger sample size and additional biological data would be needed to expand on that finding, the researchers said.

Because brain changes can begin long before cognitive symptoms surface, a better understanding of the multiple risk factors for Alzheimer's could open the door to better prevention options, Moody said.

"If you can identify people at higher risk before symptoms manifest, you could implement interventions and prevention techniques to either slow or prevent that progression from happening altogether," she said.

To date, scientists have suggested preventive steps include maintaining a healthy weight and diet and participating in activities that reduce inflammation and promote neurofunctioning, such as exercise and mentally stimulating activities.

"We're finding again and again how important inflammation is in the process," Hayes said. "Especially in midlife, trying to keep that inflammation down is such an important aspect of maintaining a healthy lifestyle and preventing accelerated aging."

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