Tag: appetite

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Metformin’s Weight Loss Tied to “Anti-hunger” Molecule

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A new study finds that the modest weight loss from taking metformin is attributable to an appetite-suppressing molecule that is abundant after exercise

Photo by I Yunmai on Unsplash

An “anti-hunger” molecule produced after vigorous exercise is responsible for the moderate weight loss caused by the diabetes medication metformin, according to a new study in mice and humans. The anti-hunger molecule, lac-phe, was discovered by Stanford Medicine researchers in 2022.

The finding, made jointly by researchers at Stanford Medicine and at Harvard Medical School and published in Nature Metabolism, further cements the critical role the molecule, called lac-phe, plays in metabolism, exercise and appetite. It may pave the way to a new class of weight loss drugs.

“Until now, the way metformin, which is prescribed to control blood sugar levels, also brings about weight loss has been unclear,” said Jonathan Long, PhD, an assistant professor of pathology. “Now we know that it is acting through the same pathway as vigorous exercise to reduce hunger. Understanding how these pathways are controlled may lead to viable strategies to lower body mass and improve health in millions of people.”

Many people with diabetes who are prescribed metformin lose around 2% to 3% of their body weight within the first year of starting the drug. Although this amount of weight loss is modest when compared with the 15% or more often seen by people taking semaglutide, the discoveries that led to those drugs also grew from observations of relatively minor, but reproducible, weight loss in people taking first-generation versions of the medications.

Post-workout appetite loss

When Long and colleagues at Baylor University discovered lac-phe in 2022, they were on the hunt for small molecules responsible for curtailing hunger after vigorous exercise. What they found was a mishmash of lactate and an amino acid called phenylalanine. They dubbed the hybrid molecule lac-phe and went on to show that it’s not only more abundant after exercise but it also causes people (as well as mice and even racehorses) to feel less hungry immediately after a hard workout.

“There is an intimate connection between lac-phe production and lactate generation,” Long said. “Once we understood this relationship, we started to think about other aspects of lactate metabolism.”

Metformin was an obvious candidate because as it stimulates the breakdown of glucose (thus reducing blood sugar levels) it can trigger the generation of lactate.

The researchers found that obese laboratory mice given metformin had increased levels of lac-phe in their blood. They ate less than their peers and lost about 2 grams of body weight during the nine-day experiment.

Long and his colleagues also analysed stored blood plasma samples from people with Type 2 diabetes before and 12 weeks after they had begun taking metformin to control their blood sugar. They saw significant increases in the levels of lac-phe in people after metformin compared with their levels before treatment. Finally, 79 participants in a large, multi-ethnic study of atherosclerosis who were also taking metformin had significantly higher levels of lac-phe circulating in their blood than those who were not taking the drug.

“It was nice to confirm our hunch experimentally,” Long said. “The magnitude of effect of metformin on lac-phe production in mice was as great as or greater than what we previously observed with exercise. If you give a mouse metformin at levels comparable to what we prescribe for humans, their lac-phe levels go through the roof and stay high for many hours.”

Further research revealed that lac-phe is produced by intestinal epithelial cells in the animals; blocking the ability of mice to make lac-phe erased the appetite suppression and weight loss previously observed.

Finally, a statistical analysis of the people in the atherosclerosis study who lost weight during the several-year study and follow-up period found a meaningful association between metformin use, lac-phe production and weight loss.

“The fact that metformin and sprint exercise affect your body weight through the same pathway is both weird and interesting,” Long said. “And the involvement of the intestinal epithelial cells suggests a layer of gut-to-brain communication that deserves further exploration. Are there other signals involved?”

Long noted that, while semaglutide drugs are injected into the bloodstream, metformin is an oral drug that is already prescribed to millions of people. “These findings suggest there may be a way to optimize oral medications to affect these hunger and energy balance pathways to control body weight, cholesterol and blood pressure. I think what we’re seeing now is just the beginning of new types of weight loss drugs.”

Source: Stanford Medicine

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Desirability of Ultra-processed Foods no Better than Less Processed Ones

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Photo by Skyler Ewing

New research that had participants compare the taste perception of less processed foods with ultra-processed foods (UPFs), found that UPFs were no more pleasant tasting than less processed foods. The University of Bristol-led findings, published in the journal Appetite, support the theory that humans are programmed to learn to like foods with more equal amounts of carbohydrate and fat. Carbohydrate (including sugars) and fat provide most of the calories in human diets.

The study wanted to test the common but largely untested assumptions that food energy density (calories per gram), level of processing, and carbohydrate-to-fat ratio are key factors influencing food liking and desirability.

In the experiment, involving 224 adult volunteers, participants were presented with colour images of between 24 and 32 familiar foods, varying in energy density, level of processing (including UPFs), and carbohydrate-to-fat ratio. There were 52 different foods in total, including avocado, grapes, cashew nuts, king prawns, olives, blueberry muffin, crispbread, pepperoni sausage, and ice cream.

Participants were then asked to rate the foods for taste pleasantness (liking), desire to eat, sweetness, and saltiness while imagining tasting them. The validity of this method was confirmed by, for example, finding a strong relationship between sweetness ratings and food sugar content.

Results from the study showed that, on average, UPFs were no more liked or desired than processed or unprocessed foods. But foods that combined more equal amounts (in calories) of carbohydrate and fat were more liked and desired than foods equivalent in calories but mostly from either carbohydrate or fat. This is known, from previous research, as the ‘combo’ effect.

Further results revealed that foods with higher amounts of dietary fibre were less liked and desired, and foods tasting more intense (mainly related to the level of sweetness and saltiness), were more liked and desired.

Lead author Professor Peter Rogers found the results for UPFs surprising.  He said: “Our results challenge the assumption that ultra-processed foods are ‘hyperpalatable’, and it seems odd that this has not been directly tested before.

“However, whilst ultra-processing didn’t reliably predict liking (palatability) in our study, food carbohydrate-to-fat ratio, food fibre content, and taste intensity did – actually, together, these three characteristics accounted for more than half of the variability in liking across the foods we tested.

“The results for sweetness and saltiness, are consistent with our innate liking for sweetness and saltiness. And the results for carbohydrate-to-fat ratio and fibre might be related to another important characteristic that determines food liking.

“Our suggestion is that humans are programmed to learn to like foods with more equal amounts of carbohydrate and fat, and lower amounts of fibre, because those foods are less filling per calorie. In other words, we value calories over fullness.

“In turn, this trait helps us to maximise calorie intake and build up fat reserves when food is abundant – which is adaptive in circumstances when food supplies are uncertain or fluctuate seasonally, but not when food is continuously available in excess of our immediate needs.”

The researchers at the Nutrition and Behaviour Group are currently testing the calories versus fullness idea in further studies of food liking and meal preferences, including across different countries and cuisines.

Source: University of Bristol

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The Seasons Affect Appetite in Unexpected Ways

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Photo by Julian Jagtenberg on Pexels

Many people may feel that they are healthier in the summer: the sun is shining, they get plenty of vitamin D, and the days are long. However, recent research from the University of Copenhagen suggests that eating habits in winter may be better for metabolic health than eating habits in summer – at least in the case of mice. Researchers have examined the metabolism and weight of mice exposed to both ‘winter light’ and ‘summer light’.

“We found that even in non-seasonal animals, differences in light hours between summer and winter do cause differences in energy metabolism. In this case, body weight, fat mass and liver fat content,” says Lewin Small, who carried out the research while a postdoc at Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen. He adds:

“We found this mostly in mice exposed to winter light hours. These mice had less body weight gain and adiposity. They have more rhythmicity in the way they eat over a 24-hour period. And this then led to benefits in metabolic health.”

The study, published in Cell Metabolism, is the first of its kind to examine light hour’s influence on metabolism in mice, that are not considered seasonal animals as like humans they do not only breed in specific seasons. Animals breeding in specific seasons gain weight before the breeding season to save energy supplies.

Light hours impact metabolism

Lewin Small’s inspiration for initiating the study stemmed from the significant variation in daylight hours across various regions of the world.

“We study the influence of the time-of-day on aspects of metabolism such as exercise, obesity and diabetes. However, most studies that investigate this link do so assuming an equal length of day and night all year round,” says Lewin Small.

Therefore, they wanted to find out what the seasonal light differences meant for the metabolism. Most people in the world live with at least a two-hour difference in light between summer and winter.

“I come from Australia, and when I first moved to Denmark, I was not used to the huge difference in light between summer and winter and I was interested in how this might affect both circadian rhythms and metabolism,” says Lewin Small and adds:

“Therefore, we exposed laboratory mice to different light hours representing different seasons and measured markers of metabolic health and the circadian rhythms of these animals.”

Because the research was conducted using mice as the experimental subjects, it is not possible to assume that the same thing goes for humans.

“This is a proof of principle. Do differences in light hours affect energy metabolism? Yes, it does. Further studies in humans may find that altering our exposure to artificial light at night or natural light exposure over the year could be used to improve our metabolic health,” says Juleen Zierath, Professor at the Novo Nordisk Center for Basic Metabolism Research (CBMR) and senior author of the study.

Lewin Small adds that the findings are important to understand how eating patterns are affected by the light and seasons which might help us understand why some people gain more weight or if people gain more weight in a specific time of year.

“Differences in light between summer and winter could affect our hunger pathways and when we get hungry during the day,” he says.

Source: University of Copenhagen – The Faculty of Health and Medical Sciences

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Obesity Genetic Risk Could be Curbed by Practising Restraint

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Photo by Jonathan Borba

Obesity risk genes make people feel hungrier and lose control over their eating, but practisng dietary restraint could counteract this, according to new research from University of Exeter. Published in the International Journal of Epidemiology, the study found that those with higher genetic risk of obesity can reduce the effects that are transmitted via hunger and uncontrolled eating by up to half through dietary restraint.

Lead author psychology PhD student, Shahina Begum said: “At a time when high calorie foods are aggressively marketed to us, it’s more important than ever to understand how genes influence BMI. We already know that these genes impact traits and behaviours such as hunger and emotional eating, but what makes this study different is that we tested the influence of two types of dietary restraint – rigid and flexible – on the effect of these behaviours. What we discovered for the first time was that increasing both types of restraint could potentially improve BMI in people genetically at risk; meaning that restraint-based interventions could be useful to target the problem.”

Genes linked to obesity increase BMI, with up to a quarter of this effect explained by increases in hunger and uncontrolled (including emotional) eating. There are over 900 genes that have so far been identified by researchers as being associated with BMI and several studies suggest these risk genes influence feelings of hunger and loss of control towards food.

This study examined 3780 adults aged between 22 and 92 years old from two UK cohorts: the Genetics of Appetite Study, and Avon Longitudinal Study of Parents and Children. Their weight and height were measured, and they provided a DNA sample via their blood to calculate an overall score for their genetic risk of obesity. They then completed questionnaires to measure 13 different eating behaviours, including disinhibition (a tendency to engage in binge or emotional eating) and over-eating due to hunger.

As expected, researchers found that a higher genetic risk score was associated with a higher BMI, partly due to increased disinhibition and hunger. However, results also found that those who had high levels of dietary restraint reduced those effects by almost half for disinhibition and a third for hunger, suggesting that restraint may counteract some of the effects of genetic risk.

There are different types of dietary restraint, including flexible strategies to rigid strategies, like calorie counting. The study tested the influence of both types of restraint for the first time and found both could potentially improve BMI in people genetically at risk.

Interventions to facilitate dietary restraint could include changing the food environment (by reducing the calorie content or portion size of food) or supporting individuals. To this end, members of the research team have developed a Food Trainer app (https://www.exeter.ac.uk/research/foodt/) to help achieve that. The app works as a game that trains people to repeatedly stop to high calorie food and research suggests this training may be particularly beneficial for those with a higher BMI.

Source: University of Exeter

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Sun Exposure Triggers Appetite in Men but not Women

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Photo by Julian Jagtenberg on Pexels

A new study from Tel Aviv University reveals that solar exposure increases appetite in males – but not in females. It is the first gender-dependent medical study ever conducted on UV exposure, and reveals a molecular connection between UV exposure and appetite.

Skin as a regulator of appetite

The groundbreaking study was led by Prof. Carmit Levy and PhD student Shivang Parikh and published in Nature Metabolism.

The study was based on epidemiological data collected in a year-long survey about the eating habits of approximately 3000 Israelis of both sexes, including self-reports from students who had spent time in the sun, combined with the results of a genetic study in a lab model. The findings identify the skin as a primary regulator of metabolism in both lab models and humans, influencing appetite.

In females, oestrogen blocks appetite after sun exposure

The study unravels the differences between males and females in the activation of the metabolic mechanism. The researchers explain that in males of both animal species and humans, sun exposure activates a protein called p53, to repair any DNA damage in the skin that might have been caused by the exposure. The activation of p53 signals the body to produce a hormone called ghrelin, which stimulates the appetite.

In females, oestrogen blocks the interaction between p53 and ghrelin, and consequently does not catalyse the urge to eat following exposure to the sun.

Males and females, have differences in metabolism which impacts both their health and their behaviour. However, so far it has not been established whether the two sexes respond differently to environmental triggers such as exposures to the sun’s UV radiation.

“We examined the differences between men and women after sun exposure and found that men eat more than women because their appetite has increased. Our study was the first gender-dependent medical study ever conducted on UV exposure, and for the first time, the molecular connection between UV exposure and appetite was deciphered. Gender-dependent medical studies are particularly complex, since twice the number of participants is required to find statistically significant differences,” explained Prof Levy.

“As humans, we have cast off our fur and consequently, our skin, the largest organ in our body, is exposed to signals from the environment. The protein p53, found in the skin, repairs damage to the DNA caused by sun exposure, but it does more than that. It signals to our bodies that winter is over, and we are out in the sun, possibly in preparation for the mating season. Our results provide an encouraging basis for more research, on both human metabolism and potential UV-based therapies for metabolic diseases and appetite disorders,” Prof Levy concluded.

Source: Tel Aviv University