Tag: metabolism

Categories : Metabolic DisordersTags :

A Single Gene Causes Mitochondria to ‘Fragment’ in Obesity

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These coloured streaks are mitochondrial networks within fat cells. Researchers from UC San Diego discovered that a high-fat diet dismantles mitochondria, resulting in weight gain. Credit: UC San Diego

While lifestyle factors like diet and exercise play a role in the development and progression of obesity, scientists have come to understand that obesity is also associated with intrinsic metabolic abnormalities. Now, researchers from University of California San Diego School of Medicine have shed new light on how obesity affects our mitochondria, the all-important energy-producing structures of our cells.

In a study published January 29, 2023 in Nature Metabolism, the researchers found that when mice were fed a high-fat diet, mitochondria within their fat cells broke apart into smaller mitochondria with reduced capacity for burning fat. Further, they discovered that this process is controlled by a single gene. By deleting this gene from the mice, they were able to protect them from excess weight gain, even when they ate the same high-fat diet as other mice.

“Caloric overload from overeating can lead to weight gain and also triggers a metabolic cascade that reduces energy burning, making obesity even worse,” said Alan Saltiel, PhD, professor in the Department of Medicine at UC San Diego School of Medicine. “The gene we identified is a critical part of that transition from healthy weight to obesity.”

Obesity occurs when the body accumulates too much fat, which is primarily stored in adipose tissue. Adipose tissue normally provides important mechanical benefits by cushioning vital organs and providing insulation. It also has important metabolic functions, such as releasing hormones and other cellular signaling molecules that instruct other tissues to burn or store energy.

In the case of caloric imbalances like obesity, the ability of fat cells to burn energy starts to fail, which is one reason why it can be difficult for people with obesity to lose weight. How these metabolic abnormalities start is among the biggest mysteries surrounding obesity.

To answer this question, the researchers fed mice a high-fat diet and measured the impact of this diet on their fat cells’ mitochondria, structures within cells that help burn fat. They discovered an unusual phenomenon. After consuming a high-fat diet, mitochondria in parts of the mice’s adipose tissue underwent fragmentation, splitting into many smaller, ineffective mitochondria that burned less fat.

In addition to discovering this metabolic effect, they also discovered that it is driven by the activity of single molecule, called RaIA. RaIA has many functions, including helping break down mitochondria when they malfunction. The new research suggests that when this molecule is overactive, it interferes with the normal functioning of mitochondria, triggering the metabolic issues associated with obesity.

“In essence, chronic activation of RaIA appears to play a critical role in suppressing energy expenditure in obese adipose tissue,” said Saltiel. “By understanding this mechanism, we’re one step closer to developing targeted therapies that could address weight gain and associated metabolic dysfunctions by increasing fat burning.”

By deleting the gene associated with RaIA, the researchers were able to protect the mice against diet-induced weight gain. Delving deeper into the biochemistry at play, the researchers found that some of the proteins affected by RaIA in mice are analogous to human proteins that are associated with obesity and insulin resistance, suggesting that similar mechanisms may be driving human obesity.

“The direct comparison between the fundamental biology we’ve discovered and real clinical outcomes underscores the relevance of the findings to humans and suggests we may be able to help treat or prevent obesity by targeting the RaIA pathway with new therapies,” said Saltiel “We’re only just beginning to understand the complex metabolism of this disease, but the future possibilities are exciting.”

Source: EurekAlert!

Categories : Metabolic DisordersTags :

Obesity Reduces the Rate at Which Energy is Burnt

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Source: Pixabay CC0

A new study published in the journal Obesity found that people at a healthy weight use more energy during the day, when most people are active and eat, while those who have obesity spend more energy during the night, when most people sleep. The study, from Oregon Health & Science University, also found that during the day, those with obesity have higher levels of insulin – a sign that the body is working harder to use glucose.

“It was surprising to learn how dramatically the timing of when our bodies burn energy differed in those with obesity,” said the study’s first author, Andrew McHill, PhD, an assistant professor in the OHSU School of Nursing and the Oregon Institute of Occupational Health Sciences at OHSU. “However, we’re not sure why. Burning less energy during the day could contribute to being obese, or it could be the result of obesity.”

Obesity is defined as having a Body Mass Index, or BMI, of 30 or more. Being overweight or obese increases the risk for health conditions such as high blood pressure and Type 2 diabetes.

Schedules and when people sleep, eat and exercise can also affect health, by either complementing or going against the body’s natural, daily rhythms. Every 24 hours, people experience numerous changes that are triggered by the human body’s internal clock. These changes normally occur at certain times of the day in order to best serve the body’s needs at any given hour.

McHill and the study’s senior author, Steven A. Shea, PhD, director of the Oregon Institute of Occupational Health Sciences at OHSU, focus their research on how circadian rhythms and sleep impact the human body. McHill leads the OHSU Sleep, Chronobiology and Health Laboratory.

While previous research has suggested circadian rhythm misalignment affects energy metabolism and glucose regulation, those studies have largely involved participants who have a healthy weight. To explore this further, McHill, Shea and colleagues organized a study that included people of different body sizes.

A total of 30 participants took part in the study, which involved them staying at a specially designed circadian research lab for six days. The study followed a rigorous circadian research protocol involving a schedule designed to have participants be awake and sleep at different times throughout each day.

After each period of sleep, volunteers were awakened to eat and participate in a variety of tests for the remaining time of each day. One test had participants exercise while wearing a mask that was connected to a machine called an indirect calorimeter, which measures exhaled carbon dioxide and helps estimate energy usage. Blood samples were also collected to measure glucose levels in response to an identical meal provided during each day.

Next, the research team plans to explore eating habits and hunger in people who are obese, as well as those who have a healthy weight. That new study will also follow up on a 2013 study, led by Shea, that found circadian clocks naturally increase food cravings at night.

Source: Oregon Health & Science University

Categories : Diet and Nutrition ExerciseTags :

Female Athletes’ Metabolism Drops if They Cut Energy Intake

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Photo by Andrea Piacquadio on Pexels

Most athletes know that diet and training go hand in hand for the best results, and many of them closely monitor their energy intake and training. However, a new study from Aarhus University shows that the bodies of female athletes are negatively affected when they consume too little energy through their diet in comparison with their training volume, explains PhD student Mikkel Oxfeldt. He and Associate Professor Mette Hansen are behind the study, which is published in the Journal of Physiology.

“We know that both elite female athletes and active women at times, either consciously or unconsciously, don’t have an energy intake that matches their energy expenditure when training. The study shows that insufficient energy intake can negatively affect muscles’ ability to respond to training. After just ten days of low energy intake, we began seeing changes to the hormonal system such as a decrease in the metabolic hormone followed by a decrease in metabolism.”

The study shows that it is important that women are careful not to reduce their energy intake too much. In fact, they should actually be increasing their energy intake if they increase their training volume, says Mikkel Oxfeldt:

“When you don’t get enough energy from your diet, your body will begun to pare down processes that require a lot of energy, just like a mobile phone that goes into battery-saving mode. We know from previous studies that it can cause some women’s periods to stop. However, our results show that other processes in the body, such as building new muscle proteins, are also affected.”

We must confront the unilateral focus on weight

Thirty fit women aged 18–30 participated in the study which is part of the Novo Nordic-funded Team Denmark network called ‘competition preparation and training optimisation’. All the women started the study right after the start of their menstrual period and followed a very controlled training and diet regimen for three weeks.

“Under the supervision of the researchers, the participants carried out individual training programmes aimed at increasing muscle mass, strength and overall fitness. The women’s meals were also provided by us. By controlling their training regimen and their diets, we were able to see how much energy they expended and what they ate during the study,” says Mikkel Oxfeldt and continues:

“This is the first time that such a well-controlled study has been carried out in this area, where both the diet and training of a group of fit women has been regulated to this extent. During the study, all participants drank doubly labelled water, which is enriched with a trace material. When we combine this tracer technique with the retrieval and subsequent analysis of muscle tissue samples, we can gain detailed insight into the muscles’ response to the experimental protocol,” explains Mikkel Oxfeldt.

Mikkel and the research group believe it’s necessary to confront the idea that weight loss leads to medals when in fact weight loss can negatively impact a number of the body’s systems, including muscles.

“In recent years, we’ve heard about public weigh-ins within some elite sports. They are part of promoting a culture in which some women are constantly trying to lose weight. However, our results show that this focus on weight loss can have short and potentially long-term negative consequences for women, both in relation to their health and training results. The study will hopefully provide athletes and coaches with a more nuanced picture of possible side effects.”

In collaboration with colleagues from the University of Copenhagen and University of Southern Denmark, the researchers behind the study are now investigating how physical performance, the immune system and metabolism are affected by an insufficient energy intake. They hope to one day be able to establish whether there is a difference between how women’s and men’s bodies react to inadequate energy intake.

Source: Aarhus University

Categories : CancerTags :

Metastases Survive by Adapting to Different Tissues

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Source: National Cancer Institute on Unsplash

In a breakthrough for understanding metastases, researchers have found that, as metastatic cancers spread to different parts of the body, they adapt their metabolism to the tissue in which they grow. The findings, which help further break down the puzzle of metastasis, are published in PNAS.

Metabolism in the body is an important target for cancer treatments, where the focus is on stopping the progress of cancer cells.

“Obviously, the local environment affects the cancer cells more than previously known. The metastatic tumours should show the same metabolic properties no matter where in the body they are located, but we discovered that the cancer cells largely adapted their metabolism to the new tissue in order to continue to develop and grow. This is important knowledge, which shows that we cannot consider the metastases as their original tumours,” says Fariba Roshanzamir, PhD in Systems and Synthetic Biology at Chalmers and the study’s lead author.

Cutting off cancer metabolism

Fariba Roshanzamir works in Professor Jens Nielsen’s research group at Chalmers and has, together with Swedish and international colleagues, been able to establish the groundbreaking results. The study focused primarily on triple-negative breast cancer but the conclusions can, according to the researchers, be applied to all types of metastatic cancer. This opens new doors to develop more effective treatments.

“If we manage to shut down the metabolism in a tumour, it will stop working and this study provides important keys to better understand what to target. Selecting metabolic inhibitors that specifically target the metastases in the organs to which the tumour has spread, rather than treating them as their original tumours, is of great importance to be able to find good strategies for treatments in the future,” she says.

Source: Chalmers University of Technology

Categories : ExerciseTags :

A New Seated Exercise Using the Calf Muscle Boosts Metabolism

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Photo by TheStandingDesk on Unsplash

A simple, groundbreaking exercise developed by researchers at the University at Houston can help boost metabolism in the sedentary office-based lifestyle that causes so many health problems. By using the soleus muscle in the calf, though accounting for only 1% of the body’s weight, the metabolic health of the rest of the body can be boosted – if this muscle activated in a very specific way.

Marc Hamilton, professor of Health and Human Performance at the University of Houston, has discovered such an approach for optimal activation: the “soleus pushup” (SPU) which effectively elevates muscle metabolism for hours, even while sitting. The soleus, one of the human body’s 600 muscles, is a posterior leg muscle that runs from just below the knee to the heel.

Prof Hamilton’s research, published in the journal iScience, suggests the soleus pushup’s ability to sustain an elevated oxidative metabolism to improve the regulation of blood glucose is more effective than any popular methods currently touted as a solution including exercise, weight loss and intermittent fasting. Oxidative metabolism burns metabolites like blood glucose or fats, but it partly depends on the immediate energy needs of the muscle when it’s working.

“We never dreamed that this muscle has this type of capacity. It’s been inside our bodies all along, but no one ever investigated how to use it to optimise our health, until now,” said Prof Hamilton. “When activated correctly, the soleus muscle can raise local oxidative metabolism to high levels for hours, not just minutes, and does so by using a different fuel mixture.”

Muscle biopsies had revealed that the soleus used minimal glycogen – the predominant carbohydrate for fuelling muscular exercise. Instead of breaking down glycogen, the soleus can use blood glucose and fats.

“The soleus’s lower-than-normal reliance on glycogen helps it work for hours effortlessly without fatiguing during this type of muscle activity, because there is a definite limit to muscular endurance caused by glycogen depletion,” he added. “As far as we know, this is the first concerted effort to develop a specialised type of contractile activity centred around optimising human metabolic processes.”

When the SPU was tested, the whole-body effects on blood chemistry included a 52% improvement in the excursion of blood glucose and 60% less insulin requirement over three hours after ingesting a glucose drink.

This new approach of keeping the soleus muscle metabolism going also doubles the normal rate of fat metabolism in the fasting period, reducing levels of VLDL triglyceride.

The soleus pushup

Building on years of research, Hamilton and his colleagues developed the soleus pushup, which activates the soleus muscle in a different way than standing or walking does. The SPU targets the soleus to increase oxygen consumption more than what’s possible with these other types of soleus activities, while also being resistant to fatigue.

While seated with feet flat on the floor and muscles relaxed, a soleus pushup is performed by the heel rising while the front of the foot stays put. When the heel gets to the top of its range of motion, the foot is passively released to come back down. The aim is to simultaneously shorten the calf muscle while the soleus is naturally activated by its motor neurons.

While the SPU movement might look like walking (though performed while seated) it is the exact opposite, the researchers say. The body is designed to minimise the amount of energy used in walking, because of how the soleus moves. Prof Hamilton’s method reverses that and makes the soleus use as much energy as possible for a long duration.

However, the method is very specific, and if you are trying this while seated at your desk right now, you may not be doing it in the right way.

“The soleus pushup looks simple from the outside, but sometimes what we see with our naked eye isn’t the whole story. It’s a very specific movement that right now requires wearable technology and experience to optimise the health benefits,” said Prof Hamilton.

Additional publications are in the works focused on how to instruct people to properly learn this singular movement, but without the sophisticated laboratory equipment used in this latest study.

The researchers are quick to point out that this is not some new fitness tip or diet of the month. It’s a potent physiological movement that capitalises on the unique features of the soleus.

Potential first step toward a health care breakthrough

Prof Hamilton said it is the “most important study” ever completed at his lab, and could be a solution to a variety of health problems caused by spending hours each day living with insufficient muscle metabolism caused by inactivity. The average American sits about 10 hours a day.

Inactivity is a major health risk, and a low low metabolic rate while seated is especially troublesome for people who are at high risk for age-associated metabolic diseases such as metabolic syndrome and type 2 diabetes.

Prof Hamilton said inactive muscles require less energy than most people seem to understand, saying it’s “one of the most fundamental, yet overlooked issues” guiding the way toward discovering metabolic solutions to assist in preventing some age associated chronic diseases.

“All of the 600 muscles combined normally contribute only about 15% of the whole-body oxidative metabolism in the three hours after ingesting carbohydrate. Despite the fact that the soleus is only 1% the body weight, it is capable of raising its metabolic rate during SPU contractions to easily double, even sometimes triple, the whole-body carbohydrate oxidation.

“We are unaware of any existing or promising pharmaceuticals that come close to raising and sustaining whole-body oxidative metabolism at this magnitude.”

Source: University of Houston

Categories : Ageing Immune SystemTags :

Traitorous Immune Cells Explain Why the Elderly Feel the Cold

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Photo by Adam Birkett on Unsplash

In a new study, Yale researchers found that the immune cells within fat that are designed to burn calories to protect us from cold temperatures start to turn against us as we age, making the elderly more vulnerable to the cold.

The study, published in Cell Metabolism, found that the fat tissue of older mice loses the immune cell group 2 innate lymphoid cells (ILC2) which restore body heat in cold temperatures. However, trying to stimulate production of new ILC2 cells in aging mice actually makes them more prone to cold-induced death, showing how difficult it is to solve aging-related problems.

“What is good for you when you are young, can become detrimental to you as you age,” said Vishwa Deep Dixit, the Waldemar Von Zedtwitz Professor of Comparative Medicine and of Immunobiology and co-corresponding author of the study.

Prof Dixit and former colleague Emily Goldberg, now an assistant professor at UCSF, were curious about why there are immune cells in fat tissue, as they are usually concentrated in pathogen-exposed areas like nasal passages, lungs, and skin. When they sequenced genes from cells of old and young mice they found that older animals lacked ILC2 cells, a deficit which limited their ability to burn fat in cold conditions.

When they introduced a molecule that boosts the production of ILC2 in aging mice, the immune system cells were restored but the mice were surprisingly even less tolerant of cold temperatures.

“The simple assumption is that if we restore something that is lost, then we are also going to restore life back to normal,” Dixit said. “But that is not what happened. Instead of expanding healthy cells of youth, the growth factor ended up multiplying the bad ILC2 cells that remained in fat of old mice.”

However, when ILC2 cells were taken from younger mice and transplanted into older mice, the older animals’ cold tolerance was restored.

“Immune cells play a role beyond just pathogen defense and help maintain normal metabolic functions of life,” Dixit said. “With age, the immune system has already changed and we need to be careful how we manipulate it to restore the health of the elderly.”

Source: SciTech Daily

Categories : Environmental EffectsTags :

Obesity Connection to Commonly-used Pesticide

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Photo by Arjun MJ on Unsplash

A commonly-used pesticide could be contributing to the global obesity epidemic, according to a new study.

Researchers discovered that chlorpyrifos slows down the burning of calories in the brown adipose tissue of mice. Reducing this burning of calories, a process known as diet-induced thermogenesis, causes the body to store these extra calories, promoting obesity. Chlorpyrifos is banned for use on foods in Canada, and also now banned in the US and, as of last year, the EU, but widely sprayed on fruits and vegetables in many other parts of the world. In South Africa it is banned for residential use but is still used in agriculture.

Scientists made the discovery after studying 34 commonly used pesticides and herbicides in brown fat cells and testing the effects of chlorpyrifos in mice fed high calorie diets. Their findings were published in Nature Communications and could have important implications for public health.

“Brown fat is the metabolic furnace in our body, burning calories, unlike normal fat that is used to store them. This generates heat and prevents calories from being deposited on our bodies as normal white fat. We know brown fat is activated during cold and when we eat,” said senior author Gregory Steinberg, professor of medicine and co-director of the Centre for Metabolism, Obesity, and Diabetes Research at McMaster.

“Lifestyle changes around diet and exercise rarely lead to sustained weight loss. We think part of the problem may be this intrinsic dialling back of the metabolic furnace by chlorpyrifos.”

Steinberg said chlorpyrifos would only need to inhibit energy use in brown fat by 40 calories every day to trigger obesity in adults, which would translate to an extra 2kg of weight gain per year.

He said that while several environmental toxins including chlorpyrifos have been associated with increasing obesity rates in both humans and animals, these studies have mostly attributed weight gain to increases in food intake and not calorie burning.

“Although the findings have yet to be confirmed in humans, an important consideration, is that whenever possible consume fruits and vegetables from local Canadian sources and if consuming imported produce, make sure it is thoroughly washed,” said Steinberg.

Source: Medical Xpress

Categories : AgeingTags :

Metabolism Through Life Varies in Unexpected Ways

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Photo by Johnny Cohen on Unsplash

A new study published in Science suggests that falls in metabolism occur much later in life, with a peak at a much younger age than anticipated.

“There are lots of physiological changes that come with growing up and getting older,” said study co-author Herman Pontzer, associate professor of evolutionary anthropology at Duke University. “Think puberty, menopause, other phases of life. What’s weird is that the timing of our ‘metabolic life stages’ doesn’t seem to match those typical milestones.”

Together with an international team of scientists, Prof Pontzer analysed the average energy expenditure of more than 6,600 people ranging from one week old to age 95 as they went about their daily lives in 29 countries.

Previously, most large-scale studies measured how much energy the body uses to perform basic vital functions. But that amounts to only 50% to 70% of the calories we burn each day. It doesn’t take into account the energy we spend doing everything else.

To come up with a number for total daily energy expenditure, the researchers relied on the “doubly labeled water” method, a urine test that involves having a person drink water with isotopes of hydrogen and oxygen and measuring how quickly these were flushed. This gold standard technique for measuring energy expenditure in humans outside the lab since the 1980s, but studies have been limited in size and scope due to cost. To overcome this, multiple labs pooled their data.

The research into energy expenditures revealed some surprises: compared to body weight, infants had the highest metabolic rates of all, rather than people in their teens or 20s as might be expected.

Energy needs shoot up during the first 12 months of life, and by their first birthday, a one-year-old burns calories 50% faster for their body size than an adult.

This comes from more than just tripling their birth weight in the first year. “Of course they’re growing, but even once you control for that, their energy expenditures are rocketing up higher than you’d expect for their body size and composition,” said Pontzer, author of the book, “Burn,” on the science of metabolism. “Something is happening inside a baby’s cells to make them more active, and we don’t know what those processes are yet,” Pontzer said.

After this initial surge in infancy, the data show that metabolism slows by about 3% each year until we reach our 20s, when it stabilises.

Teenagers, despite their growth spurt, did not result in an uptick in energy intake once weight was accounted for. “We really thought puberty would be different and it’s not,” Pontzer said.

Midlife was another surprise, with a thickening waistline from the 30s often ascribed to a changing metabolism, but the results show other factors are responsible.

In fact, the researchers discovered that energy expenditures from the 20s to 50s were the most stable. Even during pregnancy, a woman’s calorie needs were no more or less than expected given her added bulk as the baby grows. Metabolism only declines after age 60, and only by 0.7% a year. A person in their 90s needs 26% fewer calories than one in midlife.

Lost muscle mass explains part but not all of the picture. “We controlled for muscle mass,” Pontzer said. “It’s because their cells are slowing down.”

The patterns held even when differing activity levels were taken into account.

Energy expenditure changes have been difficult to analyse because so much else is going on, Prof Pontzer said. But the research supports the idea that it’s more than age-related changes in lifestyle or body composition.

“All of this points to the conclusion that tissue metabolism, the work that the cells are doing, is changing over the course of the lifespan in ways we haven’t fully appreciated before,” Prof Pontzer said. “You really need a big data set like this to get at those questions.”

Source: Duke University

Categories : Cardiovascular Disease GenderTags :

Cardiovascular Diseases in Transgender Youth

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Young transgender people face a higher risk of cardiovascular diseases, according to a new study.

Anna Valentine, MD, of the University of Colorado Anschutz Medical Campus in Aurora, presented the findings of her team’s study at the Endocrine Society’s virtual ENDO 2021 meeting. Existing research shows increased cardiovascular risks in adult transgender people.

Researchers found that transgender youths assigned female at birth had a higher risk of obesity compared to cisgender female youths, as well as a nearly doubled chance of polycystic ovary syndrome. However, transgender youth did not have an increased risk of hypertension, dysglycaemia, or liver dysfunction.

These differences could be explained by any number of different mechanisms, Dr Valentine explained. “We know that some youth with gender dysphoria have higher rates of overweight and obesity, and that having overweight and obesity itself increases your risk of having other diagnoses.” It is also known that “youth with gender dysphoria have higher rates of mental health comorbidities … as well as getting less physical activity,” she said.

“And they also may be taking medication that could all influence their cardiometabolic health,” she added.

Adult transwomen taking estradiol are more likely to have higher levels of triglycerides and a higher rate of stroke, blood clots, and myocardial infarction (MI). Adult trans men are at greater risk of elevated triglycerides, low-density lipoprotein cholesterol, and body mass index (BMI), as well as lower high-density lipoprotein cholesterol, and an increased risk of MI.
The data of 4174 paediatric patients (average age of 16) diagnosed with gender dysphoria, were compared with 16 651 cisgender controls. This data came from six large paediatric centres. Participants were matched with four controls.

However, the data did not include information on which participants were receiving hormonal treatment, which is something that Dr Valentine is looking to address in her research.

“We do know that in the adult data, that there is some association with estradiol use and testosterone use with differences in cholesterol parameters, but this is still an emerging field in paediatrics,” Dr Valentine explained. “We have some small single-center studies that sometimes say ‘yes, with hormones we see an increase in BMI,’ but other studies say ‘this section looks very stable on this hormone’.”

“The fact that we have such a large cohort in this multicentre analysis for our next steps, I think it will be really interesting to look at that,” she added.

Source: MedPage Today

Presentation information: Valentine A, et al “Multicenter analysis of cardiometabolic-related diagnoses in transgender adolescents” ENDO 2021.

Categories : GeneticsTags :

Study Reveals How Thyroid Subtly Regulates Metabolism

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Thyroid hormone appears to regulate metabolism by acting as a ‘dimmer switch’ as opposed to an ‘on/off’ switch, as reported by a new study from the University of Pennsylvania.

The thyroid hormone has long been known to be an important controller of the body’s metabolism, as well development, but how exactly this is achieved remains something of a mystery. Part of this problem was that the thyroid hormone worked inside the nucleus, activating some genes and deactivating others. Being able to observe this process has been extremely challenging.

“We were able in this study to show that thyroid hormone doesn’t just turn things on or off, as the canonical model suggests, but instead more subtly shifts the balance between the repression and enhancement of gene activity,” said principal investigator Mitchell Lazar, MD, PhD, at Penn Medicine. “Yet, as people with hypothyroidism know, the lack of thyroid hormone can have profound effects on the body.”

Knowing how thyroid hormone regulates the body’s metabolism would be a great boon for new drug development, especially to tackle obesity. For four decades, scientists have known that thyroid hormone acts on thyroid hormone receptors, but these special proteins exist in small quantities and marking where they are on DNA has proven difficult.
In the new study, the researchers developed a mouse model in which a special tag was added to TRβ, the main thyroid hormone receptor in the liver, which is where important metabolic effects of thyroid hormone occur. With this tag, they marked the thousands of locations on DNA where TRβ binds, both in states when thyroid hormone was present and could bind to TRβ and also when no hormone was present. In this way, the team came up with strong evidence that shows the unexpectedly subtle manner in which thyroid hormone works with TRβ.

When it binds to a DNA site, TRβ will promote or suppress nearby gene activity by forming complexes with other proteins called co-activators and co-repressors. When thyroid hormone is bound to TRβ, it can alter the balance of these co-regulator proteins towards more gene activation at some sites, and more gene repression at others. Prior models of thyroid hormone / TRβ function in which thyroid hormone has a more absolute, switch-like effect on gene activity.

The researchers acknowledged that more work is needed to discover just how genes are activated or repressed at the sites. However, this is a significant advancement towards treatments which can directly influence the body’s metabolism.

Source: Medical Xpress