Beige fat cells with a 'Sisyphus mechanism'

Fat cells come in three colours: white, brown, and beige. White fat cells store fat in our body as an energy reserve. We need these cells, but having too many creates health problems. Brown fat cells are particularly active in infants. They produce heat and thus maintain the baby's body temperature. However, the amount of brown adipose tissue decreases over a person's lifetime; adults have very little of it. Then, finally, the beige fat cells. These can also produce heat, albeit somewhat less well than brown fat cells. Beige fat cells occur in adults as well: scattered throughout the white fatty tissue, especially in the neck and shoulder area, they help in using up excess energy.

Now an international research team has discovered and described a new type of beige fat cells, which differ from the ones that were already known. "Fat cells of this new beige type play an important role in energy metabolism in the human body and have a positive effect on metabolic diseases and obesity," says Anand Sharma, a postdoc in ETH Professor Christian Wolfrum's group and coauthor of the study. "That's why it's so important to understand in detail how they work." The study was led by ETH Zurich, the University of Basel, the University of Leipzig Medical Center and the Dana-Farber Cancer Institute in Boston. Numerous other hospitals and research institutions around the world were involved in the project.

Independent of a known protein

The beige fat cells that researchers were already familiar with generate heat in the same way as brown fat cells: via a protein called UCP1. This protein is located in the inner of two membranes that surround the mitochondria, the structural units often referred to as the powerhouse of the cell. As part of their normal function, mitochondria pump protons into the space between the two membranes. Protons are electrically charged elementary particles that generally play an important role in energy conversion processes in cells. Bown fat cells and the classic beige fat cells described earlier have the protein UCP1. It forms a very narrow channel in the inner membrane through which the protons flow back into the mitochondria, thereby generating heat from friction.

In recent years, scientists have discovered that there are also beige fat cells without the UCP1 protein, and that these also consume energy and thus produce heat. The research team from ETH Zurich and the participating institutions has now precisely characterised the new class of beige fat cells and shown how they do this: by means of a "Sisyphus mechanism."

Here's how it works: All biochemical processes that take place in cells always generate some heat. The new class of beige fat cells takes advantage of this and allows individual processes to run back and forth, seemingly without purpose. This primarily involves two conversion processes. In one, the cells break fats down into their components (fatty acids) at full speed and then assemble them into new fats just as quickly. In the other, they apply an enzyme to convert molecules of creatine into creatine phosphate, a related molecule, only to immediately convert it back into creatine. Scientists call these back-and-forth processes "futile cycles." They don't add anything to the biochemical budget overall, but they consume energy and generate heat.

Preventing diabetes and obesity

The research team first described the new type of beige fat cells in mice. They then examined human adipose tissue and were able to show that these fat cells occur there, too. While less than half the population has the previously known type of classical beige fat cells, almost all humans have the new futile-cycle type, albeit in differing amounts.

As the researchers were able to show, people with a high number of beige fat cells -- of either the previously known type or this new type -- are slimmer and tend to have better metabolic health. That makes them less prone to obesity and metabolic disorders such as diabetes. "Because beige fat cells convert energy into heat, they help to break down excess fat," explains Tongtong Wang, an ETH doctoral student in ETH Professor Wolfrum's group and lead author of the study.

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How obesity dismantles our mitochondria

The number of people with obesity has nearly tripled since 1975, resulting in a worldwide epidemic. 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, which affects more than 40% of adults in the United States, 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."

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Positively charged nanomaterials treat obesity anywhere you want

Researchers have long been working on how to treat obesity, a serious condition that can lead to hypertension, diabetes, chronic inflammation, and cardiovascular diseases. Studies have also revealed a strong correlation of obesity and cancer -- recent data show that smoking, drinking alcohol, and obesity are the biggest contributors to cancer worldwide.

The development of fat cells, which are produced from a tiny fibroblast-like progenitor, not only activates the fat cells' specific genes but also grows them by storing more lipids (adipocytes and adipose tissue). In fact, lipid storage is the defining function of a fat cell. But the storage of too much lipid can make fat cells unhealthy and lead to obesity.

Challenges in targeting fat cells

The ability to target fat cells and safely uncouple unhealthy fat formation from healthy fat metabolism would be the answer to many peoples' prayers. A major challenge in obesity treatment is that fat tissue, which is not continuous in the body but is found piece by piece in "depots," has been difficult to target in a depot-specific manner, pinpointed at the exact location.

There are two main kinds of fat: visceral fat, internal tissues that surround the stomach, liver, and intestines, and subcutaneous fat, found under the skin anywhere in the body. Visceral fat produces potbellies; subcutaneous fat can create chin jowls, arm fat, etc. To date, there has been no way to specifically treat visceral adipose tissue. And current treatments for subcutaneous fat like liposuction are invasive and destructive.

New studies use cationic nanonmaterials to target fat

Two new studies from researchers at Columbia Engineering and Columbia University Irving Medical Center (CUIMC) may have the answer to targeting fat cells depot-specifically and healthily. The papers demonstrate a new method to treat obesity by using cationic nanomaterials that can target specific areas of fat and inhibit the unhealthy storage of enlarged fat cells. The materials remodel fat rather than destroying it, as, for example, liposuction does. The first paper, published today by Nature Nanotechnology, focuses on visceral adiposity, or belly fat. The second paper, published online November 28 by Biomaterials, focuses on fat underneath the skin as well as chronic inflammation associated with obesity.

The team of researchers, led by Li Qiang, associate professor of pathology and cell biology at CUIMC, and Kam Leong, Samuel Y. Sheng Professor of Biomedical Engineeringand of systems biology at CUIMC, recognized that adipose tissue contains large amounts of negatively charged extracellular matrix (ECM) to hold fat cells. They thought that this negatively charged ECM network might provide a highway system of sorts for positively charged molecules. So they took a positively charged nanomaterial, PAMAM generation 3 (P-G3), and injected it into obese mice. The P-G3 quickly spread throughout the tissue and the team was excited that their method to specifically target visceral fat worked.

Unexpected results

And then something intriguing happened: P-G3 shut off the lipid storage program in fat cells and the mice lost weight. This was totally unexpected, given the well-established function of P-G3 in neutralizing negatively charged pathogens, such as DNA/RNA cell debris, to alleviate inflammation.

"Our approach is unique -- It departs from the pharmacological or surgical approaches," says Qiang, who specializes in obesity and adipocyte biology. "We used cationic charge to rejuvenate healthy fat cells, a technique no one has ever used to treat obesity. I think this novel strategy will open the door to healthier and safer reduction of fat."

P-G3 helps new fat cell formation and also inhibits the unhealthy lipid storage of enlarged fat cells

In these two studies, the researchers discovered that the cationic material, P-G3, could do an intriguing thing to fat cells -- while it helped new fat cell formation, it also uncoupled lipid storage from the housekeeping functions of fat cells. And because it inhibits the unhealthy lipid storage of enlarged fat cells, the mice had more metabolically healthy, young, small fat cells like those found in newborns and athletes. The researchers found that this uncoupling function of P-G3 also holds true in human fat biopsies, signifying the potential of translation in humans.

"With P-G3, fat cells can still be fat cells, but they can't grow up," said Leong, a pioneer in using polycation to scavenge pathogens. "Our studies highlight an unexpected strategy to treat visceral adiposity and suggest a new direction of exploring cationic nanomaterials for treating metabolic diseases."

New applications for drug delivery, gene therapy, and aesthetics

Now that they can selectively target visceral fat, Leong and Qiang envision several applications. The Biomaterials study demonstrates a simple approach that could be used for aesthetic purposes; like Botox, P-G3 can be locally injected into a specific, subcutaneous fat depot. The investigators, who have patents pending, are now engineering P-G3 into various derivatives to improve the efficacy, safety, and depot specificity.

What the researchers are particularly excited about is developing P-G3 into a platform that can deliver drugs and gene therapies specifically to a given fat depot. This may repurpose many drugs from systemic safety concerns, such as Thiazolidinediones (TZDs), a potent but unsafe drug that is a strong modulator of fat and used to treat type 2 diabetes -- but it has been linked to heart failure and banned in several countries.

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Molecule boosts fat burning

Normally, fat cells store energy. In brown fat cells, however, energy is dissipated as heat -- brown fat thus serves as a biological heater. Most mammals therefore have this mechanism. In humans it keeps newborns warm, in human adults, brown fat activation positively correlates with cardio-metabolic health.

"Nowadays, however, we're toasty warm even in winter," explains Prof. Dr. Alexander Pfeifer from the Institute of Pharmacology and Toxicology at the University of Bonn. "So our body's own furnaces are hardly needed anymore." At the same time, we are eating an increasingly energy-dense diet and are also moving far less than our ancestors. These three factors are poison for brown fat cells: They gradually cease to function and eventually even die. On the other hand, the number of severely overweight people worldwide continues to increase. "Research groups around the world are therefore looking for substances that stimulate brown fat and thus increase fat burning," says Pfeifer.

Dying fat cells boost energy combustion of their neighbors

Together with a group of colleagues, the team at the University of Bonn has now identified a key molecule named inosine that is capable of burning fat. "It is known that dying cells release a mix of messenger molecules that influence the function of their neighbors," explains Dr. Birte Niemann from Pfeifer's research group. Together with her colleague Dr. Saskia Haufs-Brusberg, she planned and conducted the central experiments of the study. "We wanted to know if this mechanism also exists in brown fat."

The researchers therefore studied brown fat cells subjected to severe stress, so that the cells were virtually dying. "We found that they secrete the purine inosine in large quantities," Niemann says. More interesting, however, was how intact brown fat cells responded to the molecular call for help: They were activated by inosine (or simply by dying cells in their vicinity). Inosine thus fanned the furnace inside them. White fat cells also converted to their brown siblings. Mice fed a high-energy diet and treated with inosine at the same time remained leaner compared to control animals and were protected from diabetes.

The inosine transporter seems to play an important role in this context: This protein in the cell membrane transports inosine into the cell, thus lowering the extracellular concentration. Therefore, inosine can no longer exert its combustion-promoting effect.

Drug inhibits the inosine transporter

"There is a drug that was actually developed for coagulation disorders, but also inhibits the inosine transporter," says Pfeifer, who is also a member of the Transdisciplinary Research Areas "Life and Health" and "Sustainable Futures" at the University of Bonn. "We gave this drug to mice, and as a result they burned more energy." Humans also have an inosine transporter. In two to four percent of all people, it is less active due to a genetic variation. "Our colleagues at the University of Leipzig have genetically analyzed 900 individuals," Pfeifer explains. "Those subjects with the less active transporter were significantly leaner on average."

These results suggest that inosine also regulates thermogenesis in human brown fat cells. Substances that interfere with the activity of the transporter could therefore potentially be suitable for the treatment of obesity. The drug already approved for coagulation disorders could serve as a starting point. "However, further studies in humans are needed to clarify the pharmacological potential of this mechanism," Pfeifer says. Neither does he believe that a pill alone will be the solution to the world's rampant obesity pandemic. "But the available therapies are not effective enough at the moment," he stresses. "We therefore desperately need medications to normalize energy balance in obese patients."

The key role played by the body's own heating system is also demonstrated by a major new joined research consortium: The German Research Foundation (DFG) recently approved a Transregional Collaborative Research Center in which the Universities of Bonn, Hamburg and Munich conduct targeted research on brown adipose tissue.

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Breakthrough in using CRISPR-Cas9 to target fat cells

Fat -- it is vital for life but too much can lead to a host of health problems. Studying how fat, or adipose, tissue functions in the body is critical for understanding obesity and other issues, yet structural differences in fat cells and their distribution throughout the body make doing so challenging.

"Fat cells are different from other cells in that they lack unique cell surface receptors and only account for a minority of the cells within fat tissue," said Steven Romanelli, Ph.D., a former member in the laboratory of Ormand MacDougald, Ph.D., in the Department of Molecular & Integrative Physiology.

In a new paper published in the Journal of Biological Chemistry, Romanelli, MacDougald and their colleagues describe a breakthrough using CRISPR-Cas9, a tool that has transformed molecular biological research, but whose use in the study of adipose tissue had been elusive.

"The biggest challenge in terms of adipose research to date has been that if you want to study a gene's function, you have to commit a considerable amount of time, resources and money into developing a transgenic mouse," said Romanelli.

The traditional way of developing mouse models involves breeding mice with a desired mutation to delete or introduce certain genes of interest, which Romanelli says can take more than a year and tens of thousands of dollars.

CRISPR-Cas9 has revolutionized this process. It's a gene editing technique comprised of an enzyme called Cas9 which can break strands of DNA and a piece of RNA that guides the Cas9 enzyme to a specific site in the genome for editing. This tool is packaged into a non-harmful virus for delivery to the cells being studied. The tool has been successfully used to study heart, liver, neurons, and skin cells to name a few, but never a certain type of adipose cells known as brown fat.

Using the technique, the team was able to successfully target brown fat, a specialized adipose tissue used to generate heat and protect core body temperature.

"What we've been able to do is take that whole process and distill it into anywhere from two weeks to a month to generate a transgenic mouse, reducing the cost to less than $2,000. Not only does it reduce time and cost, it democratizes the research so that any lab that is familiar with molecular biology techniques can adopt this method and do it themselves," said Romanelli.

They were also able to use this method to delete multiple genes simultaneously, a fact that could help researchers better understand important molecular pathways.

Using their adeno-associated virus CRISPR-Cas9 components, they were able to knockout the UCP1 gene that defines brown adipose and enables it to generate heat, in adult mice. They observed that the knockout mice were able to adapt to the loss of the gene and maintain their body temperature in cold conditions, hinting at other pathways involved in temperature homeostasis.

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