The many shades of fat
Fat is not what it used to be, but in fact it never was. Only a few years ago, fatty tissue was simply considered a storage site for fat. Philipp E. Scherer has provided some of the most important contributions to dispelling this myth. Today, researchers know that there are healthy and unhealthy types of fat cells but also that fatty tissue constantly influences the rest of the body as if it were an organ.
If it were a person, it would weigh 400 kilograms. The mouse called the world’s fattest weighed five times as much as a normal mouse. Despite this, the mouse was apparently fit and healthy and showed no signs of diabetes.
“The mouse did not produce any leptin, which suppresses appetite. The mouse also secreted three times as much of adiponectin, another important adipocyte-derived hormone that produces healthy fat tissue. This combination meant that the mouse ate without stopping. However, when we examined the mouse, it showed no signs of either diabetes or visceral fat surrounding its organs,” explains Philipp E. Scherer from the University of Texas Southwestern Medical Center in Dallas, United States.
This obese mouse helped to overturn the research world’s view of fat and questioned whether fat independently causes obese people to more often develop lifestyle-related diseases or whether other factors decide this.
“I would never recommend counting on becoming obese in a healthy way, but we have definite proof that people who are overweight can actually be pretty healthy, at least at the time we study them. And people who are thin can also have a very unhealthy metabolism, with many of the harmful health effects such as cardiovascular disease and type 2 diabetes that we otherwise associate with being overweight.”
Today, leptin and adiponectin play a key role in research on obesity and type 2 diabetes. Researchers have well-founded expectations that learning how to regulate the secretion of these two proteins may contribute to helping the many people worldwide with lifestyle-related diseases to lead better and healthier lives.
When fat communicates
The fact that two small proteins would play the major role in research on understanding the function and importance of fatty tissue on human health was not in the cards when Philipp E. Scherer began his research career 30 years ago. He began in the late 1980s in Basle, where France, Germany and Switzerland meet. Here one of the key researchers behind the discovery of mitochondrial DNA, Gottfried Schatz, was based.
“Although this was a different research field, Gottfried Schatz made me understand how incredibly important mitochondrial metabolism is for cells. In addition, proteins need to be targeted to their proper cellular location, and there are critical signals associated with proteins that will traffic them to mitochondria, where complex machinery interprets these targeting signals. Alternatively, they need to be secreted and targeted to the proper cells in distant tissues. These secreted proteins often decisively influence the communication between cells.”
This fact was crucial when Philipp E. Scherer chose to move to the United States to continue his research career after he received his PhD degree in Basle. While he had been studying protein transport in the mitochondria of yeast cells in Switzerland, researchers in the laboratory of Harvey Lodish at MIT in Cambridge had been studying the insulin-mediated transport of glucose across the membranes of fat cells.
“But I soon realized that this research field was very crowded and that I needed to try and find my own niche. I therefore decided to focus on proteins and their effects on how fat cells can communicate with each other and with the rest of the body. So we started to focus on fat cells as secretory cells and examine what they secreted and how this interacted with the rest of the body.”
Hibernating Siberian chipmunks
It soon became apparent that choosing this new angle on the function of fat cells was a quite fortuitous move. Scherer and his colleagues struck gold as early as 1995, and this turned out to be the pivotal moment for Scherer’s future research group and for overall research on obesity and diabetes.
“We discovered a previously unknown protein, Acrp 30, solely produced and secreted by fatty tissue. Fat cells secrete abundant quantities of Acrp 30; this increased more than 100-fold during the development of the fat cells themselves and should have interesting regulatory patterns under various metabolic conditions.”
Already the following year, Acrp30 was given its current name, adiponectin, by researchers in Japan. However, in 1995, Scherer and his colleagues knew nothing more about adiponectin’s function.
“Among other things, its sequence and structure resembled a part of the human immune system, and a protein observed in hibernating Siberian chipmunks. The protein turned out to have effects on many other tissues in the body. Since then, adiponectin has led us into many new fields. I am still amazed by adiponectin’s wide-ranging influence on many metabolic processes.”
Contrary to all expectations
The discovery of adiponectin followed hard on the heels of the discovery of leptin, the other well-known hormone fatty tissue secretes. When leptin is released, it affects the brain, increasing the feeling of satiety and sending the metabolism into overdrive. A lack of leptin may therefore contribute to obesity. The effect of adiponectin, however, totally surprised Scherer and his colleagues.
“Because adiponectin is produced by fat cells and is strongly boosted in the development of the fat cells themselves, we had expected high levels among people who are overweight, but we saw the reverse. Obese people had lower concentrations, whereas people with anorexia, for example, had greatly elevated concentrations of adiponectin.”
Now, more than two decades later, the researchers do not fully understand the effects and function of adiponectin, but recent research suggests that fat cells in bone marrow greatly increase their production of adiponectin in times of hunger. In any case, the discovery of leptin and adiponectin launched modern obesity research.
“The discovery of leptin and adiponectin radically changed how researchers perceive fat cells. The last 20 years have taught us that fat cells are not simply a storage location for fat, but rather are extremely active cells that secrete very many physiologically active substances that have powerful effects on other tissue. Today, we know that the communication between fatty tissue, the brain, kidney, pancreas, heart and liver is key to understanding obesity and other lifestyle-related diseases.”
The world’s largest mouse
Recent research has shown once again that the amount of fatty tissue is definitely not that important in determining whether a person’s metabolism is healthy. Comparing people with healthy versus unhealthy metabolism shows that health is not associated with a person’s body mass index but instead with such factors as the concentration of adiponectin.
“We can see, for example, that the prevalence of type 2 diabetes and even insulin resistance as a whole is closely associated with the concentration of adiponectin in the blood. We therefore tried to manipulate mice genetically to produce less leptin but excessive adiponectin to see how this affected their health.”
The lack of leptin made the mice constantly hungry. In contrast, adiponectin signalled their brains that they were in a state of starvation. This combination made the mice eat constantly and become fatter and fatter. Despite this, adiponectin apparently also made the mice store the surplus fat and sugar instead of them circulating in the blood.
“This resulted in some grossly overweight mice that actually had improved insulin resistance and no visible signs of type 2 diabetes, and they definitely had no fat or sugar in their blood. In addition, despite their increased fat mass, the mice stored the fat under their skin instead of surrounding their organs.”
The researchers had distinguished obesity as an independent factor from the harmful effects of metabolic diseases. Thus, although obesity is often associated with metabolic diseases, it is apparently not obesity in itself but altered signalling patterns and especially where and how fat is stored that determine whether a person’s metabolism becomes healthy or unhealthy and thereby increases the risk of cardiovascular disease and type 2 diabetes.
“Despite being the heaviest mice ever, they could effectively keep all the extra calories and thus the negative effects away from all other tissue other than fatty tissue, but that was not all. The enormous adipose tissue the mice built up under their skin comprised small fat cells without dangerous inflammation and with an efficient blood supply, which is important for healthy fatty tissue.”
The research by Scherer and others has shown that fatty tissue only becomes a health hazard when the oxygen supply declines, since this is especially important for maintaining healthy fatty tissue and metabolism. The fat from surplus food is normally stored as drops in the fat cells, which thus slowly expand. Stress signals are emitted when oxygenation is insufficient, and this ensures that new paths for blood supply are formed so that the fat cells can continue to be oxygenated.
“Storing nutrients for hard times was vital historically. But today, with no shortage of food, the fat stores often grow so much that the blood supply and therefore oxygenation becomes insufficient. This damages the fat cells, which eventually die. This conversion of healthy fatty tissue into unhealthy tissue, sharply increases the risk of lifestyle-related diseases such as type 2 diabetes.”
White, brown and beige
Healthy fatty tissue is therefore not determined by size but more by oxygenation, blood supply and especially hormones signalling from tissue to other organs. Recent research in this field has therefore focused on characterizing fatty tissue. Today, researchers distinguish at least three types of fat: white, brown and, most recently, beige.
White fatty tissue specializes in storing surplus energy as fat, whereas brown fatty tissue can metabolize nutrients and convert their energy into heat. The fatty tissue is brown because of the iron-rich proteins present in the mitochondria – the energy-producing centres in the cells – and more blood vessels.
“We are currently trying to understand what characterizes the different types of tissue and especially how the body could convert one type to another. If, for example, the body could convert the white fat cells to beige or brown ones, this would strongly improve metabolism and the creation of healthy fatty tissue.”
Scherer and his colleagues also think that increasing the numbers of brown or beige fat cells or improving their activity may be able to reduce obesity and correct the harmful effects of unhealthy metabolism. Nevertheless, they have no definitive proof that converting fat cells from white to beige or brown is all that is required.
Body fat as an organ
The research in the past two decades thus shows that the once monochromatic and unequivocal picture of fat has become much more colourful and multifaceted. Philipp E. Scherer also believes that the time is ripe to perceive fatty tissue completely differently.
“Basically, fatty tissues behave as a distinct organ like any other in the body: an aggregation of cells that performs one or more specialized functions. And the more we study fatty tissue, the more important it appears to be in the human body. For example, recent research has shown that fatty tissue plays a major role in developing cancer and fending off infectious diseases.”
Several parasites target fat cells in such diseases as Chagas disease, caused by Trypanosoma cruzi, just as the malaria parasite does in red blood cells. Further, fat cells may apparently also play an important role in breast cancer.
“Fatty tissue plays a major role in several types of cancer in which the tissue is slowly infiltrated by cancer cells. One such example is the lactiferous ducts in breasts, in which cancer cells use the growth factors and other substances secreted by the fat cells.”
No magic pill yet
Time has thus shown that leptin and adiponectin are just two of the many crucial signalling hormones that fatty tissue secretes to communicate with other tissue and cells. But the focus on these two hormones results from many researchers, including Scherer, considering them to be the key to solving global problems with metabolic diseases such as type 2 diabetes and cardiovascular disease.
“Adiponectin appears to have an incredibly important role. In fatty tissue, it helps to ensure the development of new small fat cells and veins and thereby sufficient oxygenation of the tissue. We have found adiponectin receptors in the liver, heart, kidneys and pancreas, and evidence shows that it directly increases insulin sensitivity in several of these tissues. Adiponectin has also been shown to reduce the risk of blood clots and improve wound healing.”
Philipp E. Scherer therefore believes that adiponectin is one of the most important biomarkers for determining health, including the risk of type 2 diabetes and cardiovascular disease. Genetic studies have shown that mutations in the gene for secreting adiponectin increase the risk of developing these diseases. Adiponectin and especially the body’s adiponectin receptors are therefore an important target for future treatment.
“Unfortunately, there is no magic pill yet, because adiponectin cannot be used in treatment. It is difficult to produce synthetically and is also unstable as a pill. However, research is already taking place to develop substances similar to adiponectin that can stimulate the adiponectin receptors in the various types of tissue for people who cannot secrete sufficient amounts. This may potentially enable such diseases as type 2 diabetes to be treated and effectively improve insulin sensitivity.”
Professor Philipp Scherer receives the 2017 EASD–Novo Nordisk Foundation Diabetes Prize for Excellence accompanied by DKK 6 million (€806,000) for his outstanding contributions that have increased our knowledge of diabetes.