Obesity: EPAC1 protein that increases brown fat identified

Researchers from the University Hospital Bonn (UKB) and the transdisciplinary research area “Life & Health” at the University of Bonn have now identified, in a study on theobesity, the EPAC1 protein as a new pharmacological target to increase brown fat mass and activity. Brown fat cells convert energy into heat, a key to eliminating unwanted fat deposits. Furthermore, they also protect against cardiovascular diseases.

The results of research were published in the journal Nature Cell Biology.

Obesity: why brown fat matters

The long-term goal of the study is to find drugs that support weight loss. Obesity is defined as a pathological increase in white fat and has become a major problem worldwide, with a significantly increased risk of cardiovascular diseases such as heart attack and stroke.

“Exercise and diet are not enough to lose weight effectively and permanently,” says corresponding author Prof. Alexander Pfeifer, director of the Institute of Pharmacology and Toxicology at the University Hospital Bonn and member of the areas of transdisciplinary research (TRA) “Life & Health” and “Sustainable Future” at the University of Bonn.

“Our high-energy foods cause energy to be stored in white fat. But losing weight is not so easy, as the body saves energy in response to a low-calorie diet. So our goal is to get a further release of energy.”

Brown fat cells, on the other hand, act like a biological oven and ensure, for example, that newborns can cope with exposure to cold after birth. However, adults rarely have brown fat, which is mostly found in young, thin people. “We then asked ourselves how to increase brown fat mass while simultaneously reducing bad white fat,” says Bonn postdoctoral researcher and first author of the obesity study, Dr. Laia Reverte-Salisa.

Together with researchers from the University Medical Center Hamburg-Eppendorf, Helmholtz Munich and the University of Toulouse-Paul Sabatier, the Bonn team studied the cAMP signaling pathway in fat metabolism which plays a central role in fat cells and is fundamental in the study of obesity.

Using a mouse model, they found that the relatively unknown protein, “cAMP-directly activated exchange proteins” (EPAC1), is responsible for the growth of brown fat. Furthermore, EPAC1 even increases the formation of brown fat cells in white fat, also called “beige” cells.

Prof. Pfeifer's team also demonstrated that the signaling pathway is also active in human fat cells. Furthermore, they confirmed the function of EPAC1 in human organoids, organ-like microstructures that serve as a model of human brown fat.

The Bonn researchers also found that a non-functional variant of the human EPAC1 gene is associated with increased body mass index (BMI). “Our study shows that EPAC1 is an interesting target for increasing brown fat mass and thus also energy expenditure,” says Prof. Pfeifer, speaking of a solution for obesity.

In view of the worldwide increase in obesity, he hopes to develop new therapies that will help those affected fight metabolic diseases. This study was conducted in the context of the DFG Transregio-SFB 333 Collaborative Research Center “Brown and Beige Fat—Organ Interactions, Signaling Pathways and Energy Balance (BATenergy)”, which is pursuing a better understanding of different types of adipose tissue and the their role in metabolic diseases.

The Asc-1 protein regulates the formation of fat-burning beige or fat-storing white adipocytes, which may impact the development of metabolic diseases. This is demonstrated by a current study by the Helmholtz Zentrum München and the German Center for Diabetes Research (DZD). The findings open up new approaches to prevent the development of metabolic diseases.

Not all fat is the same: there is white, brown and beige adipose tissue. While white fat cells serve as energy stores, excess energy is burned in brown and beige fat tissue. Too much white fat is considered unhealthy. If white adipose tissue increases significantly in adults with obesity, metabolic diseases such as diabetes or metabolic syndrome may develop.

The situation is different in children: there the initial formation of white adipose tissue is a prerequisite for a healthy metabolism. But how does adolescent adipose tissue differ from adult white adipose tissue? To answer this question, the researchers studied the composition of white adipose tissue from juvenile and adult mice using single-cell RNA sequencing.

The researchers found that adolescent adipose tissue differs markedly from adult white fat, especially in terms of the properties and composition of fat precursor cells.

The researchers discovered a special subset of fat precursor cells in adolescent adipose tissue that contain the protein Asc-1, which would otherwise be present in mature adipocytes.

These precursor cells differentiate predominantly into white adipocytes, and the formation of “healthy” beige adipocytes is actively suppressed. In further cell biological investigations, the team led by first author Lisa Suwandhi was able to demonstrate that loss of Asc-1 function promotes the formation of beige adipocytes.

“This knowledge about the physiological processes of adipose tissue growth allows us to develop new strategies to prevent the harmful metabolic consequences of obesity,” said last author, Dr. Siegfried Ussar. Researchers are already taking this approach further.

They are currently establishing strategies to modulate Asc-1 function in the adipose tissue of the living organism and exploring ways to promote healthy expansion of adipose tissue. The goal is to help obese patients maintain a healthy metabolism in the future and thus buy time to treat obesity with a holistic approach.

The function and distribution of adipose tissue in the body changes throughout life. Beige fat cells, a special type of adipocytes, have the ability to use energy reserves – fat stores – by generating heat in a process known as thermogenesis. With advancing age, beige adipocytes take on the morphology of white adipocytes. Thermogenic activity ceases and with it the ability of cells to burn fat.

As a result, the risk of obesity increases. A team working with Freiburg researchers Prof. Dr. Roland Schüle and Dr. Delphine Duteil has now shown that the epigenetic enzyme specific lysine demethylase 1 (Lsd1) plays a key role in this transformation.

The number of beige adipocytes decreases as LSD1 levels decline in aging adipose tissue. The team was, however, able to maintain the production of Lsd1 specifically in fat cells, thus reducing the age-related transformation of fat tissue from beige to white.

In an experiment with mice, the amount of beige adipocytes in older animals was maintained at almost the same level as in younger mice.

In contrast, the research team also demonstrated that loss of Lsd1 in younger animals leads to premature transformation of fat cells. To observe this, the researchers labeled beige adipocytes with a fluorescent protein and reproduced their transformation into white adipose tissue.

Beige fat cells can be generated, for example, using cold treatment. These then use fatty acids to produce heat. As a result, body weight gain is limited.

The researchers demonstrated, in their obesity study, that LSD1 is not only essential for the development of beige adipocytes, but also for the maintenance of beige fat cells. Therefore, a high level of LSD1 is essential for efficient calorie burning.

Analyzes further showed that Lsd1 maintains beige adipocytes via the target gene Pparα. This gene is interesting from a therapeutic point of view, because selective and effective drugs for obest can activate or suppress it with relative ease.

In their experiments, the team demonstrated that pharmacological activation of Pparα is sufficient to hinder premature loss of beige fat cells in mice with low levels of Lsd1. The animals were therefore protected from obesity caused by the loss of Lsd1.

Roland Schüle and Delphine Duteil carry out their research on obesity at the Department of Urology and Clinical Research Center of the Medical Center of the University of Freiburg. Schüle is a member of the cluster of excellence of the BIOSS Center for Biological Signaling Studies at the University of Freiburg.