Tackling the Big Questions in Metabolism

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Neatly arranged on the windowsill that overlooks Alexander Bartelt’s desk are a blue Bud Light aluminum bottle – and five model cars, all of them American and all still in their original packaging. Clearly, this desk belongs to someone who has spent a significant period of his life in the US. Indeed, Bartelt (36) worked in the US for several years. During our conversation at the Institute for Cardiovascular Prevention (IPEK), he mentioned a meeting at Harvard University where, while still a young doctoral student from Germany, he presented data from his PhD project on brown adipose tissue (BAT) – more specifically, on aspects of lipid metabolism in a common experimental model for atherosclerosis. The results themselves made little impression, he recalls. But the audience posed probing questions and made many suggestions as to how he should proceed. In retrospect, he realized that “this was a key moment in my career,” he says. “My American colleagues were pushing me to tackle the big questions!”

Bartelt followed their advice. Since then, he has won several prizes for his research. The latest is a Starting Grant from the ERC for a research project named PROTEOFIT. These grants are specifically intended for early-career researchers, and are among the most sought-after awards available in Europe.

The quest for key mechanisms

On that all-important afternoon at Harvard, Bartelt began to reconsider his approach to scientific research. “I needed to leave my comfort zone,” he says, and he chose to focus on central mechanisms in human metabolism. “Like cancer, metabolism is an area of medical research in which one can make a real impact. Scientific advances in metabolism have a beneficial effect on the lives of very many people.” He continued to work on BAT, which uses its lipid reserves to maintain body temperature (unlike white adipose tissue which serves as a storage depot). But now he posed a basic question: How do lipids get to adipose tissues? At the time, nobody really knew the answer, he says. He went on to reconstruct the underlying molecular processes and became an expert on the metabolism of lipids in BAT. Having spent 5 years at the Harvard School of Public Health in Boston, he set up his own research group last year in the department led by Prof. Christian Weber at LMU. “Assuming the responsibility of becoming a group leader is the most critical step for a young researcher,” he points out. His group is now studying the molecular bases of metabolic diseases including atherosclerosis, diabetes and obesity.

Bartelt is pursuing two main projects. His group seeks to define how the heart copes with stress, while his ERC-funded project PROTEOFIT focuses on the molecular biology of metabolic processes in muscle cells and exercise. These projects may appear to have little in common, but both investigate the transcription factor Nfe2l1. This protein is found in muscle cells, in the BAT and in the heart, and the evidence indicates that it plays a key role in protecting these tissues against metabolic stress.

While he was still at Harvard, Bartelt discovered a novel mechanism in active BAT, primarily involved in the degradation of damaged proteins and is triggered by Nfe2l1. “Nfe2l1 is an evolutionarily ancient protein, which is present in a less elaborated form in nematode worms, where it is involved in the control of aging,” Bartelt explains. Variants emerged at later stages of evolution, and mammals like us have three different forms.

The variant Nfe2l1 has become a focal point of Bartelt’s research, and it could help him answer some of the most important fundamental questions in metabolism of which his Harvard colleagues had spoken on his first visit. This is because Nfe2l1 is specifically expressed in tissues that are critical for the control of metabolism, in the BAT, in skeletal muscle and in heart muscle. “Interestingly, these tissues are closely related to one another developmentally,” he says. “Brown fat and skeletal muscle develop from very similar precursor cells.”

That might underlie why exercise and sports, which increase the demands made on the skeletal musculature, and brown fat have a positive effect on metabolism. The idea is intriguing, but what happens at the molecular level in a regular jogger, or when one sprints to catch a bus, is not well understood, says Bartelt. “We plan to search for the vital molecular switches in skeletal muscle, which makes up 60% of body weight.”

Understanding the molecular operations

The focus on the molecular level requires the design of separate experimental approaches for each of the three tissues, as each must cope with specific challenges. To explore the responses of skeletal muscles to exercise, Bartelt uses mice. They run on treadmills and he records the changes in oxygen consumption as a measure of their levels of fitness. These tests are carried out on a variety of genetic models. In each mouse strain, the goal is to determine how Nfe2L1 behaves under various physiological conditions.

An intracellular organelle called the endoplasmic reticulum (ER) is at the heart of these molecular processes. This membranous network serves as a central regulatory hub in the cell, and it controls much of intermediate metabolism. It is also highly sensitive to metabolic stress, and Nfe2l1 is normally localized in the ER. This is where important metabolic pathways reside, where the structures and activities of proteins are monitored, the levels of fats and carbohydrates are measured, and decisions are made as to how the cell should react to metabolic imbalances. In other words, the ER coordinates the multiple strands in the complex web of metabolic transformations that take place in the three tissues.

The organelle also protects tissues from the consequences of metabolic stress – and this is where Nfe2l1 comes into play. Proteins that have been damaged by reactive chemicals, have failed to fold correctly or have reached the end of their productive lives, must be disposed of. Here too, mechanisms have evolved that take care of this task. Specific tags are attached to damaged proteins, which mark them for delivery to organelles called proteasomes. The proteasome is a large protein complex, which acts as a shredder of damaged proteins and reduces them to their amino-acid subunits. “Nfe2l1 regulates the activity of the proteasome,” says Bartelt, “and is therefore responsible for protein quality control in cells.”

The goal of the PROTEOFIT project is to elucidate how this regulation works under specific environmental conditions. “Nothing is yet known about how Nfe2l1 acts in skeletal muscle or in the heart. We are entering uncharted territory here,” says Bartelt.

Once again, the challenge is to develop informative experimental models. In the case of the heart, the question at issue is how Nfe2l1 protects the organ when it is exposed to stress – the stress imposed by an acute heart attack, for instance. “Nfe2l1 probably plays a significant role in inhibiting the development of heart disease,” says Bartelt. Here he will use an animal model to determine at the molecular level how Nfe2l1 in the ER protects cardiac muscle cells from various types of toxic stimuli.

Of course, stress reactions resulting from by-products of metabolism also occur in contexts other than muscle cells. Researchers have long been interested in working out how the mechanisms which normally regulate food intake in accordance with the body’s needs become permanently disabled. This is what happens in obese individuals who consume fats, and sugar or other carbohydrates, in amounts which exceed the capacity of adipose tissues to store or metabolize lipids. Other organs are then exposed to far higher levels of fat than they would otherwise be, “and that stresses cells, too,” says Bartelt. He will therefore search for molecules that mediate stress resistance under such conditions. “This quest could lead to new strategies in drug research,” Bartelt adds. As a researcher who studies fundamental questions, he is attuned to potential applications of his work.

Indeed, the potential impact of his work on human lives is an important part of Bartelt’s motivation. “As a researcher, I believe it is important to explain scientific findings in terms that the general public understands.” He is now working on a popular science book which presents the results of his studies on the metabolism of fats. “Adipose tissue is in effect the largest gland found in humans. It produces a broad spectrum of hormones that regulate our behavior, reproduction and energy turnover,” Bartelt explains. This “gland” undoubtedly holds many of the keys to those ‘big questions, which his colleagues stimulated him to tackle, and which provide the motivation for his research. (Hubert Filser)