It’s all in the head

In September, the University of Cologne and University Hospital Cologne inaugurated the new Center for Metabolic Research. Beginning in 2025, it will bring together eleven research groups from areas such as endocrinology, dermatology, paediatrics and adolescent medicine, neurobiology, physiology, bioinformatics, psychiatry and nephrology. However, the research will not only focus on widespread conditions like overweight, obesity and type 2 diabetes. The range of research topics is broad and also includes issues related to wound healing or the influence of diet on kidney disease.

In addition to the building’s technical equipment, which includes a mass spectrometer for analysing biomolecules, the close proximity of the research groups conducting clinical as well as basic research creates good conditions for collaboration: Entirely new research questions can arise and be investigated by bringing together the various disciplines.

The new common illness

Dr Ruth Hanßen is not only a researcher, she also cares for patients at University Hospital Cologne. People who come to her for a consultation usually look back on a long struggle: countless diets followed by the yo-yo effect, leading to an even higher number on the scales. She and her colleagues offer the ‘Change Your Life’ programme at the Polyclinic for Endocrinology, Diabetology and Preventive Medicine. Over the course of a year, participants learn a health-promoting lifestyle, with changes in eating behaviour, exercise as well as stress management skills. Patients are often referred from other specialist fields because they are already suffering from secondary diseases caused by overweight and obesity. Health insurance companies can pay for people to join the programme starting at a Body Mass Index of 30 kg/m2. 

Body Mass-Index
The BMI is calculated using the formula ‘weight in kilogrammes divided by height squared’. The point at which a person is considered overweight or obese also depends on their age and sex. As a rule, a BMI of 25 indicates overweight, a BMI of 30 indicates obesity.

It is important to Hanßen that her patients are not stigmatized because they supposedly cannot ‘control themselves’. “Today we know that obesity is a chronic disease that is associated with changes in the brain. These brain changes make it more difficult to ‘simply’ change your lifestyle. We also would not tell a person who is severely depressed to just smile,” said the physician. She attaches particular importance to comprehensive aftercare, which is also provided for other physical and mental illnesses. Because losing weight is not enough. The bigger challenge is maintaining the new weight.

As head of the translational metabolic research group at University Hospital Cologne, Ruth Hanßen transfers the latest scientific findings from cell- and animal-based research to patient care. At the same time, interacting with patients gives rise to research questions that she will be working on at the new Center. She is particularly interested in what happens in the brain when people gain more and more weight: “A diet high in fat and sugar changes the reward centre. Once you have an increased weight, your brain no longer works in the same way as before: The high-calorie foods are coded as particularly rewarding, while the low-calorie foods are coded as particularly unrewarding,” said Hanßen.

This effect is amplified by increasing body weight. According to current research, however, it is completely unclear whether the changes in the brain can ever be reversed – a possible reason why it is so difficult to maintain the new weight after weight loss.

Control centre for eating behaviour

Professor Dr Tatiana Korotkova heads the Institute of Systems Physiology at the Faculty of Medicine and is a principal investigator at the CECAD Cluster of Excellence for Aging Research. Her research group, which will soon be moving into the Center for Metabolic Research, explores the processes in the brain that are responsible for eating behaviour. This is primarily the hypothalamus, a kind of control centre for various signals in our body. This brain region is further divided into different centres. 

Korotkova’s work focuses on the lateral hypothalamus, where the receptors for the metabolic signals insulin, leptin and glucose are located. The receptors function like a kind of sensor, telling the brain the levels of sugar and fat that are currently available for the body. They also receive signals from the reward centre and the prefrontal cortex, which is involved in planning actions. The lateral hypothalamus integrates these signals and thus controls eating behaviour. 

Korotkova uses a mouse model to investigate how effects on one brain region affect neurons in other regions. Changes in the functioning of the neurons in these systems can not only trigger overeating, but also eating disorders such as anorexia.

A healthy metabolism for a healthy life

The lateral hypothalamus is also one of the places in the body that is targeted by semaglutide, the agent contained in the ‘weight loss injections’ Ozempic or Wegovy. This so-called GLP-1 receptor agonist affects the hormone GLP-1, which is produced in the intestine and regulates insulin levels. Semaglutide slows down the release of insulin by blocking the receptors for this hormone in the brain. It also keeps hunger at bay because the food stays in the digestive tract longer.

However, Korotkova does not believe that this therapy is the ultimate solution to the global weight problem. “It’s good that we have these drugs. You can achieve considerable results, with a weight reduction of 15 to 20 per cent. However, in some cases, severe side effects such as nausea, dizziness, diarrhoea or vomiting occur, so that many patients stop the treatment,” said the researcher. In addition, lifelong therapy is necessary. This drug is not a cure.

Moreover, the hormone GLP-1 is only one component in a very complicated concert in which other hormones such as leptin or ghrelin and their receptors also play a part. Research therefore currently focuses on so-called dual and triple agonists. Such agents would not only target one specific hormone, but different parts of the system. This would have the potential to increase both efficacy and tolerability for a larger group of patients. One dual agonist already available today is Tirzepatide, which is contained in Munjaro.

Korotkova and her team are also interested in the metabolism because it acts as an early warning system for many age-related diseases, which are often preceded by metabolic changes leading to chronic inflammation, certain types of cancer or cardiovascular diseases. “Many research centres around the world are investigating aging when it is already too late. Then only the symptoms can be treated. The earlier we can treat the changes that lead to these diseases, the longer the person will stay healthy,” said Korotkova.

How does cellular memory work?

Professor Dr Miguel Ángel Alejandre-Alcázar is interested in a very early life stage: before birth. As a paediatrician with a focus on pulmonary medicine, he came into contact with premature babies early on in his career as a hospital physician. Since the lungs still have to develop after birth, they are often not yet fully functional in premature babies. They require respiratory support measures that can lead to serious secondary diseases such as bronchopulmonary dysplasia (BPD), a chronic neonatal lung disease whose consequences extend beyond childhood and are associated with an increased risk of lung disease in later life. 

The cellular, structural and functional changes in this disease are very similar to the changes that occur in lung aging processes. Alejandre-Alcázar wondered: “Why can’t the lungs of a premature baby develop normally or regenerate under these circumstances? What can we doctors do differently and better in terms of prevention and treatment?” Since then, the clinician, who like Tatiana Korotkova is also a principal investigator at the CECAD Cluster of Excellence, has been working in research.

Other organ systems such as the central nervous system or the kidneys can also be damaged in the womb, so that the structure, physiology and ultimately the function of the organs remain permanently altered. A risk factor for this is a pathological metabolic environment, for example as a result of placental insufficiency, which exposes the foetus to a lack of nutrients, or because the mother is overweight. In addition to many ‘good’ hormones that are necessary for physiological control cycles, the increased fatty tissue also produces inflammatory messengers. These can pass via the placenta to the unborn child and cause chronic subacute inflammation. All these factors can impair the maturation of organs and tissues in the long term.

This is how Alejandre-Alcázar likes to explain it to his students: “Like a house, health and resilience must be built on a strong foundation, which is laid in the uterus. But if the house is unstable, it will always be vulnerable. If there is a storm, it is more likely to collapse than a solidly built house with a strong foundation. During a person’s development, various adverse factors can lead to damage and conditions that make them more susceptible to chronic diseases later in life.” The ‘storm’ could then come in the form of stress, malnutrition or overeating, smoking or smog. 

In experimental transgenerational studies with mothers, children and grandchildren as well as in clinical cohorts, including at the German Center for Lung Research (DZL), Alejandre-Alcázar investigates how metabolic risks are passed from one generation to the next. In addition to upbringing and socialization, epigenetics – the way the activity of our genes is influenced by environmental factors – plays a key role. External influences can affect the expression of our genes and thus also determine our genetic profile. In addition to DNA methylation, another basic mechanism of epigenetics includes histone acetylation – both processes that influence how genetic information is read (or transcribed) during cell division. However, the exact process by which an altered metabolic environment in early development changes the epigenome and the transcriptome throughout life is still unclear. “The most important question is: How is ‘cellular memory’ shaped? What molecular mechanisms are at work when we observe a tendency towards obesity or cardiopulmonary diseases across generations?”

Man in his environment

Although he now spends a lot of time in the laboratory, Alejandre-Alcázar never loses sight of the bigger picture: children developing in their world. He said: “Normal physiology can develop when all organs communicate and interact optimally with one another. But we also have to look at external interactions – with the family and the entire environment.”

However, this environment also includes a food industry that markets products with too much sugar and fat. Therefore, research alone cannot solve the global overweight and obesity problem; political and industry action is also needed. The work of Ruth Hanßen, Tatiana Korotkova and Miguel Alejandre-Alcázar and their colleagues will ideally lead to the development of new therapies for metabolic diseases. That is their contribution to fighting the ‘pandemic of the 21st century’. 

Center for Metabolic Research
The newly founded Center brings together researchers from the Faculty of Medicine and the Faculty of Mathematics and Natural Sciences to identify new metabolic regulation principles as biomarkers or targets for therapies for a wide range of diseases. The Center is another flagship project for the university and complements the aging research area established with the CECAD Cluster of Excellence.

The new building at Robert-Koch-Straße 10 has a floor area of 3,774 m² and was built in four years at a cost of approximately 83 million euros by University Hospital Cologne and the University’s Faculty of Medicine, with financial support from the federal government and the state of North Rhine-Westphalia. It comprises 38 laboratories, eight seminar and meeting rooms and a two-storey foyer with a café. medfacilities GmbH was responsible for construction management and used the BIM (Building Information Modelling) planning method. BIM provides up-to-date data for the planning, construction and operation of the building using a digital twin.