1. Research Background:

Obesity is one of the major health challenges of modern societies. It is associated with increased morbidity, metabolic deterioration and reduced life expectancy. Despite extensive efforts to understand and treat obesity, its prevalence continues to rise. A key challenge is that body weight typically changes gradually. Rather, relatively small changes in food intake, accumulated over weeks, months and years, progressively shape an individual’s body-weight trajectory and metabolic health. Understanding the mechanisms that maintain or disrupt this long-term regulation is therefore essential for understanding healthy ageing.

Food intake is controlled by the brain through dedicated neural circuits that continuously integrate information about the nutritional state of the body, the gastrointestinal system and the external environment. Importantly, these circuits are not static. They adapt to previous experiences, and changes in transmission and function can persist long after the initial stimulus has disappeared. Such neural plasticity is likely to be essential for adapting feeding behavior to changing environments and metabolic demands. However, the same adaptive mechanisms may become maladaptive under conditions of nutritional excess, contributing to overeating and the development and maintenance of obesity.

Our group investigates how neural circuits controlling appetite and body weight adapt to nutritional experiences. We aim to understand how these adaptations are established, maintained and modified over time, and how they ultimately influence feeding behavior, body weight and metabolic health across the lifespan.

2. Research questions addressed by the group:

Our research is centered on the concept that the regulation of feeding and body weight depends on the ability of the nervous system to adapt to previous experiences. We investigate how changes in the transmission and function of neural circuits translate nutritional experiences, such as fasting or exposure to palatable foods, into persistent changes in feeding and body weight.

A major focus of our research is the melanocortin circuitry that controls hunger and satiety. We study how the synaptic connections and intrinsic properties of melanocortin neurons are remodeled, and how these adaptations influence feeding over extended periods. We are particularly interested in identifying the molecular and synaptic mechanisms that allow hunger circuits to retain information about previous weight loss. We further investigate how persistent exposure to palatable, high-caloric diet alters the communication between the gut and the brain. Here, we ask how nutritional excess alters transmission and processing of signals that normally regulate meal termination and energy balance, and whether these adaptations contribute to persistent dysregulation of appetite. Finally, we study how access to high-sugar foods modifies neural circuits to drive consumption in response to sensory cues despite current energy needs being met. Specifically, we aim to determine how sugar experiences can cause persistent neural adaptations that promote overeating in an obesogenic environment.

Across these research areas, we seek to understand how neural plasticity can maintain physiological control of feeding and body weight, but can also become maladaptive and contribute to metabolic deterioration over the lifespan..

3. Possible projects:

A) Neural plasticity in hypothalamic hunger circuits

Why do most people regain lost body weight in the long term? We propose that weight loss induces synaptic adaptations in key neural circuits controlling hunger, thereby promoting energy intake until the lost body weight is regained. This neural memory of hunger may be induced not only by caloric restriction but also by treatment with incretin mimetics such as Semaglutide, after discontinuation of which substantial weight regain is typically observed. Possible projects will investigate the molecular and synaptic mechanisms underlying these adaptations and determine how they drive persistent changes in hunger and body weight.

B) Obesity-induced adaptations of gut–brain control of appetite

Obesity is associated with impaired sensing of caloric content in the gastrointestinal tract and diminished satiation. We hypothesize that exposure to diets high in fat induces long-lasting alterations in gut–brain communication, mediated by the vagus nerve, and the processing of visceral feedback signals controlling appetite. Possible projects will investigate where in the nervous system these adaptations are established, how they persist over time, and whether they contribute to the difficulty of reversing established obesity.

C) Neural adaptations to sugar and the development of obesity

How can exposure to high-sugar foods create long-lasting memories that drive feeding in response to environmental cues? We study the neural plasticity mechanisms that promote sugar appetite beyond energy needs. Possible projects will determine how initially transient responses to high-sugar foods develop into persistent neural adaptations and how these changes contribute to chronic overeating and obesity.

4. Applied Methods and model organisms:

Our research combines behavioral and metabolic phenotyping of transgenic mice with circuit neuroscience and molecular approaches, including optogenetics, chemogenetics, electrophysiology, calcium imaging and fiber photometry, viral circuit manipulations, molecular profiling, and high-resolution microscopy. These approaches allow us to investigate neural plasticity and circuit functions across different metabolic states over extended time periods.

5. Desirable skills and qualifications:

We are looking for highly motivated students with a strong interest in neuroscience, metabolism and the biological mechanisms underlying behavior. A background in neuroscience, biology, molecular biology, biomedicine, nutrition or a related discipline is desirable. Previous experience with animal experimentation, electrophysiology, microscopy, molecular biology, genetics or computational data analysis is advantageous but not required. More important are curiosity, scientific independence, enthusiasm for learning new techniques, and the ability to formulate and pursue mechanistic questions. Students will work in an interdisciplinary and highly collaborative research environment and will be encouraged to develop their own scientific ideas while receiving close mentorship and training in experimental design, quantitative analysis and scientific communication. 

6. References and key publications:

1. Minère M, …, Fenselau H. Thalamic opioids from POMC satiety neurons switch on sugar appetite. Science. 2025 Jan 2;387(6735):750-758. doi: 10.1126/science.adp1510. 
2. Grzelka K, …, Fenselau H. A synaptic amplifier of hunger for regaining body weight in the hypothalamus. Cell Metab. 2023 May 2;35(5):770-785.e5. doi: 10.1016/j.cmet.2023.03.002.     
3. Borgmann D, …, Fenselau H. Gut-brain communication by distinct sensory neurons differently controls feeding and glucose metabolism. Cell Metab. 2021 Jul 6;33(7):1466-1482.e7. doi: 10.1016/j.cmet.2021.05.002. 
4. Brüning JC, Fenselau H. Integrative neurocircuits that control metabolism and food intake. Science. 2023 Sep 29;381(6665):eabl7398. doi: 10.1126/science.abl7398.  
5. Mirabella PN, Fenselau H. Advanced neurobiological tools to interrogate metabolism. Nat Rev Endocrinol. 2023 Nov;19(11):639-654. doi: 10.1038/s41574-023-00885-6.