Adipocytes are key regulators of metabolic health: healthy white adipocytes are essential as in the complete absence of white adipose tissue in mice and humans systemic metabolic homeostasis is compromised. Adipogenesis, the process by which precursor cells differentiate into mature adipocytes, is crucial for maintaining a functional adipose tissue. Understanding its regulation helps identify mechanisms that prevent adipocyte dysfunction, which is a key driver of metabolic diseases. 

In obesity, excess accumulation of white adipocytes leads to the same phenotypic alterations of metabolic disease. Obesity is a chronic inflammatory disease and adipocytes are actively recruiting professional immune cells with chemokines when they are stressed. Interestingly, white adipose tissue inflammation is both required for the development of healthy fat cells but also contributes to their dysfunction in obesity. Our goal is to define molecular mechanisms of adipocyte health that direct the nature of adipose inflammation and associated systemic pathologies such as diabetes and atherosclerosis.

Thermogenic adipocytes are a remarkable type of metabolic cell. These UCP1-expressing cells are activated by cold and use energy-dense nutrient such as fatty acids, carbohydrates, and derived carbohydrates for producing heat to maintain body temperature homeostasis. Activation of thermogenic adipocytes has been shown to improve metabolic health in regular rodents, preclinical animal models of metabolic disease and humans. Thermogenesis is a process that depends on the environmental temperature and the physiognomy of the animal. Hence the thermogenic activity greatly varies from warmer to colder season as well as differs from mice to men. Our goal is to understand how thermogenic adipocytes adapt their metabolism to the extreme challenges of high metabolic flux, high oxidative activity, as well as synthesis of new organelles and cellular structural remodeling.

Proteostasis is essential for cellular function and stress adaptation. In metabolically active tissues such as adipose, muscle, and heart, proteome integrity prevents dysfunction associated with oxidative stress, inflammation, and metabolic disease. It is regulated by the integrated stress response (ISR), which includes the unfolded protein response (UPR), autophagy, and the ubiquitin-proteasome system (UPS). UPS activity is finetuned through multiple regulatory mechanisms. The UPS dynamically adjusts proteasomal activity through multiple regulatory mechanisms. A key transcriptional regulator is Nuclear factor erythroid 2-like-1 (Nfe2l1), a bZIP cap’n’collar transcription factor. If proteasomal activity is compromised, Nfe2l1 increases the expression of proteasomal subunits, thereby adapting proteasomal activity to proteostatic needs.

Next to age and genetic predisposition, physical activity and exercise are the most important factors for maintaining a healthy metabolism throughout life. Also, even as a therapeutic life style intervention, exercise or mild physical activity have beneficial effects on cardiometabolic health. Surprisingly, we know very little about how skeletal muscle cells control the change in metabolism during the transition from sedentariness to physical activity and such knowledge would be critical for developing molecular therapies in support of life style changes or vice versa. Somewhat paradoxically, in other severe myopathies, such as muscle wasting in immobilized subjects or cancer cachexia, similar metabolic alterations take place as in beneficial exercise but the underlying mechanisms remain elusive. Our goal is to identify novel regulators of skeletal myocyte adaptation, and explore how these relate to physical activity and metabolic disease.

The heart is a fascinating and dynamic organ essential for human life. However, its metabolic flexibility is compromised in many critical medical conditions such as cardiohypertrophy, heart failure and during myocardial infarction. Both physiological changes in heart rate as well as the very distinct condition of heart disease require special mechanisms of adaptation. This is even more apparent in light of the unique structural features of myocyte organelles, particularly the endoplasmic reticulum and mitochondria. Like in other conditions of metabolic disease, heart disease has s strong inflammatory component, both for healthy as well as maladaptive regeneration and tissue scarring. Our goal is to understand the molecular adaption of a trained heart versus dysfunctional heart, particularly after myocardial infarction. A detailed molecular understanding of cardiomyocyte-immune cell interaction would be transformative for designing new therapeutic strategies of myocardial infarction outcomes.

Oxidative stress is a major contributor to cellular dysfunction and inflammation in metabolic diseases. Excess reactive oxygen species (ROS) can disrupt cellular homeostasis by damaging lipids, proteins, and DNA, ultimately impairing organ function. The body relies on antioxidant defense systems to maintain redox balance and prevent oxidative damage. When these systems are overwhelmed, lipid peroxidation can occur, potentially leading to regulated cell death processes such as ferroptosis. Dysregulated oxidative stress, is implicated in the progression of obesity, diabetes, and cardiovascular diseases. It contributes to insulin resistance, endothelial dysfunction, and chronic inflammation, linking it to metabolic complications such as atherosclerosis and fatty liver disease. Understanding the molecular mechanisms that regulate oxidative stress responses, including ferroptosis, is critical for identifying therapeutic strategies to mitigate their impact on metabolic health.