Comparative biology and biomedicine of brown adipose tissue

Project leader: Dr. Martin Jastroch

Our research on the biology of thermogenic adipose tissue is best known for our discoveries on the evolution of adipose thermogenesis in vertebrates. Despite getting fundamental insights, we aim to apply this knowledge to develop technologies activating metabolism in human adipose tissue to combat metabolic diseases. 
In previous studies, we have fused ecological, physiological, cellular, biochemical and molecular data to discover and characterize the evolutionary origin of mammalian thermogenesis and brown adipose tissue. We disproved the tenet claiming that uncoupling protein 1 (UCP1) is restricted to mammals (Jastroch et al. 2005, Physiol Genomics); delineated controversial research on the presence of brown fat in marspials by identifying marsupial UCP1 (Jastroch et al. 2008); discovered functional brown fat in proto-endothermic eutherian species, suggesting an important role for eutherian evolution (Oelkrug et al. 2013, Nature Commun); and were involved in projects to demonstrate the disappearance of the UCP1 gene during mammalian evolution (Gaudry et al. 2017, Science Adv). Next, we aim to understand the molecular networks that wire thermogenesis into adipocytes using systems biology and "omics" approaches. 

Uncoupling proteins 

Project leaders: Mr Michael Gaudry (MSc), Mr Erik Rollwitz (MSc)/Dr. Martin Jastroch

We focus on uncoupling proteins/UCPs and their physiological function, as they may control the adjustments and adaptation of mitochondrial bioenergetics in response to physiological challenge and metabolic stress. We apply the comparative analyses to identify UCP1 structure-function relationships to understand the molecular mechanisms and ecophysiological adaptation (Project lead: Gaudry).  We generated knockout models to understand the ancient function of UCPs in the vertebrate kingdom, in particular in ectothermic vertebrates (Project lead: Rollwitz). Specifically, we aim to delineate the original function of UCP1 before executing mammalian thermogenesis.

Human adipocyte bioenergetics and thermogenesis

Project leader: Dr. Michaela Keuper/Dr. Martin Jastroch

We use our discoveries of thermogenic networks in animal models to engineer thermogenesis into human adipocytes. With the aim to improve fat burning capacities and metabolic turnover in human fat, we hope to form the biomedical basis to combat metabolic diseases such as diabetes and obesity. In our current work, we explore the ability of human adipocytes to combust energy through alternative, UCP1-independent thermogenesis.

Mouse metabolic phenotyping

Project leader: Ms Maria Kutschke/Dr. Martin Jastroch

We consolidate the physiological importance of our molecular findings by comprehensive mouse metabolic phenotyping. Recently, we have shown that major metabolic regulators, such as the hormone FGF21 and UCP1 of brown fat, are dispensable for long-term maintenance of metabolism and body temperature in the cold, opening opportunities to study alternative routes of thermogenesis (Keipert et al. 2017, Cell Metabolism). To achieve this, we have created new mouse models to address the importance of UCP-independent thermogenesis and metabolism.

Collaborations on cellular bioenergetics

We provide our expertise in cellular and mitochondrial bioenergetics to several collaboration partners around the world to address questions on cancer biology, immunology, diabetes and drug development (Divakaruni et al. 2014, Methods in Enzymology; for further details pubmed query : Jastroch M).

We have committed collaboration partners helping us with bioenergetic analyses (Dr. Ajit Divakaruni UCLA, USA), animal studies (Dr. Frank van Breukelen, UNLV, USA) and structural work on UCP1 (Dr. Paul Crichton, University of East Anglia, UK).

Key technologies

• Measurement of modular kinetics in isolated mitochondria by simultaneous polarographic, potentiometric and fluorescent measurements;
• Measurement of oxygen consumption (mitochondrial activity) and extracellular acidification (glycolysis) using the extracellular flux analyzer (Seahorse Bioscience);
• Measurement of plasma and mitochondrial membrane potential in intact cells (using time-lapse fluorescence microscopy and platereader-based kinetic measurements);
• Measurement of mitochondrial reactive oxygen species in isolated mitochondria (using hydrogenperoxide sensitive probes) and intact cells (using superoxide sensitive probes).
• Mouse metabolic phenotyping