Uncoupling proteins

As our interest focuses on the adjustments and adaptation of mitochondrial bioenergetics in response to physiological challenge and metabolic stress, we explore molecular mechanisms of mitochondrial efficiency, focusing on uncoupling proteins/UCPs (which reside in the mitochondrial inner membrane controlling energy transduction) and their physiological function. We put forward models that utilize the modulation of mitochondrial efficiency by UCPs to express specific function. UCP2 modulates insulin secretion in beta cells (Affourtit et al. 2011, Free Rad Biol Med). UCP1 is pivotal for thermogenesis in brown adipose tissue but also modulates reactive oxygen species production (Oelkrug et al. 2010, J Biol Chem).

Evolutionary medicine and comparative biology of brown adipose tissue

Our research is best known and unique for deciphering the evolution of mammalian brown adipose tissue and comparative biology that we aim to unconventionally translate to human disease. In the comparative approach, we aim to apply the “lesson’s from nature” to understand why and how pathophysiological impairments of energy metabolism in metabolic disease, such as obesity and diabetes, occur.

In past studies, we have identified and characterized the evolutionary and molecular origin of mammalian thermogenesis and brown adipose tissue by fusing ecological, physiological, cellular, biochemical and molecular data.

We disproved the tenet that UCP1 is restricted to mammals (Jastroch et al. 2005, Physiol Genomics). We identified UCP1 in marsupials and delineated controversial research on the presence of brown fat in marspials (Jastroch et al. 2008). We identified functional brown fat in proto-endothermic species, suggesting a function in parental care and the evolution of eutherian endothermy (Oelkrug et al. 2013, Nature Commun). We comprehensively analyzed the disappearance of the UCP1 gene in mammalian evolution (Gaudry et al. 2017, Science Adv). Embracing Krogh’s principle, our research takes advantage of animal diversity to identify specialized and common mechanisms of metabolic adaptation and adaption. Next, we aim to unravel the original function of UCP1 before thermogenesis and we use systems biology and "omics" approaches to identify the networks integrating UCP1 in brown adipose tissue.

Mouse metabolic phenotyping

We consolidate the importance of molecular findings in physiology by comprehensive mouse metabolic phenotyping. Recently, we have shown that major metabolic regulators, the hormone FGF21 and UCP1 of brown fat, are dispensable for long-term maintenance of metabolism and body temperature in the cold (Keipert et al. 2017, Cell Metabolism).

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