Calorimetry of brown and brite fat

• Applicants: Professor Dr. Martin Klingenspor; Professor Dr. Florian Mertens
• Subject Area: Nutritional Sciences ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 563766775

Brown fat has an exceptional capacity to generate heat by uncoupling oxidative phosphorylation. The underlying mechanism, known as nonshivering thermogenesis (NST), is catalysed by the uncoupling protein 1 (UCP1), which dissipates the proton motive force at the inner mitochondrial membrane. Activated UCP1 enables a high rate of the mitochondrial electron transport system, resulting in a high oxygen consumption rate. The free energy of glucose and fatty acids is not conserved as ATP but converted to heating power. UCP1-dependent thermogenesis occurs in “classical” brown fat and brown-like brite (brown-in-white) adipocytes. Since the discovery of metabolically active brown or brite fat in healthy adult humans, the general interest in the role of thermogenic adipocytes in mitigating obesity development and ameliorating impaired glucose tolerance and insulin resistance has been revitalized. The potential implications of these findings on our understanding and management of obesity and metabolic disorders are significant. The beneficial metabolic effects of thermogenic adipocytes may not be solely UCP1-dependent. Mice with impaired brown and brite fat function, e.g. Ucp1 knockout mice (KO) mice, can recruit additional thermogenic capacity when cold acclimatized gradually. One critically discussed thesis proposes that futile substrate cycles in adipose tissues are activated, with simultaneous metabolic pathways dissipating chemical energy as heat without altering substrate levels. These futile cycles include ATPdriven cyclic Ca2+ pumping, cyclic interconversion of creatine/creatine-phosphate, and a futile cycle of lipolysis and reesterification of fatty acids. Increased use of futile cycles could result in a larger contribution of anaerobic metabolism to total heat production. This project will use a newly developed miniaturised chip calorimeter to investigate the UCP1-independent thermogenic mechanisms in adipose tissues. Most studies addressing the metabolic rate of brown and brite fat routinely apply respirometry (indirect calorimetry). Since only aerobic metabolic rates are recorded, using direct calorimetric methods is obvious if a significant part of anaerobic metabolic rates is expected. The following main questions will be answered by direct calorimetric measurements using the new chip calorimeter: • What is the heating power of thermogenic brown and brite fat? • Which futile cycles are involved, and how much heating power do they deliver? • What is the contribution of anaerobic metabolism to thermogenesis?

• DFG Programme: Research Grants
• Co-Investigator: Privatdozent Dr. Johannes Lerchner