Cold-stimulated brown adipose tissue activation is related to changes in serum metabolites relevant to NAD+ metabolism in humans

Authors: U-DIN, MUEEZ - Turku University Hospital; DE MELLO, VANESSA - University Of Eastern Finland; TUOMAINEN, MARJO - University Of Eastern Finland; RAIKO, JUHO - Turku University Hospital; NIEMI, TARJA - Turku University Hospital; FROMME, TOBIAS - Technical University Of Munich; KLAVUS, ANTON - University Of Eastern Finland; GAUTIER, NADINE - National Council For Scientific Research-Cnrs; HAIMILAHTI, KIMMO - University Of Helsinki; LEHTONEN, MARKO - University Of Eastern Finland; KRISTIANSEN, KARSTEN - University Of Copenhagen; Newman, John; PIETILÄINEN, KIRSI - University Of Helsinki; PIHLAJAMÄKI, JUSSI - University Of Eastern Finland; AMRI, EZ-ZOUBIR - National Council For Scientific Research-Cnrs; KLINGENSPOR, MARTIN - Technical University Of Munich; NUUTILA, PIRJO - University Of Turku; PIRINEN, EIJA - University Of Helsinki; HANHINEVA, KATI - University Of Eastern Finland; VIRTANEN, KIRSI - University Of Eastern Finland

Submitted to: Cell Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/29/2023
Publication Date: 9/13/2023
Citation: U-Din, M., de Mello, V.D., Tuomainen, M., Raiko, J., Niemi, T., Fromme, T., Klavus, A., Gautier, N., Haimilahti, K., Lehtonen, M., Kristiansen, K., Newman, J.W., Pietiläinen, K.H., Pihlajamäki, J., Amri, E., Klingenspor, M., Nuutila, P., Pirinen, E., Hanhineva, K., Virtanen, K.A. 2023. Cold-stimulated brown adipose tissue activation is related to changes in serum metabolites relevant to NAD+ metabolism in humans. Cell Reports. 42(9). Article 113131. https://doi.org/10.1016/j.celrep.2023.113131.
DOI: https://doi.org/10.1016/j.celrep.2023.113131

Interpretive Summary: Brown fat or brown adipose tissue (BAT) is a type of fat tissue that uses energy to generate heat when stimulated by cold exposure. In mice, cold stimulation increases the energy metabolism and the availablity of cationic nicatinamide adenine diphosphate (NAD+), the activated form of vitamin B3 (i.e. niacin). Until recently, it was thought that human BAT reservoirs only existed in babies, however adults with BAT have been identified using modern functional imaging techniques. In the current study we found that humans exposed to cold increased NAD+ recycling and decreased the biosynthesis of new NAD+ molecules. Furthermore, the expression of genes involved in BAT NAD+ metabolism was related to systemic metabolic health. Together these results suggest that enhancing BAT NAD+ metabolism is a potential clinical target to improve metabolic health.

Technical Abstract: Cold exposure induces brown adipose tissue (BAT) thermogenesis and metabolic function, which is considered an approach to improve metabolic health. In mice, cold increases the fundamental molecule for mitochondrial function, NAD+, in BAT and improves metabolic health, although limited knowledge on human BAT exists. We show that cold induced changes in serum metabolites are relevant to NAD+ metabolism in humans. Cold increased metabolites of the salvage (nicotinamide and 1-methylnicotinamide) and decreased those of the de novo (tryptophan, kynurenine) NAD+ biosynthesis pathways. Serum nicotinamide showed positive correlation with cold-stimulated BAT activation, while for tryptophan and kynurenine this relationship was inverse. Further, the expression of genes involved in NAD+ biosynthesis in BAT was related to systemic metabolic health. Our data indicate that cold increases tryptophan conversion towards nicotinamide to be further utilized by BAT and reinforces BAT NAD+ metabolism as one potential clinical target for enhancing BAT activity to promote metabolic health.