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bioRxiv · 10.1101/2024.12.04.626093

Non-shivering thermogenesis is intact upon brown-adipocyte specific loss of ATGL and HSL due to white adipose tissue browning

Manandhar, Y.·Pirchheim, A.·Hofer, P.·Vujic, N.·Kolb, D.·Hoefler, G.·Kratky, D.·Schweiger, M.·Taschler, U.·Zimmermann, R.·Zechner, R.·Schreiber, R.
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Abstract

Intracellular fatty acids (FAs) activate and fuel non-shivering thermogenesis (NST) via uncoupling protein 1 (UCP1). Adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) control FA availability. Since mice lacking ATGL in brown adipose tissue (BAT) exhibit intact recruitable adrenergic thermogenesis, we hypothesized that HSL-mediated FA release is sufficient to activate UCP1-dependent NST. We demonstrate that mice with inducible brown adipocyte-specific loss of ATGL and HSL (iBDKO) exhibit normal recruitable adrenergic thermogenesis upon prolonged cold exposure. Mechanistically, we show that BAT thermogenic capacity is impaired in cold-adapted iBDKO mice due to diminished mitochondrial numbers. Increased browning of white adipose tissue (WAT) in iBDKO mice indicates a shift in thermogenesis from BAT to WAT. Consistently, the loss of ATGL and HSL in BAT and WAT disrupts thermogenesis in both depots, resulting in blunted UCP1-dependent NST. Our study highlights the metabolic adaptability of adipose tissue and the critical role of intracellular lipolysis in regulating thermogenesis.

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Manandhar, Y., Pirchheim, A., Hofer, P., Vujic, N., Kolb, D., Hoefler, G., Kratky, D., Schweiger, M., Taschler, U., Zimmermann, R., Zechner, R., Schreiber, R.. 2024-12-05. Non-shivering thermogenesis is intact upon brown-adipocyte specific loss of ATGL and HSL due to white adipose tissue browning. https://doi.org/10.1101/2024.12.04.626093

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