Inflammatory Control of Brown Fat Function
Gastroenterology
Final Report Abstract
Adipocytes possess remarkable adaptive plasticity to maintain metabolic homeostasis in conditions of nutrient excess, fasting or cold exposure. While the endoplasmic reticulum (ER) is the central organelle of protein and lipid homeostasis it is unclear which mechanisms mediate adaptation of the ER in adipocytes. Surprisingly, we found that pathways of the canonical unfolded protein response, which have been linked to metabolic homeostasis in other tissues, are dispensable for adipocyte function. In this project, we discovered that proteasomal protein degradation is the major mechanism by which ER homeostasis is maintained in brown adipocytes. Proteasomal activity was induced by cold and required for non-shivering thermogenesis. Furthermore, we identified the ER-localized transcription factor Nuclear factor erythroid factor-2, like-1 (Nfe2l1, also known as Nrf1) as a fundamental, coldinducible regulator of the ubiquitin-proteasome protein quality control system in brown adipose tissue (BAT). Using Tandem Mass Spectrometry we identified hyperubiquitinated proteins in BAT from cold-adapted mice lacking Nrf1 specifically in brown adipocytes, particularly metabolic enzymes, mitochondrial and ER proteins, which was associated with mitochondria dysfunctional, diminished ER function and activation of ER stress pathways. Isolated mitochondria from these mice were dysfunctional, leading to abolished oxidative capacity in BAT in vivo, which in turn led to progressive deterioration of the tissue characterized by diminished iron content, adipocyte hypertrophy as well as increased tissue inflammation, making brown fat in these animals appear white. Interestingly, these phenotypic features were not present in mice at thermoneutrality, indicating that only BAT experiencing increased proteometabolic demand upon activation requires the adaptive functions of Nrf1. Finally, in the distinct metabolic challenge of obesity, loss of Nrf1 expression in BAT resulted in increased inflammatory cytokines in plasma as well as exacerbated glucose intolerance and insulin resistance, indicating a crucial role for the BAT Nrf1 pathway in the immunometabolic development of obesity-induced metabolic disease. On the other hand adenoviral delivery of Nrf1 into BAT alleviated insulin resistance in ob/ob mice, indicating the exciting therapeutic potential of targeting Nrf1. In conclusion, Nrf1 emerges as a novel metabolic guardian of brown adipocyte function, providing increased proteometabolic quality control for the adaptation to cold and obesity.
Publications
- Adipose tissue browning and metabolic health. Nat Rev Endocrinol. 2014 Jan;10(1):24-36
Bartelt A, Heeren J
(See online at https://doi.org/10.1038/nrendo.2013.204) - Brown fat activation reduces hypercholesterolemia and protects from atherosclerosis development. Nat Commun. 2015 Mar 10;6:6356
Berbée JF, Boon MR, Khedoe PP, Bartelt A, Schlein C, Worthmann A, Kooijman S, Hoeke G, Mol IM, John C, Jung C, Vazirpanah N, Brouwers LP, Gordts PL, Esko JD, Hiemstra PS, Havekes LM, Scheja L, Heeren J, Rensen PC
(See online at https://doi.org/10.1038/ncomms7356) - Surgical Injury Induces Local and Distant Adipose Tissue Browning. Adipocyte Epub 2015 Nov 20
Longchamp A, Tao M, Bartelt A, Ding K, Lynch L, Hine C, Corpataux JM, Kristal B, Mitchell, JR, Ozaki, CK
(See online at https://doi.org/10.1080/21623945.2015.1111971) - Brown adipose tissue thermogenic adaptation requires Nrf1-mediated proteasomal activity. Nature Medicine volume 24, pages 292–303 (2018)
Bartelt A, Widenmaier SB, Schlein C, Johann K, Goncalves RLS, Eguchi K, Alexander W Fischer, Günes Parlakgül, Snyder N, Nguyen TB, Bruns OT, Franke F, Bawendi MG, Lynes MD, Leiria LO, Tseng YH, Arruda AP, Inouye K, Hotamisligil GS
(See online at https://doi.org/10.1038/nm.4481)
