Control of energy homeostasis through BRITE adipocytes
Final Report Abstract
A tight regulation of energy homeostasis is a prerequisite for the maintenance of body weight and metabolic adaptation to changing nutritional and (patho)-physiological conditions. Given their capability to burn excess energy by uncoupling the respiratory chain from ATP synthesis, Ucp1-expressing, thermogenic brown adipose tissues may protect mammals to a certain degree from developing obesity during high caloric intake. On the other side, hyperactivity of these tissues potentially results in energy wasting and is suspected to contribute to body weight loss in cancer cachexia. Contrary to a former paradigm, substantial amounts of thermogenically active adipose tissues were recently found in discrete areas of adult humans and thus have gained attention as therapeutic targets for combating conditions of energy dysbalance. Especially, BRITE (brown-in-white) adipose tissue is of interest in this context, as its formation can be induced in energy storing white adipose depots by physiological stimuli or pharmacological compounds, and thus it might likely to be targeted by nutritional or pharmacological approaches. For exploitation of the therapeutic potential of BRITE adipose tissue, a better understanding of its differentiation and function in various settings is still urgently needed. Here, we addressed the functional role of BRITE adipose tissue in metabolic health and disease. Specifically, we have demonstrated that BRITE adipocytes improve systemic glucose utilization in an insulin-independent manner. Furthermore, we have investigated the role of specific immune cells – namely regulatory T cells and alternatively activated macrophages – in the regulation of brown fat activity. Additionally, our research contributed to the identification of a novel micro RNA that directs differentiation of human preadipocytes towards a BRITE phenotype. In-depth understanding of the molecular regulation of BRITE progenitor cells is required to exploit their therapeutic potential in the treatment of obesity and insulin resistance. Therefore we used expression profiling in a physiological model of BRITE adipocyte differentiation to identify new regulatory factors controlling the early steps of progenitor cell activation. In this way we discovered and functionally validated a signaling pathway crosstalk linking transient inflammation to the activation of BRITE progenitor cells and a transcriptional cofactor mediating sex-specific differentiation of BRITE adipocytes and insulin sensitization in the context of treatment with the antidiabetic drug rosiglitazone. In the context of the second objective we scrutinized the involvement of BRITE adipose tissue in body wasting associated to cancer cachexia. Intriguingly, in disagreement with our initial hypothesis and recent studies from labs in the US and Austria, we found no induction of Ucp1 in cachectic adipose tissue, and, more important, that Ucp1 knockout mice were not protected from cachexia. In line with this, energy expenditure in cachectic animals was not augmented, altogether supporting the hypothesis that BRITE-independent processes lead to decay of adipose tissue under these conditions. We found that under cachectic conditions, destabilization of AMPK by CIDEA interaction induces a futile cycle of lipolysis and lipogenesis in WAT. Interfering with this interaction resulted in protection from body wasting in tumor-bearing mice, thereby providing an unprecedented entry point into developing novel treatments to combat this yet incurable condition. Altogether, the Reinhart Koselleck Project reported here, yielded novel insights into the function and dysfunction of BRITE adipocytes. Our findings provide first steps in the development of innovative adipose-tissue-targeting therapies for conditions of metabolic dysbalance.
Publications
- MicroRNA-26 family is required for human adipogenesis and drives characteristics of brown adipocytes. Stem Cells 2013; 32(6):1578-1590
Karbiener M, Pisani DF, Frontini A, Oberreiter LM, Lang E, Vegiopoulos A, Mössenböck K, Bernhardt G, Mayr T, Hildner F, Grillari J, Ailhaud G, Herzig S, Cinti S, Amri EZ, Scheideler M
(See online at https://doi.org/10.1002/stem.1603) - Browning of white adipose tissue uncouples glucose uptake from insulin signaling. PLoS One 2014; 9(10):e110428
Mössenböck K, Vegiopoulos A, Rose AJ, Sijmonsma TP, Herzig S, Schafmeier T
(See online at https://doi.org/10.1371/journal.pone.0110428) - Thermogenic adipocytes: from cells to physiology and medicine. Metabolism 2014; 63(10):1238-1249
Berriel Diaz M, Herzig S, Vegiopoulos A
(See online at https://doi.org/10.1016/j.metabol.2014.07.002) - Brown adipose tissue harbors a distinct sub-population of regulatory T cells. PLoS One 2015; 10(2):e118534
Medrikova D, Sijmonsma TP, Sowodniok K, Richards DM, Delacher M, Sticht C, Gretz N, Schafmeier T, Feuerer M, Herzig S
(See online at https://doi.org/10.1016/j.cmet.2015.04.013) - Hematopoietic Kit deficiency, rather than lack of mast cells, protects mice from obesity and insulin resistance. Cell Metab 2015; 21(5):678-691
Gutierrez D A, Muralidhar S, Feyerabend TB, Herzig S, Rodewald HR
(See online at https://doi.org/10.1016/j.cmet.2015.04.013) - Transcriptional Pathways in cPGI2-Induced Adipocyte Progenitor Activation for Browning. Front Endocrinol (Lausanne) 6:129
Bayindir I, Babaeikelishomi R, Kocanova S, Sousa IS, Lerch S, Hardt O, Wild S, Bosio A, Bystricky K, Herzig S, Vegiopoulos A
(See online at https://doi.org/10.3389/fendo.2015.00129) - A liver stress-endocrine nexus promotes metabolic integrity during dietary protein dilution. J Clin Invest 2016; 126(9):3263-3278
Maida A, Zota A, Sjøberg KA, Sijmonsma TP, Pfenninger A, Christensen MM, Schmidt K, Fuhrmeister J, Rothermell U, Okun JG, Schmoll D, Kiens B, Herzig S, Rose AJ
(See online at https://doi.org/10.1172/JCI85946) - An AMP-activated protein kinase– stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice. Nat Med 2016; 22(10):1120-1130
Rohm M, Schäfer M, Laurent V, Ekim Üstünel B, Niopek K, Algire C, Hautzinger O, Sijmonsma TP, Zota A, Medrikova D, Pellegata NS, Ryden M, Kulyte A, Dahlman I, Arner P, Petrovic N, Cannon B, Amri EZ, Kemp BE, Steinberg GR, Janovska P, Kopecky J, Wolfrum C, Blüher M, Berriel Diaz M, Herzig S
(See online at https://doi.org/10.1038/nm.4171) - Adipose Tissue: Between the Extremes. EMBO J 2017; 36(14):1999-2017
Vegiopoulos A, Rohm M, Herzig S
(See online at https://doi.org/10.15252/embj.201696206) - Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis. Nat Med 2017; 23(5):623-630
Fischer K, Ruiz HH, Jhun K, Finan B, van der Heide V, Kalinovich A, Petrovic N, Wolf Y, Clemmensen C, Shin AC, Divanovic S, Brombacher F, Glasmacher E, Keipert S, Jastroch M, Nagler J, Schramm KW, Medrikova D, Collden G, Woods SC, Herzig S, Homann D, Jung S, Nedergaard J, Cannon B, Tschöp MH, Müller TD, Buettner C
(See online at https://doi.org/10.1038/nm.4316) - Repletion of branched chain amino acids reverses mTORC1 signalling but not improved metabolism during dietary protein dilution. Mol Metab 2017; 6(8):873-881
Maida A, Chan J, Sjøberg KA, Zota A, Schmoll D, Kiens B, Herzig S, Rose AJ
(See online at https://doi.org/10.1016/j.molmet.2017.06.009) - A proteolytic fragment of histone deacetylase 4 protects the heart from failure by regulating the hexosamine biosynthetic pathway. Nat Med 2018; 24(1):62-72
Lehmann LH, Jebessa ZH, Kreusser MM, Horsch A, He T, Kronlage M, Dewenter M, Sramek V, Oehl U, Krebs-Haupenthal J, von der Lieth AH, Schmidt A, Sun Q, Ritterhoff J, Finke D, Völkers M, Jungmann A, Sauer SW, Thiel C, Nickel A, Kohlhaas M, Schäfer M, Sticht C, Maack C, Gretz N, Wagner M, El-Armouche A, Maier LS, Londoño JEC, Meder B, Freichel M, Gröne HJ, Most P, Müller OJ, Herzig S, Furlong EEM, Katus HA, Backs J
(See online at https://doi.org/10.1038/nm.4452) - Cited4 is a sex-biased mediator of the antidiabetic glitazone response in adipocyte progenitors. EMBO Mol Med 2018; 10(8):pii:e8613
Bayindir-Buchhalter I, Wolff G, Lerch S, Sijmonsma T, Schuster M, Gronych J, Billeter A T, Babaei R, Krunic D, Ketscher L, Spielmann N, Hrabe de Angelis M, Ruas J L, Müller-Stich B P, Heikenwalder M, Lichter P, Herzig S, Vegiopoulos A
(See online at https://doi.org/10.15252/emmm.201708613) - Jak-TGFbeta crosstalk links transient adipose tissue inflammation to adipogenesis. Sci Signal 2018; 11(527):pii:eaai7838
Babaei R, Schuster M, Meln I, Lerch S, Ghandour RA, Pisani DF, Bayindir-Buchhalter I, Marx J, Wu S, Billeter AT, Krunic D, Mauer J, Lee YH, Granneman JG, Fischer L, Müller- Stich BP, Amri EZ, Kershaw EE, Heikenwälder M, Herzig S, Vegiopoulos A
(See online at https://doi.org/10.1126/scisignal.aai7838)
