ESR Project 5:  ‘Trib-dependent reprogramming of adipocytes and its implications for immuno-metabolic conditions’



The tribbles pseudo-kinase family is an evolutionarily conserved mammalian homolog of the drosophila Tribbles gene. Within humans there are 3 genes that encode the distinct tribbles proteins, comprising TRIB1, TRIB2 and TRIB3. The structure of these proteins is well described, exhibiting a catalytically inactive kinase like domain, a C-terminal binding site for E3 ubiquitin ligases (Eyers, 2015).

These three genes impact individual tissues and disease states differently. Tribbles proteins have been associated with a number of disease states including myocardial infarction (Burkhardt et al, 2010), macrophage differentiation (Satoh et al, 2013), Cataplexy (Kawashima et al, 2010), insulin resistance (Oberkofler et al, 2010) several cancers (Mashima et al, 2014; Wang et al, 2013) including anticancer therapy resistance (Hill et al, 2017) and prediction of patient outcomes (Miyoshi et al, 2009).

In the context of adipose Tribbles are known to target AKT/FOXO & CCAAT/ enhancer binding protein (C/EBP), which play critical roles in regulation of adipose differentiation. (Johnston et al, 2015). TRIB1 is seen to have increased expression in adipose tissue in response to inflammation, where it acts as a regulator of inflammatory cytokine expression (Angyal and Kiss-Toth, 2012). Such inflammation responses in WAT have been demonstrated to have the highest expression fraction from the adipocytes themselves as well as being elevated in WAT of early onset diabetes mouse models (Ostertag et al, 2010). While TRIB3 has been demonstrated to block differentiation of pre-adipocytes (Beyz et al,2007). TRIB3 expression is elevated in the eWAT of rats fed on a high fat diet (Bi et al, 2008).

There is still a need to understand the adipose-specific modulation of TRIB1/3 on adipocyte differentiation and function both in vitro and in vivo. Additionally the impact of TRIB1/3 on thermogenesis, BAT functionality, and cytokine secretion are still poorly understood.

This project proposes to determine the murine and human impact of the TRIB1/3 proteins within adipose tissue, with a focus on adipose differentiation, energy homeostasis, difference in expression of cytokines and their impact on distant tissues, with a focus on the energy and immune homeostasis in adipose associated disease states.

To complete this research I plan to make use of adiponectin-cre/ TRIB1 floxed mouse KO model and an adiponectin-cre/ ROSA TRIB1 overexpression model currently being bred (as well as TRIB3 models yet to be established) to demonstrate the importance of these proteins in differentiation of adipose and adipose function in vivo, with a focus on the impact upon disease states.



TRIBBLES: A Twist in the Pseudokinase Tail. Eyers, P.
Structure. 2015;23(11):1974–1976

Trib1 is a lipid- and myocardial infarction–associated gene that regulates hepatic lipogenesis and VLDL production in mice. Burkhardt, R., Breslow, J., Rader, D.

J Clin Invest. 2010;120(12):4410-4414. doi:10.1172/JCI44213.

Critical role of Trib1 in differentiation of tissue-resident M2-like macrophages. Satoh, T., Kidoya, H., Naito, H., Yamamoto, M., Takemura, N., Nakagawa, K., Yoshioka, Y., Morii, E., Takakura, N., Takeuchi, O., Akira, S.

NATURE. 2013;49520:524–528. doi:10.1038/nature11930

Anti-Tribbles Homolog 2 (TRIB2) Autoantibodies in Narcolepsy Are Associated with Recent Onset of Cataplexy. Kawashima, M., Lin, L., Tanaka, S., Jennum, P., Knudsen, S., Nevsimalova, S., Plazzi, G., Mignot, E. Sleep. 2010;33(7):869–874.

Aberrant hepatic TRIB3 gene expression in insulin-resistant obese humans. Oberkofler, H., Pfeifenberger, A., Soyal, S.Diabetologia. 2010;53:1971. doi:10.1007/s00125-010-1772-2

TRIB1 Supports Prostate Tumorigenesis and Tumor-Propagating Cell Survival by Regulation of Endoplasmic Reticulum Chaperone Expression. Mashima, T.,  Soma-Nagae, T.,  Migita, T., Kinoshita, R., Iwamoto, A., Yuasa, T., Yonese, J., Ishikawa, Y., Seimiya, H.

Cancer Res. 2014;74(17):4888-4897; DOI:10.1158/0008-5472.CAN-13-3718

TRIB2 Acts Downstream of Wnt/TCF in Liver Cancer Cells to Regulate YAP and C/EBPα Function Wang, J. Molecular Cell. 2013;51(2):211 – 225
TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT. Hill, R., Madureira, P., Ferreira, B., Baptista, I., Machado, S., Colaço, L., Santos, M., Liu, N., Dopazo, A., Ugurel, S., Adrienn, A., Kiss-Toth, E., Isbilen, M., Gure, A., Link, W.
Nature Communications. 2017;8(14687) doi:10.1038/ncomms14687

Abnormal expression of TRIB3 in colorectal cancer: a novel marker for prognosis
Miyoshi, N., Ishii, H., Mimori, K., Takatsuno, Y., Kim, H., Hirose, H., Sekimoto, M., Doki, Y., Mori, M.
British Journal of Cancer . 2009;101:1664–1670. doi:10.1038/sj.bjc.6605361

Tribbles in inflammation. Johnston, J., Basatvat, S., Ilyas, Z., Francis, S., Kiss-Toth, E. Biochemical Society Transactions. 2015;43(5):1069-1074 DOI: 10.1042/BST20150095

The tribbles gene family and lipoprotein metabolism. Angyal, A., Kiss-Toth, E.
Curr Opin Lipidol. 2012;23(2):122-6. doi: 10.1097/MOL.0b013e3283508c3b

Control of adipose tissue inflammation through TRB1.Ostertag, A., Jones, A., Rose, AJ., Liebert, M., Kleinsorg, S., Reimann, A., Vegiopoulos, A., Berriel Diaz, M., Strzoda, D., Yamamoto, M., Satoh, T., Akira, S., Herzig, S.
Diabetes. 2010;59(8):1991-2000. doi: 10.2337/db09-1537

TRB3 blocks adipocyte differentiation through the inhibition of C/EBPbeta transcriptional activity.
Bezy, O., Vernochet, C., Gesta, S., Farmer, SR., Kahn, CR.
Mol Cell Biol. 2007;27(19):6818-31.

Overexpression of TRB3 gene in adipose tissue of rats with high fructose-induced metabolic syndrome. Bi, XP., Tan, HW., Xing, SS., Wang, ZH., Tang, MX., Zhang, Y., Zhang, W.
Endocr J. 2008;55(4):747-52.