Metabolic Syndrome


Metabolic syndrome is a term that describes obesity, type II diabetes, fibrosis, cardiovascular and other diseases. This research program intersects with our various projects in antiinflammatory therapies and inflammation research.

Originally we were interested in how our various novel targets signal in inflammatory disease, and we developed novel drug leads to investigate these signaling events. As we progressed through effects on and in different cell types, we became interested in adipocytes, pancreatic islets, hepatocytes, different immune cell types, and then epithelial cells in general in disrupted homeostasis.

We found that a number of our most potent and receptor selective compounds (developed for human macrophages, human enzymes or other human proteins associated with inflammatory diseases) also acted on their protein targets which are present in the endocrine system and epithelial tissues. Obesity, type II diabetes, fibrosis and many cardiovascular diseases are now thought to be inflammatory diseases.

Our studies have been aimed at unravelling mechanisms (at the protein, enzyme and cellular level) by which immunological and endocrinology systems intersect, and generating proof of concept by examining our new drug classes in animal models of cardiovascular disease, diabetes and obesity.



Protease-activated receptor 2 induces glycolysis and sterile inflammation for autonomous cell homeostasis. Iyer A, Vesey DA, Ward MS. Hodson MP, Jiang Y, Suen JY, Yau M-K, Liu L, Johnson DW, Prins JB, Fairlie DP.

Inhibitors of class I histone deacetylases attenuate thioacetamide-induced liver fibrosis in mice by suppressing hepatic type 2 inflammation. Loh Z, Fitzsimmons RL, Reid RC, Ramnath D, Clouston A, Gupta PK, Irvine KM, Powell EE, Schroder K, Stow JL, Sweet MJ, Fairlie DP, Iyer A. Br J Pharmacol 2019, 176, 3775-3790. 

 Protease-activated receptor 2 does not contribute to renal inflammation or fibrosis in the obstructed kidney. Ma FY, Han Y, Ozols E, Chew P, Vesey DA, Gobe GC, Morais C, Lohman RJ, Suen JY, Johnson DW, Fairlie DP, Nikolic-Paterson DJ. Nephrology (Carlton) 2019, 24, 983-991. 

Lysine Deacetylases and Regulated Glycolysis in Macrophages. Shakespear MR, Iyer A, Cheng CY, Das Gupta K, Singhal A, Fairlie DP, Sweet MJ. Trends Immunol 2018, 39, 473-488.

Hepatic expression profiling identifies steatosis-independent and steatosis-driven advanced fibrosis genes. Ramnath D, Irvine KM, Lukowski SW, Horsfall LU, Loh Z, Clouston AD, Patel PJ, Fagan KJ, Iyer A, Lampe G, Stow JL, Schroder K, Fairlie DP, Powell JE, Powell EE, Sweet MJ. JCI Insight 2018, 3(14). pii: 120274. doi: 10.1172/jci.insight.120274. 

Chemical Approaches to Modulating Complement-Mediated Diseases. Iyer A, Xu W, Reid RC, Fairlie DP. J Med Chem 2018, 61, 3253-3276.

Histone deacetylases in monocyte/macrophage development, activation and metabolism: refining HDAC targets for inflammatory and infectious diseases. Das Gupta K, Shakespear MR, Iyer A, Fairlie DP, Sweet MJ. Clin Transl Immunology 2016, 5(1), e62. 

Nutrient and immune sensing are obligate pathways in metabolism, immunity, and disease. Iyer A, Brown L, Whitehead JP, Prins JB, Fairlie DP. FASEB J 2015, 29, 3612-3625.

Diet-induced obesity, adipose tissue inflammation and metabolic dysfunction correlating with PAR2 expression are attenuated by a PAR2 antagonist. Lim J, Iyer A, Suen JY, Liu L, Lohman RJ, Seow V, Yau MK, Brown L, Fairlie DP. FASEB J 2013, 27, 4757-4767. 

C5aR and C3aR antagonists each inhibit diet-induced obesity, metabolic dysfunction, and adipocyte and macrophage signaling. Lim J, Iyer A, Suen JY, Seow V, Reid RC, Brown L, Fairlie DP. FASEB J. 201327, 822-831.

An inhibitor of pla2g2a modulates adipocyte signaling and protects against diet-induced metabolic syndrome in rats. Iyer A, Lim J, Poudyal H, Reid RC, Suen JY, Webster J, Prins JB, Whitehead JP, Fairlie DP*, Brown L* Diabetes 2012, 61(9), 2320-2329.

Lysine acetylation in obesity, diabetes and metabolic disease. Iyer A, Fairlie DP, Brown L. Immunol Cell Biol. 2012, 90, 39-46.

Antifibrotic activity of an inhibitor of histone deacetylases in DOCA-salt hypertensive rats. Iyer A, Fenning A, Lim J, Le GT, Reid RC, Halili MA, Fairlie DP, Brown L. Br J Pharmacol. 2010, 159, 1408-1417.

Profiling gene expression induced by protease-activated receptor 2 (PAR2) activation in human kidney cells. Suen JY, Gardiner B, Grimmond S, Fairlie DP. PLoS One. 2010, 5(11), e13809.

Iyer, A.; Fairlie, D. P.; Prins J.; Hammock B. D.; Brown, L. Inflammatory lipid mediators in adipocyte function and obesity. Nature Reviews Endocrinology 2010, 6, 71-82.