Although it has been known since the 1960s that trypsin and chymotrypsin can mimic hormone action in tissues, it took until the 1990s to discover that serine proteinases can regulate cells by cleaving and activating a unique four‐member family ofGPCRs known as proteinase‐activated receptors (PARs).PARactivation involves the proteolytic exposure of itsN‐terminal receptor sequence that folds back to function as a ‘tethered’ receptor‐activating ligand (TL). A keyN‐terminal arginine in each ofPARs1 to 4 has been singled out as a target for cleavage by thrombin (PARs1, 3 and 4), trypsin (PARs2 and 4) or other proteases to unmask theTLthat activates signalling viaG_q, G_iorG_12/13. Similarly, synthetic receptor‐activating peptides, corresponding to the exposed ‘TLsequences’ (e.g.SFLLRN—, forPAR1orSLIGRL— forPAR2) can, like proteinase activation, also drive signalling viaG_q,G_iandG_12/13, without requiring receptor cleavage. Recent data show, however, that distinct proteinase‐revealed ‘non‐canonical’PARtethered‐ligand sequences andPAR‐activating agonist and antagonist peptide analogues can induce ‘biased’PARsignalling, for example, viaG_12/13‐MAPKinase instead ofG_q‐calcium. This overview summarizes implications of this ‘biased’ signalling byPARagonists and antagonists for the recognized roles thePARs play in inflammatory settings.Linked Articles: This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visithttp://dx.doi.org/10.1111/bph.2014.171.issue‐5

Mammalian survival depends on metabolizing nutrients, storing energy, and combating infection. Complement activation in blood triggers energy‐depleting immune responses to fight infections. Here we identify surprising energy‐conserving roles for complement proteins C5a and C3a and their receptors, C5aR and C3aR, roles that are contraindicated in complement biology. Rats fed a high‐carbohydrate high‐fat diet developed obesity, visceral adiposity, adipose inflammation, glucose/insulin intolerance, and cardiovascular dysfunction that correlated with increased plasma C3a, adipose C5aR, and C3aR. These in vivo changes were dramatically attenuated by receptor‐selective antagonists of either C5aR (5 mg/kg/d p.o.) or C3aR (30 mg/kg/d p.o.), which both reduced proinflammatory adipokines and altered expression of inflammatory genes in adipose tissue. In vitro C5a and C3a (100 nM) exhibited novel insulin‐like effects on 3T3‐L1 adipocytes, promoting energy conservation by increasing glucose and fatty acid uptake while inhibiting cAMP signaling and lipolysis, and induced PGE ₂ release from macrophages, effects all blocked by each respective antagonist (10 μM). These studies reveal important new links between complement signaling and metabolism, highlight new complement functions on adipocytes and in adipose tissue, demonstrate how aberrant immune responses may exacerbate obesity and metabolic dysfunction, and show that targeting C3aR or C5aR with antagonists is a new strategy for treating metabolic dysfunction.—Lim, J., Iyer, A., Suen, J. Y., Seow, V., Reid, R. C., Brown, L., Fairlie, D. P. C5aR and C3aR antagonists each inhibit diet‐induced obesity, metabolic dysfunction, and adipocyte and macrophage signaling. FASEB J. 27, 822–831 (2013). www.fasebj.org

Multiple serine proteases exert proinflammatory actions by signaling through protease‐activated receptor‐2 (PAR2) on the cell surface. Although inhibitors of individual proteases are anti‐inflammatory, we sought to discover whether the first potent antagonist of their common target PAR2 might be beneficial in treating chronic arthritis‐like inflammatory disease. Using a fluorescence assay, a novel compound, GB88, was shown to antagonize PAR2‐induced intracellular Ca ²⁺ release in human monocyte‐derived macrophages, being 1000 times more potent than a control compound, ENMD‐1068 (IC ₅₀ 1.6±0.5 μM vs. 1.2±0.4 mM, respectively). In Wistar rats, GB88 was orally bioavailable ( F =55%, T _max 4 h, C _max 1.7 μM, 10 mg/kg). GB88 inhibited the acute paw edema induced in Wistar rats by intraplantar λ‐carrageenan or PAR2 agonists 2‐furoyl‐LIGRLO‐NH ₂ or mast cell β‐tryptase, without inhibiting proteolytic activity of tryptase in vitro. In the chronic collagen‐induced model of arthritis in rats, GB88 (10 mg/kg) was disease modifying and ameliorated pathological and histopathological changes (edema, pannus formation, synovial hyperplasia, collagen degradation, macrophage invasion, mast cell degranulation) compared to untreated arthritic controls. The results suggest that an orally active PAR2 antagonist is effective in treating chronic arthritis in rats through inhibiting macrophage infiltration, mast cell degranulation, and β‐tryptase‐PAR2 signaling in joint inflammation.—Lohman, R.‐J., Cotterell, A. J., Barry, G. D., Liu, L., Suen, J. Y., Vesey, D. A., Fairlie, D. P. An antagonist of human protease activated receptor‐2 attenuates PAR2 signaling, macrophage activation, mast cell degranulation, and collagen‐induced arthritis in rats. FASEB J. 26, 2877–2887 (2012). www.fasebj.org

Excessive uptake of fatty acids and glucose by adipose tissue triggers adipocyte dysfunction and infiltration of immune cells. Altered metabolic homeostasis in adipose tissue promotes insulin resistance, type 2 diabetes, hypertension, and cardiovascular disease. Inflammatory and metabolic processes are mediated by certain proteolytic enzymes that share a common cellular target, protease‐activated receptor 2 (PAR2). This study showed that human and rat obesity correlated in vivo with increased expression of PAR2 in adipose tissue, primarily in stromal vascular cells (SVCs) including macrophages. PAR2 was expressed more than other PARs on human macrophages and was increased by dietary fatty acids (palmitic, stearic, and myristic). A novel PAR2 antagonist, GB88 (5‐isoxazoyl‐Cha‐Ile‐spiroindene‐1,4‐piperidine), given orally at 10 mg/kg/d (wk 8–16) reduced body weight by ~10% in obese rats fed a high‐carbohydrate high‐fat (HCHF) diet for 16 wk, and strongly attenuated adiposity, adipose tissue inflammation, infiltrated macrophages and mast cells, insulin resistance, and cardiac fibrosis and remodeling; while reversing liver and pancreatic dysfunction and normalizing secretion of PAR2‐directed glucose‐stimulated insulin secretion in MIN6 β cells. In summary, PAR2 is a new biomarker for obesity, and its expression is stimulated by dietary fatty acids; PAR2 is a substantial contributor to inflammatory and metabolic dysfunction; and a PAR2 antagonist inhibits diet‐induced obesity and inflammatory, metabolic, and cardiovascular dysfunction.—Lim, J., Iyer A., Liu, L., Suen J. Y., Lohman R.‐J., Seow V., Yau M.‐K., Brown, L., Fairlie, D. P., Diet‐induced obesity, adipose inflammation, and metabolic dysfunction correlating with PAR2 expression are attenuated by PAR2 antagonism. FASEB J. 27, 4757–4767 (2013). www.fasebj.org