Beyond genetic ablation, abrogation of endogenous IKK BNF ��B signaling is also achieved by the activation selleck of a G protein coupled receptor of the rhodopsin family and also a bona fide long chain fatty acid sensor coined GPR120. GPR120 activation by unsaturated FAs particularly of the omega 3 variety prevents signaling through the IKK BNF ��B pathway by physically Inhibitors,Modulators,Libraries interact ing with B2 arrestin and sequestering the major activator of the pathway, transforming growth factor B activated kinase 1 binding protein. Without sufficient TAB1 available to activate its partner protein TAK1 the downstream kinase IKK B and key transcription factor NF��B remain dormant and the transcriptional in flammatory response is not induced.

Despite the fact that GPR120 is well documented to signal through the Gqll subunit Inhibitors,Modulators,Libraries activating the protein kinase C mitogen activated Inhibitors,Modulators,Libraries protein kinase extracellular signal regulated kinase and the phosphoinositide 3 kinase AKT cascades, the relevance of either cascade in mediating the anti inflammatory properties of GPR120 remains unex plored. The presence of functional GPR120 and adequate omega 3 FAs for its activation is sufficient to lower sys temic inflammatory state and improve overall energy utilization in mice. Genetic disruption of GPR120 eliminates the ability of dietary omega 3 FAs to improve energy homeostasis in obese mice, attesting to the potency of this receptor. Importantly, GPR120 activity is also physiologically relevant in humans given the recent dis covery of functionally disrupted GPR120 mutations in obese Europeans.

Inhibitors,Modulators,Libraries The anti inflammatory actions of GPR120 in response to long chain FAs, in particular omega 3 FAs, have been elegantly demonstrated in adipo cytes and macrophages, but little is known regarding these actions in other tissues throughout the body. Recently, GPR120 expression and the GPR120 B2 arrestin TAB1 interaction were identified in the hypothalamus, but its role in the CNS remains poorly understood. Given the anti inflammatory actions of GPR120 in the periphery and the conservation the IKK BNF ��B pathway in the CNS, we hypothesize that GPR120 may modulate hypo thalamic function by altering the inflammatory status of this tissue. We test this hypothesis at the Inhibitors,Modulators,Libraries cellular level using a hypothalamic neuronal model, rHypoE 7, isolated from the rat.

Methods Cell culture The hypothalamic all targets cell line from the embryonic rat, rHypoE 7, was isolated and immortalized as previously de scribed. Cell lines were maintained and grown to confluency in Dulbeccos Modified Eagle Medium supplemented with 5% fetal bovine serum, 1% penicillin, and 1% streptomycin and seeded into 60 mm cul ture plates 24 hrs prior to experimental treatments. Production of cDNA and quantitative real time reverse transcriptase PCR Total cellular RNA was isolated as previously described using the guanidium thiocyanate phenol chloroform extrac tion method.