gw9508 and Obesity

The free fatty acid receptor 4 (FFA4), also known as GPR120, is a G protein-coupled receptor that is activated by long-chain fatty acids and that has been associated with regulation of appetite, release of insulin controlling hormones, insulin sensitization, anti-inflammatory and potentially anti-obesity activity, and is progressively appearing as an attractive potential target for the treatment of metabolic dysfunctions such as obesity, type 2 diabetes and inflammatory disorders. Ongoing investigations of the pharmacological functions of FFA4 and validation of its potential as a therapeutic target depend critically on the appropriateness and quality of the available pharmacological probes or tool compounds. After a brief summary of the pharmacological functions of FFA4 and some general considerations on desirable properties for these pharmacological tool compounds, the individual compounds that have been or are currently being used as tools for probing the function of FFA4 in various in vitro and in vivo settings will be discussed and evaluated.

Topics: Animals; Biphenyl Compounds; Humans; Inflammation; Insulin Resistance; Methylamines; Obesity; Phenylpropionates; Propionates; Receptors, G-Protein-Coupled

Activation of free fatty acid receptors (FFAR1 and FFAR4) which are G protein-coupled receptors (GPCRs) with established (patho)physiological roles in a variety of obesity-related disorders, induce human airway smooth muscle (HASM) cell proliferation and shortening. We reported amplified agonist-induced cell shortening in HASM cells obtained from obese lung donors. We hypothesized that FFAR1 modulate excitation-contraction (EC) coupling in HASM cells and play a role in obesity-associated airway hyperresponsiveness.. In HASM cells pre-treated (30 min) with FFAR1 agonists TAK875 and GW9508, we measured histamine-induced Ca. Unexpectedly, we found that TAK875, a synthetic FFAR1 agonist, attenuated histamine-induced MLC phosphorylation and cortical tension development in HASM cells. These physiological outcomes were unassociated with changes in histamine-evoked Ca. Taken together, our findings identified the FFAR1 agonist TAK875 as a novel bronchoprotective agent that warrants further investigation to treat difficult-to-control asthma and/or airway hyperreactivity in obesity.

Topics: Adrenergic beta-2 Receptor Agonists; Benzofurans; Bronchoconstriction; Bronchodilator Agents; Cells, Cultured; Histamine; Humans; Lung; Methylamines; Muscle, Smooth; Myocytes, Smooth Muscle; Myosin Light Chains; Obesity; Phosphorylation; Propionates; Receptors, G-Protein-Coupled; Signal Transduction; Sulfones