FFAR4: A New Player in Cardiometabolic Disease?

Abstract

Free fatty acids (FFAs) are implicated in the pathogenesis of metabolic diseases that include obesity, type 2 diabetes mellitus (T2DM), and cardiovascular disease (CVD). FFAs serve as ligands for free fatty acid receptors (FFARs) that belong to the family of rhodopsin-like G protein-coupled receptors (GPCRs) and are expressed throughout the body to maintain energy homeostasis under changing nutritional conditions. Free fatty acid receptor 4 (FFAR4), also known as G protein-coupled receptor 120 (GPR120), is a long-chain fatty acid receptor highly expressed in adipocytes, endothelial cells, and macrophages. Activation of FFAR4 helps maintain metabolic homeostasis by regulating adipogenesis, insulin sensitivity, and inflammation. Furthermore, dysfunction of FFAR4 is associated with insulin resistance, obesity, and eccentric remodeling in both humans and mice, making FFAR4 an attractive therapeutic target for treating or preventing metabolic diseases. While much of the previous literature on FFAR4 has focused on its role in obesity and diabetes, recent studies have demonstrated that FFAR4 may also play an important role in the development of atherosclerosis and CVD. Most notably, FFAR4 activation reduces monocyte-endothelial cell interaction, enhances cholesterol efflux from macrophages, reduces lesion size in atherogenic mouse models, and stimulates oxylipin production in myocytes that functions in a feed-forward cardioprotective mechanism. This review will focus on the role of FFAR4 in metabolic diseases and highlights an underappreciated role of FFAR4 in the development of atherosclerosis and CVD.

Does FFAR4 Agonism have Therapeutic Potential in Cardiometabolic Disease?

“…Their article ( 3 ) follows a recent publication which reports a cardioprotective role for FFAR4 in models of pressure overload and associations between the R270H polymorphism (affecting Ga/q signaling capacity) and eccentric remodeling in patient cohorts ( 5 ). Of note, this FFAR4 variant has previously been associated with an increased risk of obesity in European populations ( 6 ), though this association has not been consistently observed in different study populations ( 7 ) and the loss of FFAR4 expression or activity alone may not be sufficient to induce obesity.…”

“…In their article, Stuttgen and Sahoo ( 3 ) highlight the potential role of FFAR4 in the pathogenesis of cardiometabolic disease, noting that while there is extensive evidence of an involvement of FFAR4 in metabolic and inflammatory disease (including type 2 diabetes and obesity); the role of FFAR4 in the development of atherosclerosis and CVD is only recently emerging. Given the long-standing associations between FFAR4/GP120 and obesity, diabetes, and inflammation, and the considerable interest in developing therapeutic FFAR4 agonists ( 4 ), it is surprising that the role of FFAR4 in atherosclerosis and CVD (particularly in the context of metabolic disease) is not more well studied.…”

“…Mechanistically, it seems likely that the involvement of FFAR4 in cardiometabolic disease is at least in part due to the role in modulating vascular inflammation. As detailed by Stuttgen and Sahoo ( 3 ) there are several lines of evidence supporting a role for FFAR4 in regulating macrophage activation; 1 of the beneficial effects of FFAR4 agonists reported in preclinical models is in improving chronic inflammation associated with insulin resistance, via regulating macrophage activity ( 4 ). This potentially makes FFAR4 activation an attractive target for treating vascular damage, atherosclerosis, and CVD, which are driven by chronic, low-grade inflammation.…”

“…This potentially makes FFAR4 activation an attractive target for treating vascular damage, atherosclerosis, and CVD, which are driven by chronic, low-grade inflammation. Indeed, there is also evidence that FFAR4 can limit monocyte–endothelial interactions ( 3 ), though there is again some contradictory evidence for this role; in a study of FFAR4 in leukocytes, it was concluded that activation by polyunsaturated FAs had no effect in an animal model of atherosclerosis ( 8 ). In this instance it is important to note that the concentrations of FAs were comparatively much lower than those in other studies ( 1 , 2 ) and, crucially, the level of FFAR4 activation achieved by these FAs will not necessarily be comparable to the chronic and consistent FFAR4 activation possible with synthetic agonists.…”

“…Important sex-specific differences in the role of FFAR4 have also been noted ( 3 ), requiring further investigation and consideration in future studies. It will also be important to delineate the tissue- and cell-specific effects of FFAR4 activation, as the potential roles in chemoresistance and survival of certain cancers ( 3 ) suggests therapies based on activating FFAR4 may not always be beneficial.…”