Effects of a Naturally Occurring Dual FFAR Agonist on Incretins, Insulin Secretion, Lipids and Inflammation in Obesity and Type 2 Diabetes

Type 2 diabetes (T2D) is one of the greatest health challenges worldwide. The disease is strongly associated with obesity, and develops via pre-diabetic conditions, where insulin resistance and low-grade inflammation play an important role, to T2D, where failure of the pancreatic beta-cell to compensate for insulin resistance causes hyperglycemia. According to recent estimates, 350 million people worldwide suffer from diabetes. The disease typically leads to many years of reduced quality of life due to side complications such as cardiovascular disease (CVD), blindness, kidney failure and amputations. T2D is estimated to be the 4th leading cause of death in the Western world with 5-10 years reduced life expectancy. It is generally agreed that a healthy diet and increased physical activity are effective in preventing T2D, and also may help to achieve a better control of T2D and reduce risk of CVD. There is, however, not a general agreement as to what a healthy diet constitutes.

During the last decade, several cell surface receptors that respond to free fatty acids (FFA) have been discovered. These free fatty acid receptors (FFARs) belong to the superfamily of G protein-coupled 7-transmembrane receptors (GPRs), and have all been implicated in metabolic processes, energy expenditure and inflammation. Consequently, several of the receptors have attracted interest as potential targets for the treatment of metabolic and inflammatory diseases, including obesity and T2D.

FFAR1 (GPR40), which is activated by long-chain FFA, is highly expressed in pancreatic β-cells and increases glucose-stimulated insulin secretion (GSIS) [4]. There is evidence that FFAR1 is also expressed in intestinal enteroendocrine cells, where it promotes secretion of incretin hormones such as GLP-1 and GIP. GLP-1 is highly interesting for treatment of obesity and T2D because of its ability to increase GSIS, enhance β-cell growth, increase insulin sensitivity, reduce gastric motility, increase satiety and cause a loss of weight. The published phase II clinical trial with the selective FFAR1 agonist TAK-875 demonstrated high efficacy in reducing plasma glucose without increased incidence of hypoglycemia, and has caused considerable interest in the receptor as a new target for treatment of T2D.

FFAR4 (GPR120), which is activated by unsaturated long-chain FFA, is expressed in the gastrointestinal system, adipose tissue, and β-cells, and is reported to promote GLP-1 secretion from intestinal cells, to counteract inflammation and to increase insulin sensitivity in adipose tissue. Notably, dysfunctional FFAR4 was recently connected to the development of obesity in both mice and humans. This has considerably increased the interest on the receptor as a target for obesity and metabolic diseases. This is supported by indications that unsaturated FFA revert diet-induced hypothalamic inflammation through FFAR4, and thereby reduce body weight in diet-induced obese (DIO) mice. These FFARs are thus expressed in different tissues in the body where they potentially can affect metabolic and inflammatory conditions such as T2D and obesity.

These functions combined and the abundance of fatty acids in food suggests that FFARs can be considered as nutrient sensing regulators of metabolism.