A Novel Antidiabetic Therapy: Free Fatty Acid Receptors as Potential Drug Target
2015
Excessive dietary intake of fat is strongly involved in the development of type 2 diabetes
(T2D). Free fatty acids (FFAs), which are provided from dietary fat, are not only important nutrients,
but also act as signaling molecules and stimulate key biological functions. Recent physiological and
pharmacological studies have shown that several G-protein coupled receptors, such as FFAR1–4, are
receptors for FFAs. FFAR1 and FFAR4 are activated by medium- and long-chain fatty acids, whereas
FFAR2 and FFAR3 are activated by short-chain fatty acids (SCFAs). These FFA receptors (FFARs) mediate various
physiological functions, depending on the carbon chain length of the FFAs and the ligand specificity of the FFARs. Functional
analyses have revealed that FFARs mediate important metabolic functions, such as peptide hormone secretion and
inflammation, and thereby contribute to energy homeostasis. Since imbalances in energy homeostasis lead to metabolic
disorders, such as obesity and T2D, FFARs are considered to be key therapeutic targets in these diseases. In particular, recent
studies have shown that the administration of selective agonists of FFAR1 and FFAR4 improved glucose metabolism
and ameliorated systemic metabolic disorders. Furthermore, the biological functions of SCFAs in anti-inflammation and
energy metabolism are linked with the activation of FFAR2 and FFAR3. Hence, in this review, we summarize the physiological
functions of FFARs and discuss the potential of selective ligands of FFARs for development as drugs to treat
metabolic disorders, such as T2D and obesity.
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