Fat Sensing Receptors and Obesity
Several novel G-protein coupled receptors (GPCRs) have identified in recent
years using a variety of screens or as a result of the complete sequencing of the human genome
that, subsequent to their characterization, were all shown to bind and be
activated by free fatty acids and/or lipid molecules. GPR120 was identified as a result of the human genome sequencing project and shown to be a member of the class A (rhodopsin-like) family of
GPCRs. GPR120 is specifically activated by long-chain non-esterified fatty acids (NEFAs) in particular in the intestines by alpha-linolenic acid (ALA) an omega-3 polyunsaturated fatty acid
(PUFA). Activation of GPR120 in the intestines results in increased glucagon-like peptide-1 (GLP-1) secretion from enteroendocrine L cells. GLP-1 is called an incretin because it induces insulin secretion from the pancreas in response to food intake (for more details on GLP-1 function visit the Gut-Brain Interactions page). GPR120 is highly expressed in adipose tissue, and proinflammatory
macrophages. The high expression level of GPR120 in mature
adipocytes and macrophages is indicative of the fact that GPR120 is likely
to play an important role in biologic functions of these cell types. In
contrast, negligible expression of GPR120 is seen in muscle,
pancreatic beta-cells (insulin secreting cells), and hepatocytes. Although not expressed at
appreciable levels in hepatocytes expression of GPR120 is highly inducible in
liver resident macrophage-like cells known as Kupffer cells. GPR120 can
be activated with a synthetic agonist (GW9508) as well as omega-3 PUFAs. For more detailed information on the mode of action of omega fat activation of, and signaling by, GPR120 visit the Omega-3 & Omega-6 Fatty Acid Synthesis, Metabolism, Functions page. Recent studies have found that some individuals harbor loss-of-function mutations in the gene encoding GPR120 are at increased risk for obesity and insulin resistance (a hallmark of type 2 diabetes). A clinically significant mutation results in the change of an arginine residue at amino acid position 270 to histidine (R270H) in the GPR120 protein. This mutation acts as a dominant-negative meaning that it interferes with the function of the GPR120 protein synthesized from the normal gene copy. Patients with this mutation are obese, more insulin resistant, and more glucose intolerant than obese persons without the R270H mutation. Given its important role in inflammation, obesity, and insulin sensitivity, one can expect that soon there will be drugs targeting activation of GPR120 to treat obesity and diabetes.
years using a variety of screens or as a result of the complete sequencing of the human genome
that, subsequent to their characterization, were all shown to bind and be
activated by free fatty acids and/or lipid molecules. GPR120 was identified as a result of the human genome sequencing project and shown to be a member of the class A (rhodopsin-like) family of
GPCRs. GPR120 is specifically activated by long-chain non-esterified fatty acids (NEFAs) in particular in the intestines by alpha-linolenic acid (ALA) an omega-3 polyunsaturated fatty acid
(PUFA). Activation of GPR120 in the intestines results in increased glucagon-like peptide-1 (GLP-1) secretion from enteroendocrine L cells. GLP-1 is called an incretin because it induces insulin secretion from the pancreas in response to food intake (for more details on GLP-1 function visit the Gut-Brain Interactions page). GPR120 is highly expressed in adipose tissue, and proinflammatory
macrophages. The high expression level of GPR120 in mature
adipocytes and macrophages is indicative of the fact that GPR120 is likely
to play an important role in biologic functions of these cell types. In
contrast, negligible expression of GPR120 is seen in muscle,
pancreatic beta-cells (insulin secreting cells), and hepatocytes. Although not expressed at
appreciable levels in hepatocytes expression of GPR120 is highly inducible in
liver resident macrophage-like cells known as Kupffer cells. GPR120 can
be activated with a synthetic agonist (GW9508) as well as omega-3 PUFAs. For more detailed information on the mode of action of omega fat activation of, and signaling by, GPR120 visit the Omega-3 & Omega-6 Fatty Acid Synthesis, Metabolism, Functions page. Recent studies have found that some individuals harbor loss-of-function mutations in the gene encoding GPR120 are at increased risk for obesity and insulin resistance (a hallmark of type 2 diabetes). A clinically significant mutation results in the change of an arginine residue at amino acid position 270 to histidine (R270H) in the GPR120 protein. This mutation acts as a dominant-negative meaning that it interferes with the function of the GPR120 protein synthesized from the normal gene copy. Patients with this mutation are obese, more insulin resistant, and more glucose intolerant than obese persons without the R270H mutation. Given its important role in inflammation, obesity, and insulin sensitivity, one can expect that soon there will be drugs targeting activation of GPR120 to treat obesity and diabetes.
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