Positive Reinforcing Mechanisms between GPR120 and PPARγ Modulate Insulin Sensitivity

Paschoal, Vivian A.; Walenta, Evelyn; Talukdar, Saswata; Pessentheiner, Ariane; Osborn, Olivia; Hah, Nasun; Tyler, Jessica K.; Tye, George; Armando, Aaron M.; Evans, Ronald M.; Wen, Nai; Quehenberger, Oswald; Olefsky, Jerrold M.; Oh, Da Young

doi:10.1016/j.cmet.2020.04.020

Cited by 49 publications

(46 citation statements)

References 77 publications

(120 reference statements)

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“…GPR40 has been shown to alleviate inflammation, promote insulin secretion, enhance pancreatic βcell survival, and regulate energy homeostasis (57)(58)(59). GPR120 enhances insulin sensitivity, regulates neutrophil activation, inhibits inflammatory macrophage infiltration, promotes the development of anti-inflammatory M2 macrophages, and enhances energy expenditure (60)(61)(62)(63). Interestingly, insulin exposure is associated with reduced histamine release, enhanced LTC 4 production, and increased resolvin D1 and E1 synthesis in RBL-2H3 cells (64).…”

Section: Discussionmentioning

confidence: 99%

Disrupted Lipid Raft Shuttling of FcεRI by n-3 Polyunsaturated Fatty Acid Is Associated With Ligation of G Protein-Coupled Receptor 120 (GPR120) in Human Mast Cell Line LAD2

et al. 2020

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n-3 polyunsaturated fatty acids (PUFA) influences a variety of disease conditions, such as hypertension, heart disease, diabetes, cancer and allergic diseases, by modulating membrane constitution, inhibiting production of proinflammatory eicosanoids and cytokines, and binding to cell surface and nuclear receptors. We have previously shown that n-3 PUFA inhibit mast cell functions by disrupting high affinity IgE receptor (FcεRI) lipid raft partitioning and subsequent suppression of FcεRI signaling in mouse bone marrow-derived mast cells. However, it is still largely unknown how n-3 PUFA modulate human mast cell function, which could be attributed to multiple mechanisms. Using a human mast cell line (LAD2), we have shown similar modulating effects of n-3 PUFA on FcεRI lipid raft shuttling, FcεRI signaling, and mediator release after cell activation through FcεRI. We have further shown that these effects are at least partially associated with ligation of G protein-coupled receptor 120 expressed on LAD2 cells. This observation has advanced our mechanistic knowledge of n-3 PUFA's effect on mast cells and demonstrated the interplay between n-3 PUFA, lipid rafts, FcεRI, and G protein-coupled receptor 120. Future research in this direction may present new targets for nutritional intervention and therapeutic agents.

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Section: Discussionmentioning

confidence: 99%

Disrupted Lipid Raft Shuttling of FcεRI by n-3 Polyunsaturated Fatty Acid Is Associated With Ligation of G Protein-Coupled Receptor 120 (GPR120) in Human Mast Cell Line LAD2

et al. 2020

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“…Whether there is a synergistic effect between hepatic AMPK activation by metformin and Gq receptor activation in the muscle (and other tissues, including liver) is a subject to be examined. Additionally, Paschoal et al showed that GPR120 and PPARγ agonists functionally interact and markedly improve insulin resistance by using adipocytes and macrophages [ 92 ]. Also, chronic cholesterol depletion by statins in HEK cells has been shown to switch the serotonin 1A receptor (5-HT1A) endocytosis pathway from clathrin-mediated endocytosis to caveolin-mediated endocytosis [ 93 ].…”

Section: Gpcr Signaling In Relation To Metformin Pparγ Agonist Amentioning

confidence: 99%

Metabolic Functions of G Protein-Coupled Receptors in Hepatocytes—Potential Applications for Diabetes and NAFLD

et al. 2020

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G protein-coupled receptors (GPCRs) are cell surface receptors that mediate the function of extracellular ligands. Understanding how GPCRs work at the molecular level has important therapeutic implications, as 30–40% of the drugs currently in clinical use mediate therapeutic effects by acting on GPCRs. Like many other cell types, liver function is regulated by GPCRs. More than 50 different GPCRs are predicted to be expressed in the mouse liver. However, knowledge of how GPCRs regulate liver metabolism is limited. A better understanding of the metabolic role of GPCRs in hepatocytes, the dominant constituent cells of the liver, could lead to the development of novel drugs that are clinically useful for the treatment of various metabolic diseases, including type 2 diabetes, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). In this review, we describe the functions of multiple GPCRs expressed in hepatocytes and their role in metabolic processes.

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“…In rodents, gpr120 is expressed in several tissues implicated in energy homeostasis including the central nervous system, enteroendocrine cells, liver, bone, adipose tissue and macrophages [2]. GPR120 activation in adipocytes and macrophages alleviates obesity-induced insulin resistance [3][4][5] in part via interaction with peroxisome proliferator-activated receptor γ [6]. GPR120 also promotes adipogenesis [7][8][9] and brown adipose tissue thermogenesis [10,11], regulates food intake [12] and modulates gut endocrine hormone secretion, including ghrelin [13][14][15] and the incretin hormones glucagon-like peptide-1 (GLP-1) [16], gastric inhibitory polypeptide (GIP) [17], cholecystokinin [18,19] and somatostatin [20].…”

Section: Introductionmentioning

confidence: 99%

Combined deletion of free fatty-acid receptors 1 and 4 minimally impacts glucose homeostasis in mice

Croze¹,

Guillaume²,

Ethier³

et al. 2020

Preprint

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The fatty-acid receptors FFAR1 (Gpr40) and FFAR4 (Gpr120) are implicated in the regulation of insulin secretion and insulin sensitivity, respectively. Although the properties of Gpr120 and Gpr40 converge on glucose homeostasis, few studies have addressed possible interactions between these two receptors in the control of β cell function. Here we generated mice deficient in Gpr120 or Gpr40, alone or in combination, and metabolically phenotyped male and female mice fed a normal chow or high-fat diet. We assessed insulin secretion in isolated mouse islets exposed to selective Gpr120 and Gpr40 agonists singly or in combination. Following normal chow feeding, body weight and energy intake were unaffected by deletion of either receptor, although fat mass increased in Gpr120 knockout (KO) females. Fasting blood glucose levels increased in Gpr120/40 double KO mice, and in a sex-dependent manner in Gpr120 KO and Gpr40 KO animals. Oral glucose tolerance was reduced in Gpr120/40 double KO male mice and in Gpr120 KO females, whereas insulin secretion and insulin sensitivity were unaffected. In hyperglycemic clamps, the glucose infusion rate and disposition index were lower in Gpr120/40 double KO. In contrast, we did not observe changes in glucose tolerance in either single or double KO animals under high-fat feeding. In isolated wild-type islets, the combination of selective Gpr120 and Gpr40 agonists additively increased insulin secretion compared to each agonist alone. We conclude that Gpr120 and Gpr40 cooperate in an additive manner to regulate glucose homeostasis and insulin secretion in male mice.

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Positive Reinforcing Mechanisms between GPR120 and PPARγ Modulate Insulin Sensitivity

Cited by 49 publications

References 77 publications

Disrupted Lipid Raft Shuttling of FcεRI by n-3 Polyunsaturated Fatty Acid Is Associated With Ligation of G Protein-Coupled Receptor 120 (GPR120) in Human Mast Cell Line LAD2

Disrupted Lipid Raft Shuttling of FcεRI by n-3 Polyunsaturated Fatty Acid Is Associated With Ligation of G Protein-Coupled Receptor 120 (GPR120) in Human Mast Cell Line LAD2

Metabolic Functions of G Protein-Coupled Receptors in Hepatocytes—Potential Applications for Diabetes and NAFLD

Combined deletion of free fatty-acid receptors 1 and 4 minimally impacts glucose homeostasis in mice

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