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A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice.

Oh da Y, Walenta E, Akiyama TE, Lagakos WS, Lackey D, Pessentheiner AR, Sasik R, Hah N, Chi TJ, Cox JM, Powels MA, Di Salvo J, Sinz C, Watkins SM, Armando AM, Chung H, Evans RM, Quehenberger O, McNelis J, Bogner-Strauss JG, Olefsky JM - Nat. Med. (2014)

Bottom Line: It is well known that the ω-3 fatty acids (ω-3-FAs; also known as n-3 fatty acids) can exert potent anti-inflammatory effects.We reported that Gpr120 is the functional receptor for these fatty acids and that ω-3-FAs produce robust anti-inflammatory, insulin-sensitizing effects, both in vivo and in vitro, in a Gpr120-dependent manner.However, the amount of fish oils that would have to be consumed to sustain chronic agonism of Gpr120 is too high to be practical, and, thus, a high-affinity small-molecule Gpr120 agonist would be of potential clinical benefit.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA.

ABSTRACT
It is well known that the ω-3 fatty acids (ω-3-FAs; also known as n-3 fatty acids) can exert potent anti-inflammatory effects. Commonly consumed as fish products, dietary supplements and pharmaceuticals, ω-3-FAs have a number of health benefits ascribed to them, including reduced plasma triglyceride levels, amelioration of atherosclerosis and increased insulin sensitivity. We reported that Gpr120 is the functional receptor for these fatty acids and that ω-3-FAs produce robust anti-inflammatory, insulin-sensitizing effects, both in vivo and in vitro, in a Gpr120-dependent manner. Indeed, genetic variants that predispose to obesity and diabetes have been described in the gene encoding GPR120 in humans (FFAR4). However, the amount of fish oils that would have to be consumed to sustain chronic agonism of Gpr120 is too high to be practical, and, thus, a high-affinity small-molecule Gpr120 agonist would be of potential clinical benefit. Accordingly, Gpr120 is a widely studied drug discovery target within the pharmaceutical industry. Gpr40 is another lipid-sensing G protein-coupled receptor, and it has been difficult to identify compounds with a high degree of selectivity for Gpr120 over Gpr40 (ref. 11). Here we report that a selective high-affinity, orally available, small-molecule Gpr120 agonist (cpdA) exerts potent anti-inflammatory effects on macrophages in vitro and in obese mice in vivo. Gpr120 agonist treatment of high-fat diet-fed obese mice causes improved glucose tolerance, decreased hyperinsulinemia, increased insulin sensitivity and decreased hepatic steatosis. This suggests that Gpr120 agonists could become new insulin-sensitizing drugs for the treatment of type 2 diabetes and other human insulin-resistant states in the future.

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Gpr120 agonist and in vivo metabolic studies(a) GTT in WT and Gpr120 KO mice on HFD or HFD+cpdA. n=10 per group. (b) ITT in WT and Gpr120 KO mice on HFD or HFD+cpdA. n=10 per group. (c) Plasma insulin level during GTT at the indicated time points. (d) Hyperinsulinemic/euglycemic clamp studies in WT and Gpr120 KO mice on HFD or HFD+cpdA. Glucose infusion rate (GIR), total glucose disposal rate (GDR), insulin–stimulated glucose disposal rate (IS-GDR), percent suppression of hepatic glucose production. *, p<0.05, compared to HFD. Data are represented as mean±SEM. (e) Acute insulin response showing phosphorylation of Akt in skeletal muscle and liver from WT and Gpr120 KO mice on HFD or HFD+cpdA using 0.35 U kg–1 insulin injected via inferior vena cava. Left panel is a representative image from five independent experiments, and the scanned bar graph (right panel) shows fold induction over basal (before insulin injection) conditions. Data are expressed as the mean±SEM. *, P<0.05 versus insulin injection in WT mice on HFD. n=6 per group.
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Figure 2: Gpr120 agonist and in vivo metabolic studies(a) GTT in WT and Gpr120 KO mice on HFD or HFD+cpdA. n=10 per group. (b) ITT in WT and Gpr120 KO mice on HFD or HFD+cpdA. n=10 per group. (c) Plasma insulin level during GTT at the indicated time points. (d) Hyperinsulinemic/euglycemic clamp studies in WT and Gpr120 KO mice on HFD or HFD+cpdA. Glucose infusion rate (GIR), total glucose disposal rate (GDR), insulin–stimulated glucose disposal rate (IS-GDR), percent suppression of hepatic glucose production. *, p<0.05, compared to HFD. Data are represented as mean±SEM. (e) Acute insulin response showing phosphorylation of Akt in skeletal muscle and liver from WT and Gpr120 KO mice on HFD or HFD+cpdA using 0.35 U kg–1 insulin injected via inferior vena cava. Left panel is a representative image from five independent experiments, and the scanned bar graph (right panel) shows fold induction over basal (before insulin injection) conditions. Data are expressed as the mean±SEM. *, P<0.05 versus insulin injection in WT mice on HFD. n=6 per group.

Mentions: Next, we determined whether the synthetic Gpr120 agonist could produce beneficial metabolic effects in vivo. WT and Gpr120 KO mice were placed on 60% HFD for 15 weeks. At this point, separate groups of 10 mice each were treated for an additional 5 weeks with 60% HFD alone, or HFD containing 30 mg kg−1 cpdA. The 5 weeks treatment time point was most effective at improving glucose tolerance and lowering insulin concentration (Supplemental Fig. 2). Figure 2 shows that treatment with cpdA led to markedly improved glucose tolerance (Fig. 2a), insulin tolerance (Fig. 2b), and decreased insulin secretion compared to HFD (Fig. 2c) in WT, but not in Gpr120 KO mice, with no change in body weight (Supplemental Fig. 3). These metabolic effects of cpdA treatment were comparable to dietary ω3-FAs supplementation (Supplemental Fig. 4). Importantly, during hyperinsulinemic, euglycemic clamp studies, we found that the cpdA diet caused improved insulin sensitivity with increased glucose infusion rates (GIR), enhanced insulin stimulated-glucose disposal rate (IS-GDR), along with a marked increase in the ability of insulin to suppress hepatic glucose production (HGP) only in WT mice (Fig. 2d). This demonstrates the in vivo effects of the Gpr120 agonist to produce systemic insulin sensitivity by enhancing muscle and liver insulin action. In addition to improving hepatic insulin sensitivity, cpdA treatment had beneficial effects on hepatic lipid metabolism, causing decreased hepatic steatosis, decreased liver triglycerides, and DAGs, along with reduced saturated free fatty acid content (Supplemental Fig. 5). In contrast, cpdA administration was without effect to reduce hepatic lipid levels in the Gpr120 KO mice.


A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice.

Oh da Y, Walenta E, Akiyama TE, Lagakos WS, Lackey D, Pessentheiner AR, Sasik R, Hah N, Chi TJ, Cox JM, Powels MA, Di Salvo J, Sinz C, Watkins SM, Armando AM, Chung H, Evans RM, Quehenberger O, McNelis J, Bogner-Strauss JG, Olefsky JM - Nat. Med. (2014)

Gpr120 agonist and in vivo metabolic studies(a) GTT in WT and Gpr120 KO mice on HFD or HFD+cpdA. n=10 per group. (b) ITT in WT and Gpr120 KO mice on HFD or HFD+cpdA. n=10 per group. (c) Plasma insulin level during GTT at the indicated time points. (d) Hyperinsulinemic/euglycemic clamp studies in WT and Gpr120 KO mice on HFD or HFD+cpdA. Glucose infusion rate (GIR), total glucose disposal rate (GDR), insulin–stimulated glucose disposal rate (IS-GDR), percent suppression of hepatic glucose production. *, p<0.05, compared to HFD. Data are represented as mean±SEM. (e) Acute insulin response showing phosphorylation of Akt in skeletal muscle and liver from WT and Gpr120 KO mice on HFD or HFD+cpdA using 0.35 U kg–1 insulin injected via inferior vena cava. Left panel is a representative image from five independent experiments, and the scanned bar graph (right panel) shows fold induction over basal (before insulin injection) conditions. Data are expressed as the mean±SEM. *, P<0.05 versus insulin injection in WT mice on HFD. n=6 per group.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4126875&req=5

Figure 2: Gpr120 agonist and in vivo metabolic studies(a) GTT in WT and Gpr120 KO mice on HFD or HFD+cpdA. n=10 per group. (b) ITT in WT and Gpr120 KO mice on HFD or HFD+cpdA. n=10 per group. (c) Plasma insulin level during GTT at the indicated time points. (d) Hyperinsulinemic/euglycemic clamp studies in WT and Gpr120 KO mice on HFD or HFD+cpdA. Glucose infusion rate (GIR), total glucose disposal rate (GDR), insulin–stimulated glucose disposal rate (IS-GDR), percent suppression of hepatic glucose production. *, p<0.05, compared to HFD. Data are represented as mean±SEM. (e) Acute insulin response showing phosphorylation of Akt in skeletal muscle and liver from WT and Gpr120 KO mice on HFD or HFD+cpdA using 0.35 U kg–1 insulin injected via inferior vena cava. Left panel is a representative image from five independent experiments, and the scanned bar graph (right panel) shows fold induction over basal (before insulin injection) conditions. Data are expressed as the mean±SEM. *, P<0.05 versus insulin injection in WT mice on HFD. n=6 per group.
Mentions: Next, we determined whether the synthetic Gpr120 agonist could produce beneficial metabolic effects in vivo. WT and Gpr120 KO mice were placed on 60% HFD for 15 weeks. At this point, separate groups of 10 mice each were treated for an additional 5 weeks with 60% HFD alone, or HFD containing 30 mg kg−1 cpdA. The 5 weeks treatment time point was most effective at improving glucose tolerance and lowering insulin concentration (Supplemental Fig. 2). Figure 2 shows that treatment with cpdA led to markedly improved glucose tolerance (Fig. 2a), insulin tolerance (Fig. 2b), and decreased insulin secretion compared to HFD (Fig. 2c) in WT, but not in Gpr120 KO mice, with no change in body weight (Supplemental Fig. 3). These metabolic effects of cpdA treatment were comparable to dietary ω3-FAs supplementation (Supplemental Fig. 4). Importantly, during hyperinsulinemic, euglycemic clamp studies, we found that the cpdA diet caused improved insulin sensitivity with increased glucose infusion rates (GIR), enhanced insulin stimulated-glucose disposal rate (IS-GDR), along with a marked increase in the ability of insulin to suppress hepatic glucose production (HGP) only in WT mice (Fig. 2d). This demonstrates the in vivo effects of the Gpr120 agonist to produce systemic insulin sensitivity by enhancing muscle and liver insulin action. In addition to improving hepatic insulin sensitivity, cpdA treatment had beneficial effects on hepatic lipid metabolism, causing decreased hepatic steatosis, decreased liver triglycerides, and DAGs, along with reduced saturated free fatty acid content (Supplemental Fig. 5). In contrast, cpdA administration was without effect to reduce hepatic lipid levels in the Gpr120 KO mice.

Bottom Line: It is well known that the ω-3 fatty acids (ω-3-FAs; also known as n-3 fatty acids) can exert potent anti-inflammatory effects.We reported that Gpr120 is the functional receptor for these fatty acids and that ω-3-FAs produce robust anti-inflammatory, insulin-sensitizing effects, both in vivo and in vitro, in a Gpr120-dependent manner.However, the amount of fish oils that would have to be consumed to sustain chronic agonism of Gpr120 is too high to be practical, and, thus, a high-affinity small-molecule Gpr120 agonist would be of potential clinical benefit.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA.

ABSTRACT
It is well known that the ω-3 fatty acids (ω-3-FAs; also known as n-3 fatty acids) can exert potent anti-inflammatory effects. Commonly consumed as fish products, dietary supplements and pharmaceuticals, ω-3-FAs have a number of health benefits ascribed to them, including reduced plasma triglyceride levels, amelioration of atherosclerosis and increased insulin sensitivity. We reported that Gpr120 is the functional receptor for these fatty acids and that ω-3-FAs produce robust anti-inflammatory, insulin-sensitizing effects, both in vivo and in vitro, in a Gpr120-dependent manner. Indeed, genetic variants that predispose to obesity and diabetes have been described in the gene encoding GPR120 in humans (FFAR4). However, the amount of fish oils that would have to be consumed to sustain chronic agonism of Gpr120 is too high to be practical, and, thus, a high-affinity small-molecule Gpr120 agonist would be of potential clinical benefit. Accordingly, Gpr120 is a widely studied drug discovery target within the pharmaceutical industry. Gpr40 is another lipid-sensing G protein-coupled receptor, and it has been difficult to identify compounds with a high degree of selectivity for Gpr120 over Gpr40 (ref. 11). Here we report that a selective high-affinity, orally available, small-molecule Gpr120 agonist (cpdA) exerts potent anti-inflammatory effects on macrophages in vitro and in obese mice in vivo. Gpr120 agonist treatment of high-fat diet-fed obese mice causes improved glucose tolerance, decreased hyperinsulinemia, increased insulin sensitivity and decreased hepatic steatosis. This suggests that Gpr120 agonists could become new insulin-sensitizing drugs for the treatment of type 2 diabetes and other human insulin-resistant states in the future.

Show MeSH
Related in: MedlinePlus