Limits...
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.

Show MeSH

Related in: MedlinePlus

Production of NO and glucose uptake in adipocytes(a) mRNA levels of iNos and Arginase in adipose tissue from WT and Gpr120 KO mice on HFD or HFD+cpdA. n=10 per group. (b) Nitric oxide level in adipose tissue of WT and Gpr120 KO mice on HFD or HFD+cpdA. n=8 per group. (c) HFD-induced nitrosylation of Akt in adipose tissue is reduced only in WT on HFD+cpdA. (d) Akt phosphorylation in adipose tissue from WT or Gpr120 KO mice on HFD or HFD+cpdA before and after insulin injection. Left panel is a representative image from three independent experiments, and the scanned bar graph (right panel) shows fold induction over basal. Data are expressed as the mean±SEM. *, p<0.05 versus insulin injection in WT mice on HFD. n=6 per group. (e) Glucose uptake in primary adipocytes from WT and Gpr120 KO mice and pretreated with DHA or cpdA for 30 min and subsequently incubated in the absence and presence of insulin, followed by measurement of 2–deoxyglucose (2–DOG) uptake. Data are expressed as the mean±SEM from three independent experiments. * indicates significance at P<0.05 over basal.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4126875&req=5

Figure 4: Production of NO and glucose uptake in adipocytes(a) mRNA levels of iNos and Arginase in adipose tissue from WT and Gpr120 KO mice on HFD or HFD+cpdA. n=10 per group. (b) Nitric oxide level in adipose tissue of WT and Gpr120 KO mice on HFD or HFD+cpdA. n=8 per group. (c) HFD-induced nitrosylation of Akt in adipose tissue is reduced only in WT on HFD+cpdA. (d) Akt phosphorylation in adipose tissue from WT or Gpr120 KO mice on HFD or HFD+cpdA before and after insulin injection. Left panel is a representative image from three independent experiments, and the scanned bar graph (right panel) shows fold induction over basal. Data are expressed as the mean±SEM. *, p<0.05 versus insulin injection in WT mice on HFD. n=6 per group. (e) Glucose uptake in primary adipocytes from WT and Gpr120 KO mice and pretreated with DHA or cpdA for 30 min and subsequently incubated in the absence and presence of insulin, followed by measurement of 2–deoxyglucose (2–DOG) uptake. Data are expressed as the mean±SEM from three independent experiments. * indicates significance at P<0.05 over basal.

Mentions: It is known that nitric oxide (NO) can attenuate insulin signaling through nitrosylation of insulin signaling molecules, including Akt 21. Tissue NO levels represent the balance between iNos and Arginase activity. iNos expression was induced in adipose tissue from both WT and Gpr120 KO mice by HFD, and this effect was reduced by cpdA treatment in WT but not Gpr120 KO mice. HFD also led to increased Arginase expression, and this increase was enhanced in WT, but not Gpr120 KO mice, with cpdA treatment. Thus, the iNos/Arginase ratio was markedly reduced in WT adipose tissue by HFD+cpdA compared to HFD (Fig. 4a). As would be predicted from these gene expression changes, levels of adipose tissue NO2, a stable breakdown product of NO, were reduced ~60% in HFD+cpdA treated WT mice (Fig. 4b). This decrease was almost completely abrogated in Gpr120 KO mice. Consistent with these changes in NO levels, nitrosylation of Akt, was increased on HFD in both WT and Gpr120 KO adipose tissue and this was reduced by HFD+cpdA treatment only in WT adipose tissue (Fig. 4c). Concomitant with this, insulin-stimulated Akt phosphorylation was greater in adipose tissue from HFD+cpdA treated WT mice compared to HFD (Fig. 4d).


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)

Production of NO and glucose uptake in adipocytes(a) mRNA levels of iNos and Arginase in adipose tissue from WT and Gpr120 KO mice on HFD or HFD+cpdA. n=10 per group. (b) Nitric oxide level in adipose tissue of WT and Gpr120 KO mice on HFD or HFD+cpdA. n=8 per group. (c) HFD-induced nitrosylation of Akt in adipose tissue is reduced only in WT on HFD+cpdA. (d) Akt phosphorylation in adipose tissue from WT or Gpr120 KO mice on HFD or HFD+cpdA before and after insulin injection. Left panel is a representative image from three independent experiments, and the scanned bar graph (right panel) shows fold induction over basal. Data are expressed as the mean±SEM. *, p<0.05 versus insulin injection in WT mice on HFD. n=6 per group. (e) Glucose uptake in primary adipocytes from WT and Gpr120 KO mice and pretreated with DHA or cpdA for 30 min and subsequently incubated in the absence and presence of insulin, followed by measurement of 2–deoxyglucose (2–DOG) uptake. Data are expressed as the mean±SEM from three independent experiments. * indicates significance at P<0.05 over basal.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126875&req=5

Figure 4: Production of NO and glucose uptake in adipocytes(a) mRNA levels of iNos and Arginase in adipose tissue from WT and Gpr120 KO mice on HFD or HFD+cpdA. n=10 per group. (b) Nitric oxide level in adipose tissue of WT and Gpr120 KO mice on HFD or HFD+cpdA. n=8 per group. (c) HFD-induced nitrosylation of Akt in adipose tissue is reduced only in WT on HFD+cpdA. (d) Akt phosphorylation in adipose tissue from WT or Gpr120 KO mice on HFD or HFD+cpdA before and after insulin injection. Left panel is a representative image from three independent experiments, and the scanned bar graph (right panel) shows fold induction over basal. Data are expressed as the mean±SEM. *, p<0.05 versus insulin injection in WT mice on HFD. n=6 per group. (e) Glucose uptake in primary adipocytes from WT and Gpr120 KO mice and pretreated with DHA or cpdA for 30 min and subsequently incubated in the absence and presence of insulin, followed by measurement of 2–deoxyglucose (2–DOG) uptake. Data are expressed as the mean±SEM from three independent experiments. * indicates significance at P<0.05 over basal.
Mentions: It is known that nitric oxide (NO) can attenuate insulin signaling through nitrosylation of insulin signaling molecules, including Akt 21. Tissue NO levels represent the balance between iNos and Arginase activity. iNos expression was induced in adipose tissue from both WT and Gpr120 KO mice by HFD, and this effect was reduced by cpdA treatment in WT but not Gpr120 KO mice. HFD also led to increased Arginase expression, and this increase was enhanced in WT, but not Gpr120 KO mice, with cpdA treatment. Thus, the iNos/Arginase ratio was markedly reduced in WT adipose tissue by HFD+cpdA compared to HFD (Fig. 4a). As would be predicted from these gene expression changes, levels of adipose tissue NO2, a stable breakdown product of NO, were reduced ~60% in HFD+cpdA treated WT mice (Fig. 4b). This decrease was almost completely abrogated in Gpr120 KO mice. Consistent with these changes in NO levels, nitrosylation of Akt, was increased on HFD in both WT and Gpr120 KO adipose tissue and this was reduced by HFD+cpdA treatment only in WT adipose tissue (Fig. 4c). Concomitant with this, insulin-stimulated Akt phosphorylation was greater in adipose tissue from HFD+cpdA treated WT mice compared to HFD (Fig. 4d).

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