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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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Anti-inflammatory effects of Gpr120 agonism(a) Effect of Gpr120 agonist on 3T3-L1 adipocyte CM-induced chemotaxis of primary macrophage from WT and Gpr120 KO mice. (b)In vivo tracking of PKH26 positive monocytes in WT and Gpr120 KO mice on HFD or HFD+ω3-FA (W3) or HFD+cpdA. n=6 per group. (c) ATM content by F4/80 staining in adipose tissue sections from WT and Gpr120 KO mice on HFD or HFD+cpdA. Scale bar indicates 250 μm. (d) FACS analysis of ATMs from WT and Gpr120 KO mice on HFD or HFD+cpdA. n=6 per group. (e) Relative mRNA level of inflammatory cytokines (upper row) and anti-inflammatory cytokines (lower row) in adipose tissue from WT and Gpr120 KO mice from HFD or HFD+cpdA. n= 10 per group. (f) Serum Il–6, Mcp–1, Kc, and Pai–1 levels from WT and Gpr120 KO mice on HFD or HFD+cpdA. n= 10 per group. Data are expressed as the mean±SEM. *, P<0.05 versus WT mice on HFD.
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Figure 3: Anti-inflammatory effects of Gpr120 agonism(a) Effect of Gpr120 agonist on 3T3-L1 adipocyte CM-induced chemotaxis of primary macrophage from WT and Gpr120 KO mice. (b)In vivo tracking of PKH26 positive monocytes in WT and Gpr120 KO mice on HFD or HFD+ω3-FA (W3) or HFD+cpdA. n=6 per group. (c) ATM content by F4/80 staining in adipose tissue sections from WT and Gpr120 KO mice on HFD or HFD+cpdA. Scale bar indicates 250 μm. (d) FACS analysis of ATMs from WT and Gpr120 KO mice on HFD or HFD+cpdA. n=6 per group. (e) Relative mRNA level of inflammatory cytokines (upper row) and anti-inflammatory cytokines (lower row) in adipose tissue from WT and Gpr120 KO mice from HFD or HFD+cpdA. n= 10 per group. (f) Serum Il–6, Mcp–1, Kc, and Pai–1 levels from WT and Gpr120 KO mice on HFD or HFD+cpdA. n= 10 per group. Data are expressed as the mean±SEM. *, P<0.05 versus WT mice on HFD.

Mentions: Gpr120 stimulation by ω3-FAs decreases adipose tissue macrophage (ATM) infiltration and reduces inflammatory gene expression 8. Consistent with this, we observed that cpdA treatment blocked chemotaxis of WT macrophage induced by adipocyte condition medium (CM) as effectively as DHA, but both were without effect in Gpr120 KO macrophages (Fig. 3a). To determine if these in vitro chemotaxis results translated to the in vivo situation, we directly measured macrophage migration into adipose tissue using an in vivo macrophage tracking technique. With this approach, circulating monocytes were obtained from WT donor mice and labeled with fluorescent PKH26 dye ex vivo. The labeled monocytes were then injected into recipient HFD WT and Gpr120 KO mice with or without dietary ω3-FAs supplementation or HFD+cpdA treatment. As seen in Figure 3b, there was a substantial decrease in labeled ATM appearance in both ω3-FA and cpdA treated WT mice, with no effect in Gpr120 KO mice. These data were even more revealing when we examined the subpopulations of labeled macrophages between the groups. Thus, ATMs expressing Cd11c are M1-like and proinflammatory (ATM1) compared to M2-like Cd11c negative ATMs (ATM2), which are non-inflammatory. With this analysis, there is an even greater decrease in the number of recruited Cd11c positive ATMs. At the same time, there is an increase in the Cd11c negative ATM population in the cpdA treated WT mice, with no effect in Gpr120 KO mice (Fig. 3b). This shows that cpdA led to reduced monocyte migration with less M1-like Cd11c positive ATMs, and that the labeled monocytes that do become ATMs, favor the M2-like Cd11c negative state. Along with in vivo migration results, we also found reduced ATM content by immunohistochemistry (F4/80 staining) in adipose tissue sections from HFD+cpdA treated compared to HFD mice (Fig. 3c). This was accompanied by decreased Cd11c positive ATMs, and increased Cd11c negative ATMs (Fig. 3d and Supplemental Fig. 7a) by FACS analysis. As before, all of these effects were observed in WT, but not in 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)

Anti-inflammatory effects of Gpr120 agonism(a) Effect of Gpr120 agonist on 3T3-L1 adipocyte CM-induced chemotaxis of primary macrophage from WT and Gpr120 KO mice. (b)In vivo tracking of PKH26 positive monocytes in WT and Gpr120 KO mice on HFD or HFD+ω3-FA (W3) or HFD+cpdA. n=6 per group. (c) ATM content by F4/80 staining in adipose tissue sections from WT and Gpr120 KO mice on HFD or HFD+cpdA. Scale bar indicates 250 μm. (d) FACS analysis of ATMs from WT and Gpr120 KO mice on HFD or HFD+cpdA. n=6 per group. (e) Relative mRNA level of inflammatory cytokines (upper row) and anti-inflammatory cytokines (lower row) in adipose tissue from WT and Gpr120 KO mice from HFD or HFD+cpdA. n= 10 per group. (f) Serum Il–6, Mcp–1, Kc, and Pai–1 levels from WT and Gpr120 KO mice on HFD or HFD+cpdA. n= 10 per group. Data are expressed as the mean±SEM. *, P<0.05 versus WT mice on HFD.
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Figure 3: Anti-inflammatory effects of Gpr120 agonism(a) Effect of Gpr120 agonist on 3T3-L1 adipocyte CM-induced chemotaxis of primary macrophage from WT and Gpr120 KO mice. (b)In vivo tracking of PKH26 positive monocytes in WT and Gpr120 KO mice on HFD or HFD+ω3-FA (W3) or HFD+cpdA. n=6 per group. (c) ATM content by F4/80 staining in adipose tissue sections from WT and Gpr120 KO mice on HFD or HFD+cpdA. Scale bar indicates 250 μm. (d) FACS analysis of ATMs from WT and Gpr120 KO mice on HFD or HFD+cpdA. n=6 per group. (e) Relative mRNA level of inflammatory cytokines (upper row) and anti-inflammatory cytokines (lower row) in adipose tissue from WT and Gpr120 KO mice from HFD or HFD+cpdA. n= 10 per group. (f) Serum Il–6, Mcp–1, Kc, and Pai–1 levels from WT and Gpr120 KO mice on HFD or HFD+cpdA. n= 10 per group. Data are expressed as the mean±SEM. *, P<0.05 versus WT mice on HFD.
Mentions: Gpr120 stimulation by ω3-FAs decreases adipose tissue macrophage (ATM) infiltration and reduces inflammatory gene expression 8. Consistent with this, we observed that cpdA treatment blocked chemotaxis of WT macrophage induced by adipocyte condition medium (CM) as effectively as DHA, but both were without effect in Gpr120 KO macrophages (Fig. 3a). To determine if these in vitro chemotaxis results translated to the in vivo situation, we directly measured macrophage migration into adipose tissue using an in vivo macrophage tracking technique. With this approach, circulating monocytes were obtained from WT donor mice and labeled with fluorescent PKH26 dye ex vivo. The labeled monocytes were then injected into recipient HFD WT and Gpr120 KO mice with or without dietary ω3-FAs supplementation or HFD+cpdA treatment. As seen in Figure 3b, there was a substantial decrease in labeled ATM appearance in both ω3-FA and cpdA treated WT mice, with no effect in Gpr120 KO mice. These data were even more revealing when we examined the subpopulations of labeled macrophages between the groups. Thus, ATMs expressing Cd11c are M1-like and proinflammatory (ATM1) compared to M2-like Cd11c negative ATMs (ATM2), which are non-inflammatory. With this analysis, there is an even greater decrease in the number of recruited Cd11c positive ATMs. At the same time, there is an increase in the Cd11c negative ATM population in the cpdA treated WT mice, with no effect in Gpr120 KO mice (Fig. 3b). This shows that cpdA led to reduced monocyte migration with less M1-like Cd11c positive ATMs, and that the labeled monocytes that do become ATMs, favor the M2-like Cd11c negative state. Along with in vivo migration results, we also found reduced ATM content by immunohistochemistry (F4/80 staining) in adipose tissue sections from HFD+cpdA treated compared to HFD mice (Fig. 3c). This was accompanied by decreased Cd11c positive ATMs, and increased Cd11c negative ATMs (Fig. 3d and Supplemental Fig. 7a) by FACS analysis. As before, all of these effects were observed in WT, but not in 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