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Biologically active, high levels of interleukin-22 inhibit hepatic gluconeogenesis but do not affect obesity and its metabolic consequences.

Park O, Ki SH, Xu M, Wang H, Feng D, Tam J, Osei-Hyiaman D, Kunos G, Gao B - Cell Biosci (2015)

Bottom Line: These inhibitory effects were partially reversed by blocking STAT3 or the AMPK signaling pathway.Biologically active, high levels of IL-22 do not affect obesity and the associated metabolic syndrome.Acute treatment with IL-22 inhibits hepatic gluconeogenesis, which is mediated via the activation of STAT3 and AMPK in hepatocytes.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Liver Diseases, NIAAA/NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA.

ABSTRACT

Background: Interleukin-22 (IL-22), a cytokine with important functions in anti-microbial defense and tissue repair, has been recently suggested to have beneficial effects in obesity and metabolic syndrome in some but not in other studies. Here, we re-examined the effects of IL-22 on obesity, insulin resistance, and hepatic glucose metabolism.

Results: Genetic deletion of IL-22 did not affect high-fat-diet (HFD)-induced obesity and insulin resistance. IL-22 transgenic mice with relatively high levels of circulating IL-22 (~600 pg/ml) were completely resistant to Concanavalin A-induced liver injury but developed the same degree of high fat diet (HFD)-induced obesity, insulin resistance, and fatty liver as the wild-type littermate controls. Similarly, chronic treatment with recombinant mouse IL-22 (rmIL-22) protein did not affect HFD-induced obesity and the associated metabolic syndrome. In vivo treatment with a single dose of rmIL-22 downregulated the hepatic expression of gluconeogenic genes and subsequently inhibited hepatic gluconeogenesis and reduced blood glucose levels both in HFD-fed and streptozotocin (STZ)-treated mice without affecting insulin production. In vitro exposure of mouse primary hepatocytes to IL-22 suppressed glucose production and the expression of gluconeogenic genes. These inhibitory effects were partially reversed by blocking STAT3 or the AMPK signaling pathway.

Conclusion: Biologically active, high levels of IL-22 do not affect obesity and the associated metabolic syndrome. Acute treatment with IL-22 inhibits hepatic gluconeogenesis, which is mediated via the activation of STAT3 and AMPK in hepatocytes.

No MeSH data available.


Related in: MedlinePlus

IL-22 inhibits hepatic gluconeogenesis without affecting glucose uptake in vivo. a-c Mice were fed a HFD for 8 weeks and then injected with ad-vector or ad-IL-22 for 5 days. A glucose tracer assay in vivo was performed. Glucose turnover rates and plasma glucose levels are shown (panel a). A pyruvate tolerance test (PTT) was performed (panel b). Real-time PCR analyses of gluconeogenic genes (panel c). d-e C57BL/6 mice were fed a HFD for 8 weeks and then fasted for 4 h, followed by treatment with saline or rmIL-22 (1 μg/g) for 2 h. Real-time PCR analyses of gluconeogenic genes (panel d). Two-deoxyglucose uptake experiments in vivo were performed (panel e). Values represent the mean ± SEM (n=6-10). *P < 0.05, **P < 0.01, and ***P < 0.001 compared with the corresponding ad-IL-22-treated or rmIL-22-treated groups
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Fig6: IL-22 inhibits hepatic gluconeogenesis without affecting glucose uptake in vivo. a-c Mice were fed a HFD for 8 weeks and then injected with ad-vector or ad-IL-22 for 5 days. A glucose tracer assay in vivo was performed. Glucose turnover rates and plasma glucose levels are shown (panel a). A pyruvate tolerance test (PTT) was performed (panel b). Real-time PCR analyses of gluconeogenic genes (panel c). d-e C57BL/6 mice were fed a HFD for 8 weeks and then fasted for 4 h, followed by treatment with saline or rmIL-22 (1 μg/g) for 2 h. Real-time PCR analyses of gluconeogenic genes (panel d). Two-deoxyglucose uptake experiments in vivo were performed (panel e). Values represent the mean ± SEM (n=6-10). *P < 0.05, **P < 0.01, and ***P < 0.001 compared with the corresponding ad-IL-22-treated or rmIL-22-treated groups

Mentions: To explore the mechanisms by which IL-22 reduces blood glucose levels in HFD-fed mice, we performed an in vivo glucose turn-over assay and pyruvate tolerance test (PTT), an assay to determine hepatic gluconeogenesis in vivo. HFD-fed mice were injected with IL-22 adenovirus or control adenovirus prior to the glucose turn-over assay. Injection of Ad-IL-22 resulted in significant elevation of circulating IL-22 (~5000 pg/ml), and this elevation lasted for more than two weeks [10]. As illustrated in Fig. 6a, the glucose turn-over rate and blood glucose levels were markedly lower in ad-IL-22-treated mice compared with ad-vector-treated mice. Fig. 6b shows that blood glucose levels were significantly elevated after injection of pyruvate in ad-vector-treated mice; however, such elevation was not observed in ad-IL-22 injected mice, suggesting that injection of ad-IL-22 blocks hepatic gluconeogenesis. Indeed, expression of gluconeogenic genes, including G6Pase, PEPCK, and TORC2 (also known as CRTC2), was markedly reduced in ad-IL-22-treated mice compared with ad-vector-treated mice (Fig. 6c). In addition, administration of a single dose of rmIL-22 markedly suppressed hepatic expression of gluconeogenic genes (Fig. 6d).Fig. 6


Biologically active, high levels of interleukin-22 inhibit hepatic gluconeogenesis but do not affect obesity and its metabolic consequences.

Park O, Ki SH, Xu M, Wang H, Feng D, Tam J, Osei-Hyiaman D, Kunos G, Gao B - Cell Biosci (2015)

IL-22 inhibits hepatic gluconeogenesis without affecting glucose uptake in vivo. a-c Mice were fed a HFD for 8 weeks and then injected with ad-vector or ad-IL-22 for 5 days. A glucose tracer assay in vivo was performed. Glucose turnover rates and plasma glucose levels are shown (panel a). A pyruvate tolerance test (PTT) was performed (panel b). Real-time PCR analyses of gluconeogenic genes (panel c). d-e C57BL/6 mice were fed a HFD for 8 weeks and then fasted for 4 h, followed by treatment with saline or rmIL-22 (1 μg/g) for 2 h. Real-time PCR analyses of gluconeogenic genes (panel d). Two-deoxyglucose uptake experiments in vivo were performed (panel e). Values represent the mean ± SEM (n=6-10). *P < 0.05, **P < 0.01, and ***P < 0.001 compared with the corresponding ad-IL-22-treated or rmIL-22-treated groups
© Copyright Policy - open-access
Related In: Results  -  Collection

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Fig6: IL-22 inhibits hepatic gluconeogenesis without affecting glucose uptake in vivo. a-c Mice were fed a HFD for 8 weeks and then injected with ad-vector or ad-IL-22 for 5 days. A glucose tracer assay in vivo was performed. Glucose turnover rates and plasma glucose levels are shown (panel a). A pyruvate tolerance test (PTT) was performed (panel b). Real-time PCR analyses of gluconeogenic genes (panel c). d-e C57BL/6 mice were fed a HFD for 8 weeks and then fasted for 4 h, followed by treatment with saline or rmIL-22 (1 μg/g) for 2 h. Real-time PCR analyses of gluconeogenic genes (panel d). Two-deoxyglucose uptake experiments in vivo were performed (panel e). Values represent the mean ± SEM (n=6-10). *P < 0.05, **P < 0.01, and ***P < 0.001 compared with the corresponding ad-IL-22-treated or rmIL-22-treated groups
Mentions: To explore the mechanisms by which IL-22 reduces blood glucose levels in HFD-fed mice, we performed an in vivo glucose turn-over assay and pyruvate tolerance test (PTT), an assay to determine hepatic gluconeogenesis in vivo. HFD-fed mice were injected with IL-22 adenovirus or control adenovirus prior to the glucose turn-over assay. Injection of Ad-IL-22 resulted in significant elevation of circulating IL-22 (~5000 pg/ml), and this elevation lasted for more than two weeks [10]. As illustrated in Fig. 6a, the glucose turn-over rate and blood glucose levels were markedly lower in ad-IL-22-treated mice compared with ad-vector-treated mice. Fig. 6b shows that blood glucose levels were significantly elevated after injection of pyruvate in ad-vector-treated mice; however, such elevation was not observed in ad-IL-22 injected mice, suggesting that injection of ad-IL-22 blocks hepatic gluconeogenesis. Indeed, expression of gluconeogenic genes, including G6Pase, PEPCK, and TORC2 (also known as CRTC2), was markedly reduced in ad-IL-22-treated mice compared with ad-vector-treated mice (Fig. 6c). In addition, administration of a single dose of rmIL-22 markedly suppressed hepatic expression of gluconeogenic genes (Fig. 6d).Fig. 6

Bottom Line: These inhibitory effects were partially reversed by blocking STAT3 or the AMPK signaling pathway.Biologically active, high levels of IL-22 do not affect obesity and the associated metabolic syndrome.Acute treatment with IL-22 inhibits hepatic gluconeogenesis, which is mediated via the activation of STAT3 and AMPK in hepatocytes.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Liver Diseases, NIAAA/NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA.

ABSTRACT

Background: Interleukin-22 (IL-22), a cytokine with important functions in anti-microbial defense and tissue repair, has been recently suggested to have beneficial effects in obesity and metabolic syndrome in some but not in other studies. Here, we re-examined the effects of IL-22 on obesity, insulin resistance, and hepatic glucose metabolism.

Results: Genetic deletion of IL-22 did not affect high-fat-diet (HFD)-induced obesity and insulin resistance. IL-22 transgenic mice with relatively high levels of circulating IL-22 (~600 pg/ml) were completely resistant to Concanavalin A-induced liver injury but developed the same degree of high fat diet (HFD)-induced obesity, insulin resistance, and fatty liver as the wild-type littermate controls. Similarly, chronic treatment with recombinant mouse IL-22 (rmIL-22) protein did not affect HFD-induced obesity and the associated metabolic syndrome. In vivo treatment with a single dose of rmIL-22 downregulated the hepatic expression of gluconeogenic genes and subsequently inhibited hepatic gluconeogenesis and reduced blood glucose levels both in HFD-fed and streptozotocin (STZ)-treated mice without affecting insulin production. In vitro exposure of mouse primary hepatocytes to IL-22 suppressed glucose production and the expression of gluconeogenic genes. These inhibitory effects were partially reversed by blocking STAT3 or the AMPK signaling pathway.

Conclusion: Biologically active, high levels of IL-22 do not affect obesity and the associated metabolic syndrome. Acute treatment with IL-22 inhibits hepatic gluconeogenesis, which is mediated via the activation of STAT3 and AMPK in hepatocytes.

No MeSH data available.


Related in: MedlinePlus