1858-P: P38 MAPK Inhibition Protects against FFA-Induced Insulin Resistance and Hepatic Fat Accumulation
The liver plays a central role in metabolism. Yet, it is unclear how hepatic metabolic dysregulation promotes insulin resistance and hepatic steatosis. Some studies have investigated the role of hepatic p38, a stress mitogen-activated protein kinase (MAPK), in hepatic fat accumulation and insulin re...
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| Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2020-06, Vol.69 (Supplement_1) |
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| creator | JOSEPH, DEBORAH Y. RIVERS, SYDNEY L. GIACCA, ADRIA |
| description | The liver plays a central role in metabolism. Yet, it is unclear how hepatic metabolic dysregulation promotes insulin resistance and hepatic steatosis. Some studies have investigated the role of hepatic p38, a stress mitogen-activated protein kinase (MAPK), in hepatic fat accumulation and insulin resistance in models of obesity. However, the role of p38 in free fatty acid (FFA) induced hepatic fat accumulation and insulin resistance has not been previously investigated. Moreover, the role that p38 MAPK plays in hepatic glucose and lipid metabolism is still controversial. Here, using both genetic and pharmacological models, we investigated whether the inhibition of p38 MAPK reverses FFA-induced hepatic fat accumulation and insulin resistance. Cannulated Wistar rats were intravenously infused with one of four treatments for 48 hours: Saline (SAL), Intralipid+Heparin (IH), IH+p38 MAPK inhibitor - SB239063 (IH+SB) and SB239063 (SB) alone. After 48hr infusion, the liver was collected and stained with Oil Red O to determine hepatic fat accumulation. IH rats had significantly greater hepatic fat accumulation compared to SAL rats (p |
| doi_str_mv | 10.2337/db20-1858-P |
| format | Article |
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In conclusion, our data indicates that both the pharmacological and genetic inhibition of p38 has a protective effect on FFA-induced hepatic fat accumulation and insulin resistance.</description><identifier>ISSN: 0012-1797</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/db20-1858-P</identifier><language>eng</language><publisher>New York: American Diabetes Association</publisher><subject>Animal models ; Anticoagulants ; Diabetes ; Ethanol ; Fatty liver ; Glucose metabolism ; Heparin ; High fat diet ; Insulin ; Insulin resistance ; Kinases ; Lipid metabolism ; Liver ; MAP kinase ; Metabolism ; Obesity ; Palmitic acid ; Protein kinase ; Rodents ; Steatosis</subject><ispartof>Diabetes (New York, N.Y.), 2020-06, Vol.69 (Supplement_1)</ispartof><rights>Copyright American Diabetes Association Jun 1, 2020</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c1069-7061b4fcfb313e0575a6aed7e4af48470f7e3c19edd2e50289b9877a765e40b93</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,27905,27906</link.rule.ids></links><search><creatorcontrib>JOSEPH, DEBORAH Y.</creatorcontrib><creatorcontrib>RIVERS, SYDNEY L.</creatorcontrib><creatorcontrib>GIACCA, ADRIA</creatorcontrib><title>1858-P: P38 MAPK Inhibition Protects against FFA-Induced Insulin Resistance and Hepatic Fat Accumulation</title><title>Diabetes (New York, N.Y.)</title><description>The liver plays a central role in metabolism. Yet, it is unclear how hepatic metabolic dysregulation promotes insulin resistance and hepatic steatosis. Some studies have investigated the role of hepatic p38, a stress mitogen-activated protein kinase (MAPK), in hepatic fat accumulation and insulin resistance in models of obesity. However, the role of p38 in free fatty acid (FFA) induced hepatic fat accumulation and insulin resistance has not been previously investigated. Moreover, the role that p38 MAPK plays in hepatic glucose and lipid metabolism is still controversial. Here, using both genetic and pharmacological models, we investigated whether the inhibition of p38 MAPK reverses FFA-induced hepatic fat accumulation and insulin resistance. Cannulated Wistar rats were intravenously infused with one of four treatments for 48 hours: Saline (SAL), Intralipid+Heparin (IH), IH+p38 MAPK inhibitor - SB239063 (IH+SB) and SB239063 (SB) alone. After 48hr infusion, the liver was collected and stained with Oil Red O to determine hepatic fat accumulation. IH rats had significantly greater hepatic fat accumulation compared to SAL rats (p<0.05). IH+SB rats were protected from FFA-induced hepatic fat accumulation. To assess the role of p38 on FFA-induced insulin resistance, liver-specific p38 knockout mice and wild type mice were infused with ethyl-oleate and ethyl palmitate (EtOP) or ethanol (control) for 48 hrs. After 46 hours of the infusion, the mice underwent a hyperinsulinemic-euglycemic clamp to determine insulin sensitivity. Results thus far suggest that genetic inhibition of p38 MAPK in the liver protects from FFA-induced insulin resistance in the periphery (p=0.06), consistent with tissue cross-talk also observed by our lab in liver-specific p38 knockout mice using a high fat diet model.
In conclusion, our data indicates that both the pharmacological and genetic inhibition of p38 has a protective effect on FFA-induced hepatic fat accumulation and insulin resistance.</description><subject>Animal models</subject><subject>Anticoagulants</subject><subject>Diabetes</subject><subject>Ethanol</subject><subject>Fatty liver</subject><subject>Glucose metabolism</subject><subject>Heparin</subject><subject>High fat diet</subject><subject>Insulin</subject><subject>Insulin resistance</subject><subject>Kinases</subject><subject>Lipid metabolism</subject><subject>Liver</subject><subject>MAP kinase</subject><subject>Metabolism</subject><subject>Obesity</subject><subject>Palmitic acid</subject><subject>Protein kinase</subject><subject>Rodents</subject><subject>Steatosis</subject><issn>0012-1797</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNotkE9LwzAchoMoOKcnv0DAo0Tzr03jrYh1w4lFFLyFNP3VZWzpbNKD396VyXt4Lw_vCw9C14zecSHUfdtwSliRFaQ-QTOmhSaCq69TNKOUccKUVufoIsYNpTQ_ZIbWR_oB16LAr2X9gpdh7RuffB9wPfQJXIrYflsfYsJVVZJlaEcH7YGL49YH_A7Rx2SDA2xDixewt8k7XNmES-fG3bi109glOuvsNsLVf8_RZ_X08bggq7fn5WO5Io7RXBNFc9bIznWNYAJopjKbW2gVSNvJQiraKRCOaWhbDhnlhW50oZRVeQaSNlrM0c1xdz_0PyPEZDb9OITDpeGSaZkJLSfq9ki5oY9xgM7sB7-zw69h1EwqzaTSTHJMLf4AY-xkgA</recordid><startdate>20200601</startdate><enddate>20200601</enddate><creator>JOSEPH, DEBORAH Y.</creator><creator>RIVERS, SYDNEY L.</creator><creator>GIACCA, ADRIA</creator><general>American Diabetes Association</general><scope>AAYXX</scope><scope>CITATION</scope><scope>K9.</scope><scope>NAPCQ</scope></search><sort><creationdate>20200601</creationdate><title>1858-P: P38 MAPK Inhibition Protects against FFA-Induced Insulin Resistance and Hepatic Fat Accumulation</title><author>JOSEPH, DEBORAH Y. ; RIVERS, SYDNEY L. ; GIACCA, ADRIA</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c1069-7061b4fcfb313e0575a6aed7e4af48470f7e3c19edd2e50289b9877a765e40b93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animal models</topic><topic>Anticoagulants</topic><topic>Diabetes</topic><topic>Ethanol</topic><topic>Fatty liver</topic><topic>Glucose metabolism</topic><topic>Heparin</topic><topic>High fat diet</topic><topic>Insulin</topic><topic>Insulin resistance</topic><topic>Kinases</topic><topic>Lipid metabolism</topic><topic>Liver</topic><topic>MAP kinase</topic><topic>Metabolism</topic><topic>Obesity</topic><topic>Palmitic acid</topic><topic>Protein kinase</topic><topic>Rodents</topic><topic>Steatosis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>JOSEPH, DEBORAH Y.</creatorcontrib><creatorcontrib>RIVERS, SYDNEY L.</creatorcontrib><creatorcontrib>GIACCA, ADRIA</creatorcontrib><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><jtitle>Diabetes (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>JOSEPH, DEBORAH Y.</au><au>RIVERS, SYDNEY L.</au><au>GIACCA, ADRIA</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>1858-P: P38 MAPK Inhibition Protects against FFA-Induced Insulin Resistance and Hepatic Fat Accumulation</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><date>2020-06-01</date><risdate>2020</risdate><volume>69</volume><issue>Supplement_1</issue><issn>0012-1797</issn><eissn>1939-327X</eissn><abstract>The liver plays a central role in metabolism. Yet, it is unclear how hepatic metabolic dysregulation promotes insulin resistance and hepatic steatosis. Some studies have investigated the role of hepatic p38, a stress mitogen-activated protein kinase (MAPK), in hepatic fat accumulation and insulin resistance in models of obesity. However, the role of p38 in free fatty acid (FFA) induced hepatic fat accumulation and insulin resistance has not been previously investigated. Moreover, the role that p38 MAPK plays in hepatic glucose and lipid metabolism is still controversial. Here, using both genetic and pharmacological models, we investigated whether the inhibition of p38 MAPK reverses FFA-induced hepatic fat accumulation and insulin resistance. Cannulated Wistar rats were intravenously infused with one of four treatments for 48 hours: Saline (SAL), Intralipid+Heparin (IH), IH+p38 MAPK inhibitor - SB239063 (IH+SB) and SB239063 (SB) alone. After 48hr infusion, the liver was collected and stained with Oil Red O to determine hepatic fat accumulation. IH rats had significantly greater hepatic fat accumulation compared to SAL rats (p<0.05). IH+SB rats were protected from FFA-induced hepatic fat accumulation. To assess the role of p38 on FFA-induced insulin resistance, liver-specific p38 knockout mice and wild type mice were infused with ethyl-oleate and ethyl palmitate (EtOP) or ethanol (control) for 48 hrs. After 46 hours of the infusion, the mice underwent a hyperinsulinemic-euglycemic clamp to determine insulin sensitivity. Results thus far suggest that genetic inhibition of p38 MAPK in the liver protects from FFA-induced insulin resistance in the periphery (p=0.06), consistent with tissue cross-talk also observed by our lab in liver-specific p38 knockout mice using a high fat diet model.
In conclusion, our data indicates that both the pharmacological and genetic inhibition of p38 has a protective effect on FFA-induced hepatic fat accumulation and insulin resistance.</abstract><cop>New York</cop><pub>American Diabetes Association</pub><doi>10.2337/db20-1858-P</doi></addata></record> |
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| subjects | Animal models Anticoagulants Diabetes Ethanol Fatty liver Glucose metabolism Heparin High fat diet Insulin Insulin resistance Kinases Lipid metabolism Liver MAP kinase Metabolism Obesity Palmitic acid Protein kinase Rodents Steatosis |
| title | 1858-P: P38 MAPK Inhibition Protects against FFA-Induced Insulin Resistance and Hepatic Fat Accumulation |
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