Non-hematopoietic IL-4Rα expression contributes to fructose-driven obesity and metabolic sequelae
Objective The risks of excess sugar intake in addition to high-fat diet consumption on immunopathogenesis of obesity-associated metabolic diseases are poorly defined. Interleukin-4 (IL-4) and IL-13 signaling via IL-4Rα regulates adipose tissue lipolysis, insulin sensitivity, and liver fibrosis in ob...
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| Veröffentlicht in: | International Journal of Obesity 2021-11, Vol.45 (11), p.2377-2387 |
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| container_title | International Journal of Obesity |
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| creator | Damen, Michelle S. M. A. Stankiewicz, Traci E. Park, Se-Hyung Helsley, Robert N. Chan, Calvin C. Moreno-Fernandez, Maria E. Doll, Jessica R. Szabo, Sara Herbert, De’Broski R. Softic, Samir Divanovic, Senad |
| description | Objective
The risks of excess sugar intake in addition to high-fat diet consumption on immunopathogenesis of obesity-associated metabolic diseases are poorly defined. Interleukin-4 (IL-4) and IL-13 signaling via IL-4Rα regulates adipose tissue lipolysis, insulin sensitivity, and liver fibrosis in obesity. However, the contribution of IL-4Rα to sugar rich diet-driven obesity and metabolic sequelae remains unknown.
Methods
WT, IL-4Rα-deficient (IL-4Rα
−/−
) and STAT6-deficient mice (STAT6
−/−
) male mice were fed low-fat chow, high fat (HF) or HF plus high carbohydrate (HC/fructose) diet (HF + HC). Analysis included quantification of: (i) body weight, adiposity, energy expenditure, fructose metabolism, fatty acid oxidation/synthesis, glucose dysmetabolism and hepatocellular damage; (ii) the contribution of the hematopoietic or non-hematopoietic IL-4Rα expression; and (iii) the relevance of IL-4Rα downstream canonical STAT6 signaling pathway in this setting.
Results
We show that IL-4Rα regulated HF + HC diet-driven weight gain, whole body adiposity, adipose tissue inflammatory gene expression, energy expenditure, locomotor activity, glucose metabolism, hepatic steatosis, hepatic inflammatory gene expression and hepatocellular damage. These effects were potentially, and in part, dependent on non-hematopoietic IL-4Rα expression but were independent of direct STAT6 activation. Mechanistically, hepatic ketohexokinase-A and C expression was dependent on IL-4Rα, as it was reduced in IL-4Rα-deficient mice. KHK activity was also affected by HF + HC dietary challenge. Further, reduced expression/activity of KHK in IL-4Rα mice had a significant effect on fatty acid oxidation and fatty acid synthesis pathways.
Conclusion
Our findings highlight potential contribution of non-hematopoietic IL-4Rα activation of a non-canonical signaling pathway that regulates the HF + HC diet-driven induction of obesity and severity of obesity-associated sequelae. |
| doi_str_mv | 10.1038/s41366-021-00902-6 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8528699</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2583708794</sourcerecordid><originalsourceid>FETCH-LOGICAL-c474t-5e431f56e6ab3f0f9905244173d6da70264ccbc9aec4e2499f43f8a3f8c9f5023</originalsourceid><addsrcrecordid>eNp9kU1uFDEQhS1ERIbABVigllgbyr_d3iChiIRIIyJFYW253eXE0Ux7sN1RciwuwpkwTAiwYWF5Ue999exHyCsGbxmI4V2RTGhNgTMKYIBT_YSsmOw1VdL0T8kKBPQUlFaH5HkpNwCgFPBn5FBI0Vycrcj4Oc30Greupl2KWKPvztZUXnz_1uHdLmMpMc2dT3PNcVwqlq6mLuTF11SQTjne4tylEUus952bp26L1Y1p0zgFvy64cfiCHAS3Kfjy4T4iX04-Xh5_ouvz07PjD2vqZS8rVSgFC0qjdqMIEIwBxaVkvZj05HrgWno_euPQS-TSmCBFGFw73oT2LHFE3u-5u2Xc4uSxZXYbu8tx6_K9TS7afydzvLZX6dYOig_amAZ48wDIqUUv1d6kJc8ts-VqED0MvZFNxfcqn1MpGcPjBgb2Zy9234ttP2x_9WJ1M73-O9uj5XcRTSD2gtJG8xXmP7v_g_0BANubvg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2583708794</pqid></control><display><type>article</type><title>Non-hematopoietic IL-4Rα expression contributes to fructose-driven obesity and metabolic sequelae</title><source>MEDLINE</source><source>Nature</source><source>Alma/SFX Local Collection</source><creator>Damen, Michelle S. M. A. ; Stankiewicz, Traci E. ; Park, Se-Hyung ; Helsley, Robert N. ; Chan, Calvin C. ; Moreno-Fernandez, Maria E. ; Doll, Jessica R. ; Szabo, Sara ; Herbert, De’Broski R. ; Softic, Samir ; Divanovic, Senad</creator><creatorcontrib>Damen, Michelle S. M. A. ; Stankiewicz, Traci E. ; Park, Se-Hyung ; Helsley, Robert N. ; Chan, Calvin C. ; Moreno-Fernandez, Maria E. ; Doll, Jessica R. ; Szabo, Sara ; Herbert, De’Broski R. ; Softic, Samir ; Divanovic, Senad</creatorcontrib><description>Objective
The risks of excess sugar intake in addition to high-fat diet consumption on immunopathogenesis of obesity-associated metabolic diseases are poorly defined. Interleukin-4 (IL-4) and IL-13 signaling via IL-4Rα regulates adipose tissue lipolysis, insulin sensitivity, and liver fibrosis in obesity. However, the contribution of IL-4Rα to sugar rich diet-driven obesity and metabolic sequelae remains unknown.
Methods
WT, IL-4Rα-deficient (IL-4Rα
−/−
) and STAT6-deficient mice (STAT6
−/−
) male mice were fed low-fat chow, high fat (HF) or HF plus high carbohydrate (HC/fructose) diet (HF + HC). Analysis included quantification of: (i) body weight, adiposity, energy expenditure, fructose metabolism, fatty acid oxidation/synthesis, glucose dysmetabolism and hepatocellular damage; (ii) the contribution of the hematopoietic or non-hematopoietic IL-4Rα expression; and (iii) the relevance of IL-4Rα downstream canonical STAT6 signaling pathway in this setting.
Results
We show that IL-4Rα regulated HF + HC diet-driven weight gain, whole body adiposity, adipose tissue inflammatory gene expression, energy expenditure, locomotor activity, glucose metabolism, hepatic steatosis, hepatic inflammatory gene expression and hepatocellular damage. These effects were potentially, and in part, dependent on non-hematopoietic IL-4Rα expression but were independent of direct STAT6 activation. Mechanistically, hepatic ketohexokinase-A and C expression was dependent on IL-4Rα, as it was reduced in IL-4Rα-deficient mice. KHK activity was also affected by HF + HC dietary challenge. Further, reduced expression/activity of KHK in IL-4Rα mice had a significant effect on fatty acid oxidation and fatty acid synthesis pathways.
Conclusion
Our findings highlight potential contribution of non-hematopoietic IL-4Rα activation of a non-canonical signaling pathway that regulates the HF + HC diet-driven induction of obesity and severity of obesity-associated sequelae.</description><identifier>ISSN: 0307-0565</identifier><identifier>EISSN: 1476-5497</identifier><identifier>DOI: 10.1038/s41366-021-00902-6</identifier><identifier>PMID: 34302121</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/21 ; 38/39 ; 38/77 ; 38/90 ; 631/250/249/2510 ; 64/60 ; 692/699/249/2510 ; 96/31 ; Adipose tissue ; Animals ; Body fat ; Body weight ; Body weight gain ; Carbohydrates ; Complications ; Damage ; Diet ; Disease Models, Animal ; Energy expenditure ; Energy metabolism ; Energy Metabolism - physiology ; Epidemiology ; Fatty acids ; Fatty liver ; Fibrosis ; Fructose ; Fructose - adverse effects ; Gene expression ; Glucose ; Glucose metabolism ; Health Promotion and Disease Prevention ; High carbohydrate diet ; High fat diet ; Immunopathogenesis ; Inflammation ; Insulin ; Insulin Resistance - physiology ; Interleukin 13 ; Interleukin 4 ; Interleukin-4 - analysis ; Interleukin-4 - metabolism ; Internal Medicine ; Ketohexokinase ; Lipolysis ; Locomotor activity ; Low fat diet ; Medicine ; Medicine & Public Health ; Metabolic Diseases ; Metabolic disorders ; Metabolism ; Mice ; Obesity ; Obesity - immunology ; Obesity - metabolism ; Oxidation ; Public Health ; Signal transduction ; Signaling ; Sugar ; Synthesis</subject><ispartof>International Journal of Obesity, 2021-11, Vol.45 (11), p.2377-2387</ispartof><rights>The Author(s) 2021</rights><rights>2021. The Author(s).</rights><rights>The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-5e431f56e6ab3f0f9905244173d6da70264ccbc9aec4e2499f43f8a3f8c9f5023</citedby><cites>FETCH-LOGICAL-c474t-5e431f56e6ab3f0f9905244173d6da70264ccbc9aec4e2499f43f8a3f8c9f5023</cites><orcidid>0000-0003-4617-2564 ; 0000-0002-9933-3061 ; 0000-0001-5225-801X ; 0000-0001-7538-0499 ; 0000-0001-5000-3187</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34302121$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Damen, Michelle S. M. A.</creatorcontrib><creatorcontrib>Stankiewicz, Traci E.</creatorcontrib><creatorcontrib>Park, Se-Hyung</creatorcontrib><creatorcontrib>Helsley, Robert N.</creatorcontrib><creatorcontrib>Chan, Calvin C.</creatorcontrib><creatorcontrib>Moreno-Fernandez, Maria E.</creatorcontrib><creatorcontrib>Doll, Jessica R.</creatorcontrib><creatorcontrib>Szabo, Sara</creatorcontrib><creatorcontrib>Herbert, De’Broski R.</creatorcontrib><creatorcontrib>Softic, Samir</creatorcontrib><creatorcontrib>Divanovic, Senad</creatorcontrib><title>Non-hematopoietic IL-4Rα expression contributes to fructose-driven obesity and metabolic sequelae</title><title>International Journal of Obesity</title><addtitle>Int J Obes</addtitle><addtitle>Int J Obes (Lond)</addtitle><description>Objective
The risks of excess sugar intake in addition to high-fat diet consumption on immunopathogenesis of obesity-associated metabolic diseases are poorly defined. Interleukin-4 (IL-4) and IL-13 signaling via IL-4Rα regulates adipose tissue lipolysis, insulin sensitivity, and liver fibrosis in obesity. However, the contribution of IL-4Rα to sugar rich diet-driven obesity and metabolic sequelae remains unknown.
Methods
WT, IL-4Rα-deficient (IL-4Rα
−/−
) and STAT6-deficient mice (STAT6
−/−
) male mice were fed low-fat chow, high fat (HF) or HF plus high carbohydrate (HC/fructose) diet (HF + HC). Analysis included quantification of: (i) body weight, adiposity, energy expenditure, fructose metabolism, fatty acid oxidation/synthesis, glucose dysmetabolism and hepatocellular damage; (ii) the contribution of the hematopoietic or non-hematopoietic IL-4Rα expression; and (iii) the relevance of IL-4Rα downstream canonical STAT6 signaling pathway in this setting.
Results
We show that IL-4Rα regulated HF + HC diet-driven weight gain, whole body adiposity, adipose tissue inflammatory gene expression, energy expenditure, locomotor activity, glucose metabolism, hepatic steatosis, hepatic inflammatory gene expression and hepatocellular damage. These effects were potentially, and in part, dependent on non-hematopoietic IL-4Rα expression but were independent of direct STAT6 activation. Mechanistically, hepatic ketohexokinase-A and C expression was dependent on IL-4Rα, as it was reduced in IL-4Rα-deficient mice. KHK activity was also affected by HF + HC dietary challenge. Further, reduced expression/activity of KHK in IL-4Rα mice had a significant effect on fatty acid oxidation and fatty acid synthesis pathways.
Conclusion
Our findings highlight potential contribution of non-hematopoietic IL-4Rα activation of a non-canonical signaling pathway that regulates the HF + HC diet-driven induction of obesity and severity of obesity-associated sequelae.</description><subject>13/21</subject><subject>38/39</subject><subject>38/77</subject><subject>38/90</subject><subject>631/250/249/2510</subject><subject>64/60</subject><subject>692/699/249/2510</subject><subject>96/31</subject><subject>Adipose tissue</subject><subject>Animals</subject><subject>Body fat</subject><subject>Body weight</subject><subject>Body weight gain</subject><subject>Carbohydrates</subject><subject>Complications</subject><subject>Damage</subject><subject>Diet</subject><subject>Disease Models, Animal</subject><subject>Energy expenditure</subject><subject>Energy metabolism</subject><subject>Energy Metabolism - physiology</subject><subject>Epidemiology</subject><subject>Fatty acids</subject><subject>Fatty liver</subject><subject>Fibrosis</subject><subject>Fructose</subject><subject>Fructose - adverse effects</subject><subject>Gene expression</subject><subject>Glucose</subject><subject>Glucose metabolism</subject><subject>Health Promotion and Disease Prevention</subject><subject>High carbohydrate diet</subject><subject>High fat diet</subject><subject>Immunopathogenesis</subject><subject>Inflammation</subject><subject>Insulin</subject><subject>Insulin Resistance - physiology</subject><subject>Interleukin 13</subject><subject>Interleukin 4</subject><subject>Interleukin-4 - analysis</subject><subject>Interleukin-4 - metabolism</subject><subject>Internal Medicine</subject><subject>Ketohexokinase</subject><subject>Lipolysis</subject><subject>Locomotor activity</subject><subject>Low fat diet</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metabolic Diseases</subject><subject>Metabolic disorders</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Obesity</subject><subject>Obesity - immunology</subject><subject>Obesity - metabolism</subject><subject>Oxidation</subject><subject>Public Health</subject><subject>Signal transduction</subject><subject>Signaling</subject><subject>Sugar</subject><subject>Synthesis</subject><issn>0307-0565</issn><issn>1476-5497</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kU1uFDEQhS1ERIbABVigllgbyr_d3iChiIRIIyJFYW253eXE0Ux7sN1RciwuwpkwTAiwYWF5Ue999exHyCsGbxmI4V2RTGhNgTMKYIBT_YSsmOw1VdL0T8kKBPQUlFaH5HkpNwCgFPBn5FBI0Vycrcj4Oc30Greupl2KWKPvztZUXnz_1uHdLmMpMc2dT3PNcVwqlq6mLuTF11SQTjne4tylEUus952bp26L1Y1p0zgFvy64cfiCHAS3Kfjy4T4iX04-Xh5_ouvz07PjD2vqZS8rVSgFC0qjdqMIEIwBxaVkvZj05HrgWno_euPQS-TSmCBFGFw73oT2LHFE3u-5u2Xc4uSxZXYbu8tx6_K9TS7afydzvLZX6dYOig_amAZ48wDIqUUv1d6kJc8ts-VqED0MvZFNxfcqn1MpGcPjBgb2Zy9234ttP2x_9WJ1M73-O9uj5XcRTSD2gtJG8xXmP7v_g_0BANubvg</recordid><startdate>20211101</startdate><enddate>20211101</enddate><creator>Damen, Michelle S. M. A.</creator><creator>Stankiewicz, Traci E.</creator><creator>Park, Se-Hyung</creator><creator>Helsley, Robert N.</creator><creator>Chan, Calvin C.</creator><creator>Moreno-Fernandez, Maria E.</creator><creator>Doll, Jessica R.</creator><creator>Szabo, Sara</creator><creator>Herbert, De’Broski R.</creator><creator>Softic, Samir</creator><creator>Divanovic, Senad</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T2</scope><scope>7TK</scope><scope>7TS</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88G</scope><scope>8AO</scope><scope>8C1</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PSYQQ</scope><scope>Q9U</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-4617-2564</orcidid><orcidid>https://orcid.org/0000-0002-9933-3061</orcidid><orcidid>https://orcid.org/0000-0001-5225-801X</orcidid><orcidid>https://orcid.org/0000-0001-7538-0499</orcidid><orcidid>https://orcid.org/0000-0001-5000-3187</orcidid></search><sort><creationdate>20211101</creationdate><title>Non-hematopoietic IL-4Rα expression contributes to fructose-driven obesity and metabolic sequelae</title><author>Damen, Michelle S. M. A. ; Stankiewicz, Traci E. ; Park, Se-Hyung ; Helsley, Robert N. ; Chan, Calvin C. ; Moreno-Fernandez, Maria E. ; Doll, Jessica R. ; Szabo, Sara ; Herbert, De’Broski R. ; Softic, Samir ; Divanovic, Senad</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-5e431f56e6ab3f0f9905244173d6da70264ccbc9aec4e2499f43f8a3f8c9f5023</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>13/21</topic><topic>38/39</topic><topic>38/77</topic><topic>38/90</topic><topic>631/250/249/2510</topic><topic>64/60</topic><topic>692/699/249/2510</topic><topic>96/31</topic><topic>Adipose tissue</topic><topic>Animals</topic><topic>Body fat</topic><topic>Body weight</topic><topic>Body weight gain</topic><topic>Carbohydrates</topic><topic>Complications</topic><topic>Damage</topic><topic>Diet</topic><topic>Disease Models, Animal</topic><topic>Energy expenditure</topic><topic>Energy metabolism</topic><topic>Energy Metabolism - physiology</topic><topic>Epidemiology</topic><topic>Fatty acids</topic><topic>Fatty liver</topic><topic>Fibrosis</topic><topic>Fructose</topic><topic>Fructose - adverse effects</topic><topic>Gene expression</topic><topic>Glucose</topic><topic>Glucose metabolism</topic><topic>Health Promotion and Disease Prevention</topic><topic>High carbohydrate diet</topic><topic>High fat diet</topic><topic>Immunopathogenesis</topic><topic>Inflammation</topic><topic>Insulin</topic><topic>Insulin Resistance - physiology</topic><topic>Interleukin 13</topic><topic>Interleukin 4</topic><topic>Interleukin-4 - analysis</topic><topic>Interleukin-4 - metabolism</topic><topic>Internal Medicine</topic><topic>Ketohexokinase</topic><topic>Lipolysis</topic><topic>Locomotor activity</topic><topic>Low fat diet</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metabolic Diseases</topic><topic>Metabolic disorders</topic><topic>Metabolism</topic><topic>Mice</topic><topic>Obesity</topic><topic>Obesity - immunology</topic><topic>Obesity - metabolism</topic><topic>Oxidation</topic><topic>Public Health</topic><topic>Signal transduction</topic><topic>Signaling</topic><topic>Sugar</topic><topic>Synthesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Damen, Michelle S. M. A.</creatorcontrib><creatorcontrib>Stankiewicz, Traci E.</creatorcontrib><creatorcontrib>Park, Se-Hyung</creatorcontrib><creatorcontrib>Helsley, Robert N.</creatorcontrib><creatorcontrib>Chan, Calvin C.</creatorcontrib><creatorcontrib>Moreno-Fernandez, Maria E.</creatorcontrib><creatorcontrib>Doll, Jessica R.</creatorcontrib><creatorcontrib>Szabo, Sara</creatorcontrib><creatorcontrib>Herbert, De’Broski R.</creatorcontrib><creatorcontrib>Softic, Samir</creatorcontrib><creatorcontrib>Divanovic, Senad</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health and Safety Science Abstracts (Full archive)</collection><collection>Neurosciences Abstracts</collection><collection>Physical Education Index</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Psychology Database (Alumni)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Psychology Database</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest One Psychology</collection><collection>ProQuest Central Basic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>International Journal of Obesity</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Damen, Michelle S. M. A.</au><au>Stankiewicz, Traci E.</au><au>Park, Se-Hyung</au><au>Helsley, Robert N.</au><au>Chan, Calvin C.</au><au>Moreno-Fernandez, Maria E.</au><au>Doll, Jessica R.</au><au>Szabo, Sara</au><au>Herbert, De’Broski R.</au><au>Softic, Samir</au><au>Divanovic, Senad</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Non-hematopoietic IL-4Rα expression contributes to fructose-driven obesity and metabolic sequelae</atitle><jtitle>International Journal of Obesity</jtitle><stitle>Int J Obes</stitle><addtitle>Int J Obes (Lond)</addtitle><date>2021-11-01</date><risdate>2021</risdate><volume>45</volume><issue>11</issue><spage>2377</spage><epage>2387</epage><pages>2377-2387</pages><issn>0307-0565</issn><eissn>1476-5497</eissn><abstract>Objective
The risks of excess sugar intake in addition to high-fat diet consumption on immunopathogenesis of obesity-associated metabolic diseases are poorly defined. Interleukin-4 (IL-4) and IL-13 signaling via IL-4Rα regulates adipose tissue lipolysis, insulin sensitivity, and liver fibrosis in obesity. However, the contribution of IL-4Rα to sugar rich diet-driven obesity and metabolic sequelae remains unknown.
Methods
WT, IL-4Rα-deficient (IL-4Rα
−/−
) and STAT6-deficient mice (STAT6
−/−
) male mice were fed low-fat chow, high fat (HF) or HF plus high carbohydrate (HC/fructose) diet (HF + HC). Analysis included quantification of: (i) body weight, adiposity, energy expenditure, fructose metabolism, fatty acid oxidation/synthesis, glucose dysmetabolism and hepatocellular damage; (ii) the contribution of the hematopoietic or non-hematopoietic IL-4Rα expression; and (iii) the relevance of IL-4Rα downstream canonical STAT6 signaling pathway in this setting.
Results
We show that IL-4Rα regulated HF + HC diet-driven weight gain, whole body adiposity, adipose tissue inflammatory gene expression, energy expenditure, locomotor activity, glucose metabolism, hepatic steatosis, hepatic inflammatory gene expression and hepatocellular damage. These effects were potentially, and in part, dependent on non-hematopoietic IL-4Rα expression but were independent of direct STAT6 activation. Mechanistically, hepatic ketohexokinase-A and C expression was dependent on IL-4Rα, as it was reduced in IL-4Rα-deficient mice. KHK activity was also affected by HF + HC dietary challenge. Further, reduced expression/activity of KHK in IL-4Rα mice had a significant effect on fatty acid oxidation and fatty acid synthesis pathways.
Conclusion
Our findings highlight potential contribution of non-hematopoietic IL-4Rα activation of a non-canonical signaling pathway that regulates the HF + HC diet-driven induction of obesity and severity of obesity-associated sequelae.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>34302121</pmid><doi>10.1038/s41366-021-00902-6</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0003-4617-2564</orcidid><orcidid>https://orcid.org/0000-0002-9933-3061</orcidid><orcidid>https://orcid.org/0000-0001-5225-801X</orcidid><orcidid>https://orcid.org/0000-0001-7538-0499</orcidid><orcidid>https://orcid.org/0000-0001-5000-3187</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0307-0565 |
| ispartof | International Journal of Obesity, 2021-11, Vol.45 (11), p.2377-2387 |
| issn | 0307-0565 1476-5497 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8528699 |
| source | MEDLINE; Nature; Alma/SFX Local Collection |
| subjects | 13/21 38/39 38/77 38/90 631/250/249/2510 64/60 692/699/249/2510 96/31 Adipose tissue Animals Body fat Body weight Body weight gain Carbohydrates Complications Damage Diet Disease Models, Animal Energy expenditure Energy metabolism Energy Metabolism - physiology Epidemiology Fatty acids Fatty liver Fibrosis Fructose Fructose - adverse effects Gene expression Glucose Glucose metabolism Health Promotion and Disease Prevention High carbohydrate diet High fat diet Immunopathogenesis Inflammation Insulin Insulin Resistance - physiology Interleukin 13 Interleukin 4 Interleukin-4 - analysis Interleukin-4 - metabolism Internal Medicine Ketohexokinase Lipolysis Locomotor activity Low fat diet Medicine Medicine & Public Health Metabolic Diseases Metabolic disorders Metabolism Mice Obesity Obesity - immunology Obesity - metabolism Oxidation Public Health Signal transduction Signaling Sugar Synthesis |
| title | Non-hematopoietic IL-4Rα expression contributes to fructose-driven obesity and metabolic sequelae |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-26T09%3A57%3A13IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Non-hematopoietic%20IL-4R%CE%B1%20expression%20contributes%20to%20fructose-driven%20obesity%20and%20metabolic%20sequelae&rft.jtitle=International%20Journal%20of%20Obesity&rft.au=Damen,%20Michelle%20S.%20M.%20A.&rft.date=2021-11-01&rft.volume=45&rft.issue=11&rft.spage=2377&rft.epage=2387&rft.pages=2377-2387&rft.issn=0307-0565&rft.eissn=1476-5497&rft_id=info:doi/10.1038/s41366-021-00902-6&rft_dat=%3Cproquest_pubme%3E2583708794%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2583708794&rft_id=info:pmid/34302121&rfr_iscdi=true |