Abstract

Thealarmingincreaseintheincidenceoftype2diabetesislargelyduetotheobesity epidemic.Thefailureofdietandexercisebasedstrategiestoreduceobesityhas renewedinterestinrestoringenergybalancethroughincreasedenergyexpenditurein adiposetissueviathermogenicpathways.However,themobilizationofenergyinwhite orbeigeadiposetissueinresponsetocoldexposureorsympatheticactivationremains poorlyunderstood.Basedonourpreliminarydata,weproposethatapreviously unrecognizedautocrinesignalingpathwayinvolvingsecretionofIl-6andactivationof Stat3maybeanimportantmodulatorofadipocyteenergyexpenditureinresponseto coldexposure.Thispathwayislikelyalsorelevantinotherphysiologicalcontextsin whichsympatheticsignalingintheadiposetissueisactivated.Theexperimentsoutlined inthisproposalaredesignedtoexploreandexpandinsightsintothisnovelsignaling pathwayanditsmetabolicconsequences.Thesestudieswillutilizeeithercoldexposure orb?-3adrenergicagonistinjectiontostimulatecatecholaminesignalinginadipocytes andactivatethisnovelsignalingaxis.Whilecoldexposureisaphysiologicalstimulus,b?- 3adrenergicagonistinjectionisapowerfultooltospecificallyinvestigatecatecholamine signalinginadipocytesinvivo,duetothespecificityoftheexpressionoftheb?-3 adrenergicreceptors.
Aim1 isdesignedtodeterminetheroleofIl-6inthemetabolic responsetocoldexposure.
While aim2 investigatesthespecificroleofadipocyteStat3 intheinductionofoxidativemetabolisminresponsetosympatheticactivationof adiposetissue.Finally,aim3willelucidatethemolecularmechanismofStat3actionin matureadipocyteslookingatbothtranscriptionfactoractivityandmitochondrial localization.Theworkproposedherelaysthegroundworkforfuturestudiesintohow thissignalingpathwayisaffectedbyobesity,anditspotentialastherapeutictargetin thefightagainstobesity.Thedataobtainedfromtheexperimentsproposedhereare anticipatedtosupportR01fundingforfuturestudies,therebypropellingtheapplicants careerasanindependentinvestigator.

Public Health Relevance

World-?wideobesityratesposeasignificantthreattopublichealth.Iproposetoinvestigatea novelsignalingaxisinwhichadipocytes,uponactivationbythesympatheticnervoussystem, secretIl-?6toactivateadipocyteStat3signaling.Thisnovelautocrinesignalingaxisplaysan importantroleinregulatingoxidativemetabolismandenergyexpenditureandmaytherefore beapowerfultherapeutictargetinthefightagainstobesity.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Research Grants (R03)
Project #
1R03DK118195-01
Application #
9582931
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
Program Officer
Spain, Lisa M
Project Start
2018-07-01
Project End
2020-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost

  Institution

Name
University of California, San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093

  Publications

Oral, Elif A; Reilly, Shannon M; Gomez, Andrew V et al. (2017) Inhibition of IKK? and TBK1 Improves Glucose Control in a Subset of Patients with Type 2 Diabetes. Cell Metab 26:157-170.e7