Extracellular RNAs Are Associated With Insulin Resistance and Metabolic Phenotypes.
Insulin resistance (IR) is a hallmark of obesity and metabolic disease. Circulating extracellular RNAs (ex-RNAs), stable RNA molecules in plasma, may play a role in IR, though most studies on ex-RNAs in IR are small. We sought to characterize the relationship between ex-RNAs and metabolic phenotypes in a large community-based human cohort.



We measured circulating plasma ex-RNAs in 2,317 participants without diabetes in the Framingham Heart Study (FHS) Offspring Cohort at cycle 8 and defined associations between ex-RNAs and IR (measured by circulating insulin level). We measured association between candidate ex-RNAs and markers of adiposity. Sensitivity analyses included individuals with diabetes. In a separate cohort of 90 overweight/obese youth, we measured selected ex-RNAs and metabolites. Biology of candidate microRNAs was investigated in silico.



The mean age of FHS participants was 65.8 years (56% female), with average BMI 27.7 kg/m2; participants in the youth cohort had a mean age of 15.5 years (60% female), with mean BMI 33.8 kg/m2. In age-, sex-, and BMI-adjusted models across 391 ex-RNAs in FHS, 18 ex-RNAs were associated with IR (of which 16 were microRNAs). miR-122 was associated with IR and regional adiposity in adults and IR in children (independent of metabolites). Pathway analysis revealed metabolic regulatory roles for miR-122, including regulation of IR pathways (AMPK, target of rapamycin signaling, and mitogen-activated protein kinase).



These results provide translational evidence in support of an important role of ex-RNAs as novel circulating factors implicated in IR.
Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA rvshah@partners.org vlmurthy@med.umich.edu.
Ravi
R
Shah
Department of Medicine and Radiology, University of Michigan-Ann Arbor, Ann Arbor, MI rvshah@partners.org vlmurthy@med.umich.edu.
Venkatesh
V
Murthy
Metabolomics Core, Whitehead Institute, Massachusetts Institute of Technology, Boston, MA.
Michael
M
Pacold
Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Kirsty
K
Danielson
University of Massachusetts at Worcester, Worcester, MA.
Kahraman
K
Tanriverdi
Biostatistics Department, Boston University School of Public Health, Boston, MA.
Martin G
MG
Larson
Gladstone Institutes, San Francisco, CA.
Kristina
K
Hanspers
Gladstone Institutes, San Francisco, CA.
Alexander
A
Pico
University of Massachusetts at Worcester, Worcester, MA.
Eric
E
Mick
Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD.
Jared
J
Reis
Preventative Cardiology, Department of Medicine and Cardiology, Boston Children's Hospital, Boston, MA.
Sarah
S
de Ferranti
Metabolomics Core, Whitehead Institute, Massachusetts Institute of Technology, Boston, MA.
Elizaveta
E
Freinkman
Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD.
Daniel
D
Levy
Department of Radiology, Massachusetts General Hospital, Boston, MA.
Udo
U
Hoffmann
Department of Medicine, Division of General Pediatrics, Boston Children's Hospital, Boston, MA.
Stavroula
S
Osganian
Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Saumya
S
Das
University of Massachusetts at Worcester, Worcester, MA.
Jane E
JE
Freedman
D050154:Adiposity; D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D015992:Body Mass Index; D002097:C-Reactive Protein / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002784:Cholesterol / Q000097:blood; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood* / Q000235:genetics*; D035683:MicroRNAs / Q000097:blood* / Q000235:genetics*; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000097:blood / Q000235:genetics; D009765:Obesity / Q000097:blood / Q000235:genetics; D050177:Overweight / Q000097:blood / Q000235:genetics; D010641:Phenotype; D011446:Prospective Studies; D012680:Sensitivity and Specificity; D014280:Triglycerides / Q000097:blood; D055105:Waist Circumference; D055815:Young Adult
D015415:Biomarkers; D002097:C-Reactive Protein; D002784:Cholesterol; D006442:Glycated Hemoglobin; D007328:Insulin; D035683:MicroRNAs; D020928:Mitogen-Activated Protein Kinases; D014280:Triglycerides; C531907:MIRN122 microRNA, human