Metabolomic profiling reveals mitochondrial-derived lipid biomarkers that drive obesity-associated inflammation.
Obesity has reached epidemic proportions worldwide. Several animal models of obesity exist, but studies are lacking that compare traditional lard-based high fat diets (HFD) to "Cafeteria diets" (CAF) consisting of nutrient poor human junk food. Our previous work demonstrated the rapid and severe obesogenic and inflammatory consequences of CAF compared to HFD including rapid weight gain, markers of Metabolic Syndrome, multi-tissue lipid accumulation, and dramatic inflammation. To identify potential mediators of CAF-induced obesity and Metabolic Syndrome, we used metabolomic analysis to profile serum, muscle, and white adipose from rats fed CAF, HFD, or standard control diets. Principle component analysis identified elevations in clusters of fatty acids and acylcarnitines. These increases in metabolites were associated with systemic mitochondrial dysfunction that paralleled weight gain, physiologic measures of Metabolic Syndrome, and tissue inflammation in CAF-fed rats. Spearman pairwise correlations between metabolites, physiologic, and histologic findings revealed strong correlations between elevated markers of inflammation in CAF-fed animals, measured as crown like structures in adipose, and specifically the pro-inflammatory saturated fatty acids and oxidation intermediates laurate and lauroyl carnitine. Treatment of bone marrow-derived macrophages with lauroyl carnitine polarized macrophages towards the M1 pro-inflammatory phenotype through downregulation of AMPK and secretion of pro-inflammatory cytokines. Results presented herein demonstrate that compared to a traditional HFD model, the CAF diet provides a robust model for diet-induced human obesity, which models Metabolic Syndrome-related mitochondrial dysfunction in serum, muscle, and adipose, along with pro-inflammatory metabolite alterations. These data also suggest that modifying the availability or metabolism of saturated fatty acids may limit the inflammation associated with obesity leading to Metabolic Syndrome.
Department of Nutrition, Gillings School of Global Public Health, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
Brante P
BP
Sampey
Alex J
AJ
Freemerman
Jimmy
J
Zhang
Pei-Fen
PF
Kuan
Joseph A
JA
Galanko
Thomas M
TM
O'Connell
Olga R
OR
Ilkayeva
Michael J
MJ
Muehlbauer
Robert D
RD
Stevens
Christopher B
CB
Newgard
Heather A
HA
Brauer
Melissa A
MA
Troester
Liza
L
Makowski
D000273:Adipose Tissue / Q000378:metabolism; D000596:Amino Acids / Q000097:blood / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D002331:Carnitine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D002853:Chromatography, Liquid; D016000:Cluster Analysis; D019295:Computational Biology; D004032:Diet; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000209:etiology / Q000378:metabolism*; D007848:Laurates / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D024821:Metabolic Syndrome / Q000209:etiology / Q000378:metabolism*; D055432:Metabolomics / Q000379:methods*; D008928:Mitochondria / Q000378:metabolism*; D009765:Obesity / Q000150:complications*; D025341:Principal Component Analysis; D051381:Rats; D053719:Tandem Mass Spectrometry
D000596:Amino Acids; D015415:Biomarkers; D005227:Fatty Acids; D007848:Laurates; C116917:acylcarnitine; C091947:lauroylcarnitine; D002331:Carnitine