Abstract
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.
Highlights
Over 1 billion people worldwide and two-thirds of the US population are overweight or obese [1,2]
Serum metabolites can be predictive of insulin resistance and cardiovascular disease, including elevations in acylcarnitines and branched chain amino acids (BCAA) [28,41,42,43,44,45,46,47]
The work presented here contributes to increasing evidence that elevated acylcarnitines may act as biomarkers of insulin resistance, cardiovascular disease (CVD), defects in fat metabolism, as well as inflammation in Metabolic Syndrome [27,28,36,43]
Summary
Over 1 billion people worldwide and two-thirds of the US population are overweight or obese [1,2]. Obesity and insulin resistance are strongly associated with the infiltration of adipose tissue by inflammatory cells [3,4,5,6,7]. The factors that induce immune cells to infiltrate adipose tissue are unknown, but may be related to free fatty acid release from adipocytes [8]. Cytokines associated with obesity and insulin resistance such as tumor necrosis factor a (TNFa) can drive lipolysis and fatty acid release from adipose [13,14]. We hypothesized that saturated fatty acids and metabolites derived from mitochondrial oxidation may be biomarkers that predict inflammatory response and insulin resistance in diet-induced obesity. We evaluated the effects of lauroyl carnitine on macrophage pro-inflammatory responses, with findings that implicate lauroyl carnitine as a mediator of obesity-induced inflammation
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