Abstract

Metabolic Perturbations Triggered by Western Diet under Impaired Fatty Acid Oxidation: Getting Clues from Metabolomics Studies in PPAR-alpha Null Mice

Manuel Pazos, Postdoc, University of Córdoba

Obesity and concomitant metabolic alterations pose one of the major threats to public health and economic development in many countries. The drastic incorporation of what has been termed the Western diet, essentially enriched in saturated fats and simple sugars, explains to some extent the epidemic numbers for obesity and related diseases. The imbalance between fatty acid uptake and oxidation is believed to be a key factor in dysfunctional adipose tissue and inappropriate accumulation of lipids in the liver and skeletal muscle. This ectopic fat accumulation leads to a lipotoxic environment that blocks correct glucose transport and insulin signaling and is thought to be a major cause of insulin resistance and diabetes in obesity. Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is a master transcriptional factor in regulating fatty acid catabolism. Accordingly, PPAR-alpha null mice fed a high fat diet exhibit increased ectopic fat accumulation but are unexpectedly protected from insulin resistance. The present research evaluates for the first time the metabolic outcomes of Western diet on PPAR-alpha null mice by metabolomics. The metabolome is interrogated in plasma, liver, adipose tissue and skeletal muscle by an ample array of MS- and NMR-based platforms to monitor, among others, fatty acids, intact lipids, sugars, amino acids, oxoacids and oxidative stress metabolites. Results clearly discriminate the consumption of Western diet in liver, adipose tissue and plasma from PPAR-alpha null and wild-type mice. The findings are an important contribution to fully understand metabolic dysfunctions induced by Western diet and the role of impaired fatty acid oxidation on the development of insulin resistance and diabetes