Brain Transcriptional Responses to High-Fat Diet in Acads-Deficient Mice Reveal Energy Sensing Pathways

Abstract

BackgroundHow signals from fatty acid metabolism are translated into changes in food intake remains unclear. Previously we reported that mice with a genetic inactivation of Acads (acyl-coenzyme A dehydrogenase, short-chain), the enzyme responsible for mitochondrial beta-oxidation of C4–C6 short-chain fatty acids (SCFAs), shift consumption away from fat and toward carbohydrate when offered a choice between diets. In the current study, we sought to indentify candidate genes and pathways underlying the effects of SCFA oxidation deficiency on food intake in Acads−/− mice.Methodology/Principal FindingsWe performed a transcriptional analysis of gene expression in brain tissue of Acads−/− and Acads+/+ mice fed either a high-fat (HF) or low-fat (LF) diet for 2 d. Ingenuity Pathway Analysis revealed three top-scoring pathways significantly modified by genotype or diet: oxidative phosphorylation, mitochondrial dysfunction, and CREB signaling in neurons. A comparison of statistically significant responses in HF Acads−/− vs. HF Acads+/+ (3917) and Acads+/+ HF vs. LF Acads+/+ (3879) revealed 2551 genes or approximately 65% in common between the two experimental comparisons. All but one of these genes were expressed in opposite direction with similar magnitude, demonstrating that HF-fed Acads-deficient mice display transcriptional responses that strongly resemble those of Acads+/+ mice fed LF diet. Intriguingly, genes involved in both AMP-kinase regulation and the neural control of food intake followed this pattern. Quantitative RT-PCR in hypothalamus confirmed the dysregulation of genes in these pathways. Western blotting showed an increase in hypothalamic AMP-kinase in Acads−/− mice and HF diet increased, a key protein in an energy-sensing cascade that responds to depletion of ATP.ConclusionsOur results suggest that the decreased beta-oxidation of short-chain fatty acids in Acads-deficient mice fed HF diet produces a state of energy deficiency in the brain and that AMP-kinase may be the cellular energy-sensing mechanism linking fatty acid oxidation to feeding behavior in this model.

Short chain acyl-CoA dehydrogenase deficiency and short-term high-fat diet perturb mitochondrial energy metabolism and transcriptional control of lipid-handling in liver

“…In each case, tissue was harvested from Acads−/− or Acads+/+ mice only 2 days after initiating a single, high- or low-fat diet, to coincide with the time point at which the Acads mutants begin to eat less fat in a macronutrient diet selection paradigm [ 1 ]. Our overall aim was to uncover hepatic processes affected by fuel oxidation and ATP generation [ 3 ] that potentially could be linked to feeding behavior [ 17 ].…”

“…Hybridization of 10 μg fragmented DIG-labeled cRNA to AB Mouse Genome Survey microarray (version 2.0), processing, chemiluminescence detection, imaging, auto-gridding, and image analysis were performed according to AB protocols, using the 1700 Chemiluminescent Microarray Analyzer Software v. 1.0.3. The AB Expression system software V2.0 was used to extract assay signal and signal-to-noise ratios from the images as previously described [ 17 ].…”

Higher expression of acyl-CoA dehydrogenase genes in adipose tissues of obese compared to lean pig breeds

“…Dysfunction of ACADSB may induce lipid oxidative damage in rats (Knebel et al, 2012). ACADS is mainly responsible for mitochondrial β-oxidation of C4-C6 short-chain fatty acids (Kruger et al, 2012), and is more highly expressed in skeletal muscle of obese Korean pigs than in that of Landrace pigs (Kim et al, 2010). ACADM, which encodes an enzyme that can oxidize C6-C12 fatty acids (Tucci et al, 2012), is upregulated in the liver with high fat content, and its expression is positively correlated with fat content of human liver (Greco et al, 2008).…”

Proteomics Analysis and Identification of Critical Proteins and Network Interactions That Regulate the Specific Deposition of IMF of Jingyuan Chicken

“…Studies have shown that lack of ACADL can cause mitochondrial dysfunction and liver steatosis or liver insulin resistance (Ji & Friedman 2007;Zang Shasha et al 2014), in particular, ACADL plays an important role in the liver metabolism of chickens ( Yue Ying 2013). Shortchain acyl-CoA dehydrogenase (Acyl-CoA dehydrogenase short-chain ACADS) is a non-acyl dehydrogenase that is primarily responsible for β-oxidation of C4-C6 short-chain fatty acids and is also the rate-limiting enzyme in fatty acid degradation (Kruger et al al. 2012).…”