title: Brain transcriptional responses to high-fat diet in Acads-deficient mice reveal energy sensing pathways.
abstract: BACKGROUND
  How 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, United States of America.
authors.forename: Claudia
authors.initials: C
authors.lastname: Kruger
authors.forename: K Ganesh
authors.initials: KG
authors.lastname: Kumar
authors.forename: Randall L
authors.initials: RL
authors.lastname: Mynatt
authors.forename: Julia
authors.initials: J
authors.lastname: Volaufova
authors.forename: Brenda K
authors.initials: BK
authors.lastname: Richards
mesh_terms: D042964:Acyl-CoA Dehydrogenase / Q000172:deficiency* / Q000235:genetics; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001921:Brain; D059305:Diet, High-Fat / Q000009:adverse effects*; D005227:Fatty Acids / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: D005227:Fatty Acids; D000255:Adenosine Triphosphate; D042964:Acyl-CoA Dehydrogenase