4-methylene-2-octyl-5-oxofuran-3-carboxylic-acid and Fatty-Liver

Metabolic adaptation is required to cope with episodes of protein deprivation and malnutrition. GCN2 eIF2alpha kinase, a sensor of amino acid deficiency, plays a key role in yeast and mammals in modulating amino acid metabolism as part of adaptation to nutrient deprivation. The role of GCN2 in adaptation to long-term amino acid deprivation in mammals, however, is poorly understood. We found that expression of lipogenic genes and the activity of fatty acid synthase (FAS) in the liver are repressed and lipid stores in adipose tissue are mobilized in wild-type mice upon leucine deprivation. In contrast, GCN2-deficient mice developed liver steatosis and exhibited reduced lipid mobilization. Liver steatosis in Gcn2(-/-) mice was found to be caused by unrepressed expression of lipogenic genes, including Srebp-1c and Fas. Thus, our study identifies a novel function of GCN2 in regulating lipid metabolism during leucine deprivation in addition to regulating amino acid metabolism.

Topics: 4-Butyrolactone; Adipose Tissue; Animals; Eukaryotic Initiation Factor-2; Fatty Acid Synthases; Fatty Acid Transport Proteins; Fatty Acids; Fatty Liver; Female; Homeostasis; Leucine; Liver; Male; Mice; Mitochondrial Trifunctional Protein; Multienzyme Complexes; Organ Size; Phosphorylation; PPAR gamma; Protein Serine-Threonine Kinases; Repressor Proteins; Sterol Regulatory Element Binding Protein 1; Triglycerides; Up-Regulation

Obesity and its attendant disorders, such as type 2 diabetes, are global health problems. We previously reported that C75, an inhibitor of fatty acid synthase (FAS) and stimulator of carnitine palmitoyltransferase I (CPT I), caused anorexia and profound weight loss in lean and genetically obese mice. To approximate human obesity, we utilized a chronic C75 treatment model for diet-induced obese (DIO) mice. Chronic C75 treatment decreased food consumption and increased energy expenditure due to increased fatty acid oxidation in both DIO and lean mice. There was a substantial loss of adipose tissue and resolution of hepatic steatosis in C75-treated DIO mice. Analysis of changes in the expression of hypothalamic neuropeptides demonstrated that the reduced food consumption in C75-treated DIO mice was accompanied by an increase in cocaine and amphetamine-related transcript expression but not by changes in neuropeptide Y such as seen with acute C75 treatment of lean mice. Inhibition of FAS and stimulation of CPT I provide a means to achieve stable, sustained weight loss in DIO mice.

Topics: 4-Butyrolactone; Adipose Tissue; Animals; Body Weight; Carnitine O-Palmitoyltransferase; Chronic Disease; Diet; Eating; Fatty Acid Synthases; Fatty Acids; Fatty Liver; Male; Mice; Mice, Inbred C57BL; Obesity; Oxidation-Reduction; Treatment Outcome