4-methylene-2-octyl-5-oxofuran-3-carboxylic-acid and Anorexia

Obesity and its attendant disorders, such as Type II diabetes, have reached epidemic proportions in the USA, and their prevalence is increasing globally. C75 is a small-molecule inhibitor of fatty acid synthase (FAS) and a stimulator of carnitine palmitoyl 1 activity, which causes profound weight loss in mice. Although C75 is not a compound that is destined for human drug development, it has provided two potential pathways to target in obesity therapy: fatty acid synthesis and fatty acid oxidation. In this article, we discuss the latest data challenging the relationship between fatty acid synthase inhibition and C75-induced anorexia.

Topics: 4-Butyrolactone; AMP-Activated Protein Kinases; Animals; Anorexia; Carnitine O-Palmitoyltransferase; Disease Models, Animal; Eating; Energy Metabolism; Enzyme Inhibitors; Fatty Acid Synthases; Fatty Acids; Feeding Behavior; Hypothalamus; Mice; Multienzyme Complexes; Obesity; Protein Serine-Threonine Kinases; Rats; Rhombencephalon

Energy homeostasis and feeding are regulated by the central nervous system. C75, a fatty acid synthase (FAS) inhibitor, causes weight loss and anorexia, implying a novel central nervous system pathway(s) for sensing energy balance. AMP-activated protein kinase (AMPK), a sensor of peripheral energy balance, is phosphorylated and activated when energy sources are low. Here, we identify a role for hypothalamic AMPK in the regulation of feeding behavior and in mediating the anorexic effects of C75. 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), an activator of AMPK, increased food intake, whereas compound C, an inhibitor of AMPK, decreased food intake. C75 rapidly reduced the level of the phosphorylated AMPK alpha subunit (pAMPKalpha) in the hypothalamus, even in fasted mice that had elevated hypothalamic pAMPKalpha levels. Furthermore, AICAR reversed both the C75-induced anorexia and the decrease in hypothalamic pAMPKalpha levels. C75 elevated hypothalamic neuronal ATP levels, which may contribute to the mechanism by which C75 decreased AMPK activity. C75 reduced the levels of pAMPKalpha and phosphorylated cAMP response element-binding protein (pCREB) in the arcuate nucleus neurons of the hypothalamus, suggesting a mechanism for the reduction in NPY expression seen with C75 treatment. These data indicate that modulation of FAS activity in the hypothalamus can alter energy perception via AMPK, which functions as a physiological energy sensor in the hypothalamus.

Topics: 4-Butyrolactone; Adenosine Triphosphate; Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Animals; Anorexia; Arcuate Nucleus of Hypothalamus; Blotting, Northern; Blotting, Western; Eating; Fatty Acid Synthases; Feeding Behavior; Hypothalamus; Image Processing, Computer-Assisted; Immunohistochemistry; In Situ Hybridization; Male; Mice; Mice, Inbred BALB C; Models, Biological; Multienzyme Complexes; Neurons; Phosphorylation; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley; Ribonucleotides; RNA; Time Factors

Mice respond to fatty acid synthase (FAS) inhibitors by profoundly reducing their food intake and body weight. Evidence indicates that the central nervous system (CNS) may be the critical site of action; however, a peripheral contribution cannot be ruled out. We compared doses of the FAS inhibitor C75 in the CNS (third ventricle [i3vt]) and periphery (intraperitoneal [IP]) to reduce food intake and body weight in rats. Centrally, the threshold dose was 3 micro g, whereas a dose of 10 mg/kg was required peripherally. Such data argue for FAS activity in the CNS as a potent target for the actions of C75. To control for nonspecific effects of FAS inhibition, we compared C75 administration in two models of illness, conditioned taste aversion and need-induced sodium appetite. Our results suggest the anorexia produced by IP C75 is accompanied by visceral illness, whereas the anorexia produced by i3vt is not. In addition, we placed animals in an indirect calorimeter after an IP injection of C75. We found that consistent with behavioral measures of visceral illness, peripheral C75 reduced heat expenditure and resulted in animals losing less weight than fasted control animals, suggesting that peripherally administered C75 has aversive properties. Understanding the mechanisms by which FAS inhibition in the CNS reduces food intake could lead to specific targets for the manipulation of energy balance and the treatment of obesity.

Topics: 4-Butyrolactone; Animals; Anorexia; Avoidance Learning; Body Weight; Cerebral Ventricles; Diet; Dose-Response Relationship, Drug; Energy Intake; Enzyme Inhibitors; Fatty Acid Synthases; Injections, Intraperitoneal; Injections, Intraventricular; Male; Mice; Rats; Rats, Long-Evans; Taste