Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2007, 1, 53-62 53 1872-2148/07 $100.00+.00 © 2007 Bentham Science Publishers Ltd. C75, a Fatty Acid Synthase (FAS) Inhibitor Miguel López 1 and Carlos Diéguez 1, * 1 Department of Physiology, School of Medicine, University of Santiago de Compostela, Spain Received: November 1, 2006; Accepted: November 17, 2006; Revised: November 22, 2006 Abstract: Recent data has demonstrated that fatty acid metabolism plays a critical role in the hypothalamic regulation of food intake and the evidence is as follows. Circulating long chain fatty acids act as nutrient surplus signals in the hypothalamus. On addition, fatty acid synthesis pathway enzymes, such as fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) and its upstream regulator, AMP-activated protein kinase (AMPK) are regulated by nutritional and hormonal stimuli. Very importantly, current evidence also indicates that fatty acid metabolism pathway may be a potential target for obesity treatment. In this sense, it has been demonstrated that pharmacological inhibition of FAS results in profound decrease in food intake and body weight in rodents. These anorectic actions are mediated by the modulation of hypothalamic neuropeptide systems, through a malonyl-CoA dependent mechanism. In this review, we recapitulate what is known about hypothalamic fatty acid metabolism and the regulation of feeding, with particular interest in a specific FAS inhibitor, C75, which has been recently patented as a potential drug for adipose mass reduction. Keywords: AMP-activated protein kinase (AMPK), C75, cerulenin, fatty acid synthase (FAS), FAS inhibitors, food intake, hypothalamus, lipid sensing, tamoxifen. INTRODUCTION In both the developed and developing world, levels of obesity and its related disorders are increasing at a rate that could be considered as epidemic. The major alarm is its association with insulin resistance, type 2 diabetes, fatty liver (steatosis) and range of other disorders generally known as Metabolic Syndrome [1-5], as well as sleep apnea, muscu- loskeletal disorders and several types of cancer [6]. For this cause, much effort is focus on recognizing the basic molecular mechanisms governing energy balance and food intake [4,5,7,8]. Energy balance depends on the effectiveness of firmly regulated mechanisms of energy intake and consumption. Despite energy balance being affected by many modulatory factors, obesity is at last the result of a positive imbalance between energy acquirement and energy expenditure. At biochemical and physiological level, there is a noteworthy amount of cross-regulation between the various parts of the energy balance equation, such that changes in one part of the equation leads to counter-regulation of the other [1-3,8]. In this precise homeostatic network, the central nervous system (CNS) and more specifically the hypothalamus play a major role. Discrete nuclei within the hypothalamus respond to changes in energy status by modifying the expression of specific neuropeptides which cause changes in energy intake and expenditure [3,8-10]. Once the information is processed in discrete hypothalamic nuclei, specific signals are transmitted to other brain centers, in the cerebral cortex and the brainstem, to produce an appropriate feeding response [3,8-10]. *Address correspondence to this author at the Department of Physiology, School of Medicine, University of Santiago de Compostela, C/ San Francisco s/n 15782, Santiago de Compostela, A Coruña, Spain; Tel: 34- 981582658; Fax: 34-981574145; E-mail: fscadigo@usc.es Hypothalamic neurons respond to changes in energy status by modulating the synthesis of neuropeptides that results in appropriate changes in energy intake and expen- diture. Thus, when energy intake exceeds expenditure, expression of the orexigenic (feeding-promoting) neuropep- tides i.e., agouti-related protein (AgRP) and neuropeptide Y (NPY) decreases. Conversely, the expression of anorexigenic (feeding-inhibitors) neuropeptides, i.e., cocaine and amphet- amine-regulated transcript (CART) and proopiomelanocortin (POMC) increases. On the other hand, when energy expen- diture exceeds intake the opposite response occurs, with increase in orexigenic and decrease in anorexigenic neuro- peptides [3,8-10]. MACRONUTRIENTS AS SIGNALING MOLECULES: LIPID SENSING The role of lipids on the regulation of feeding has been proposed since long time ago. In fact, one of the first hypotheses proposed to explain the periphery-brain interac- tion in the regulation of food intake was the Lipostatic Hypothesis. This model suggested that circulating lipids, produced in proportion to body fat stores and/or nutritional status, acted as signals to the brain, eliciting changes in energy intake and expenditure [11]. During the 1980s, some convincing evidence demonstrated the anorectic effect of peripheral lipid emulsion treatments [12]. However, in spite of these data, the specific molecular nature of the signal molecule remained unidentified until four years ago when, in a series of smart experiments, Rossetti and colleagues demonstrated that central administration of LCFAs exerted a signaling role within specific hypothalamic energy centers. For instance, intracerebroventricular (ICV) administration of oleic acid (OA, C18:1) inhibited food intake [13,14], an effect that was not reproduced by medium chain fatty acids (MCFAs), such as octanoic acid (C8) [13]. Of note, octanoic