Effect of the anorectic fatty acid synthase inhibitor C75 on neuronal activity in the hypothalamus and brainstem

Abstract

c-fos ͉ arcuate nucleus ͉ paraventricular nucleus ͉ lateral hypothalamic area ͉ nucleus of the solitary tract͞area postrema P eripheral neural and hormonal signals that indicate global energy status are monitored in several regions of the brain, notably the hypothalamus and brainstem (1, 2). Within the hypothalamus, three interconnected regions, i.e., the arcuate nucleus (Arc), paraventricular nucleus (PVN), and lateral hypothalamic area (LHA), play important roles in regulating food intake and energy expenditure (1, 2). The Arc produces both orexigenic and anorexigenic neuropeptides that are sent to the LHA and PVN via dense projections (1, 2). The PVN is a heterogeneous nucleus richly supplied by axons projecting from the Arc, LHA, and brainstem and thus is the site of convergence of multiple neural inputs that affect food intake (1, 2). The LHA was viewed classically as a ''hunger center,'' because stimulation of this area of the hypothalamus increases food intake, whereas its destruction attenuates feeding and causes weight loss (1). The regulation of food intake also involves extrahypothalamic regions including the nucleus of the solitary tract (NTS) and the closely related area postrema (AP) in the brainstem (1, 2). Satiety information emanating from the gastrointestinal tract such as cholecystokinin generated during the course of a meal is primarily conveyed to the NTS͞AP by means of afferent fibers of the vagus nerve and afferents passing into the spinal cord from the upper gastrointestinal tract (1-7). The NTS sends projections to the PVN in the hypothalamus and is considered to be the first central relay nucleus in the process of termination of individual meals (1,6,8).Recent studies (9-13) showed that i.p. injection of fatty acid synthase (FAS) inhibitors, i.e., cerulenin and C75, dramatically reduces food intake and body weight in both lean mice and ob͞ob mice. In mice these effects do not result from visceral illness or malaise, because C75 administered i.p. at a dosage that resulted in Ͼ90% suppression of 24-h food intake did not induce conditioned taste aversion (12). The FAS inhibitors seem to act centrally, because when administered at much lower levels by intracerebroventricular (i.c.v.) injection, they cause marked reductions in food intake and body weight (9, 13). The anorectic effect of FAS inhibitors is elicited, at least in part, at the level of hypothalamus. Thus, C75 blocked the normal fasting-induced up-regulation of the hypothalamic orexigenic neuropeptide mRNAs for neuropeptide Y (NPY) and agouti-related protein (AgRP). Conversely, C75 blocked the normal fasting-induced down-regulation of the anorexigenic neuropeptide mRNAs for pro-opiomelanocortin and cocaine-amphetamine-related transcript in the hypothalamus (9, 10, 12).The present study was undertaken to identify the regions within the hypothalamus and the brainstem that are activated or suppressed by the FAS inhibitor C75 by using immunohistochemistry to assess c-Fos expression, a well established marker for neuronal activation (1...

Tamoxifen-Induced Anorexia Is Associated With Fatty Acid Synthase Inhibition in the Ventromedial Nucleus of the Hypothalamus and Accumulation of Malonyl-CoA

“…The expression of these neuropeptides is under the control of hormonal and nutritional signals (7)(8)(9)(10)(11)(12). More recently, it has been suggested that the precursors and break-down products of the fatty acid synthesis may be important metabolic signals regulating hypothalamic neuropeptides (10,13,14). The pathway of lipogenesis de novo and the hypothalamic levels of malonyl-CoA have been also identified as a key intermediate controlling food intake.…”

AMP-activated protein kinase in the brain

“…However, C75 also decreased feeding and body weight when administered into the brain by intracerebroventricular (i.c.v.) injection, 4,26,40,41 at doses considerably lower than effective peripheral doses, suggesting that C75 interacted directly with the brain to alter food intake. Although high doses of peripherally injected C75 produced conditioned taste aversion and other indices of malaise in rats, 42,43 C75 given i.c.v.…”

“…Our interest in hypothalamic AMPK grew from our work with C75. General brain injection of C75 in rodents decreases food intake and body weight, 4,26,40,41 so C75 exerts some of its weight loss effects by acting in CNS. Once we knew that C75 altered pAMPK in neurons in vitro, 8 we altered the brain and hypothalamic AMPK in mice using well-known pharmacological tools, and fed and fasted states, to demonstrate that AMPK was a physiological mediator of C75's effects.…”

Central lipid detection and the regulation of feeding behavior

“…Moreover, central administration of C75, a potent inhibitor of FAS, also increases malonyl-CoA concentration in the hypothalamus, suppresses food intake and leads to profound weight loss (Gao and Lane, 2003). It has been proposed that centrally, C75 and cerulenin -another inhibitor of FAS -alter the expression profiles of feeding-related neuropeptides (such as NPY), often inhibiting the expression of orexigenic peptides (Gao and Lane, 2003). C75 also increases energy consumption, which contributes to weight loss.…”

“…The molecular mechanisms relaying fatty acid action involve metabolites such as acylCoA or malonylCoA, which could be major fuel sensors and most of the enzymes involved in lipid metabolism are detected at high level in the hypothalamic nucleus that control feeding behavior like the ARC, DMN and VMN (Kim et al, 2002;Sorensen et al, 2002). Moreover, central administration of C75, a potent inhibitor of FAS, also increases malonyl-CoA concentration in the hypothalamus, suppresses food intake and leads to profound weight loss (Gao and Lane, 2003). It has been proposed that centrally, C75 and cerulenin -another inhibitor of FAS -alter the expression profiles of feeding-related neuropeptides (such as NPY), often inhibiting the expression of orexigenic peptides (Gao and Lane, 2003).…”