Comparison of Central and Peripheral Administration of C75 on Food Intake, Body Weight, and Conditioned Taste Aversion

Procter & Gamble, Cincinnati, Ohio, United States
Diabetes (Impact Factor: 8.1). 12/2002; 51(11):3196-201. DOI: 10.2337/diabetes.51.11.3196
Source: PubMed

ABSTRACT 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.

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Available from: Matthew D Wortman, Nov 17, 2014
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    • "Similarly, ip injection of malaise-inducing doses of LiCl causes c-fos activation in the hypothalamic PVN and in the brainstem NTS [52]–[54]. Systemic injection of C75 produces conditioned taste aversion further supporting the notion of visceral illness [39], [55]. "
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    ABSTRACT: Sleep is greatly affected by changes in metabolic state. A possible mechanism where energy-sensing and sleep-regulatory functions overlap is related to lipid metabolism. Fatty acid synthase (FAS) plays a central role in lipid metabolism as a key enzyme in the formation of long-chain fatty acids. We studied the effects of systemic administration of C75, an inhibitor of FAS, on sleep, behavioral activity and metabolic parameters in mice. Since the effects of C75 on feeding and metabolism are the opposite of ghrelin's and C75 suppresses ghrelin production, we also tested the role of ghrelin signaling in the actions of C75 by using ghrelin receptor knockout (KO) mice. After a transient increase in wakefulness, C75 elicited dose-dependent and long lasting inhibition of REMS, motor activity and feeding. Simultaneously, C75 significantly attenuated slow-wave activity of the electroencephalogram. Energy expenditure, body temperature and respiratory exchange ratio were suppressed. The diurnal rhythm of feeding was completely abolished by C75. There was significant correlation between the anorectic effects, the decrease in motor activity and the diminished energy expenditure after C75 injection. We found no significant difference between wild-type and ghrelin receptor KO mice in their sleep and metabolic responses to C75. The effects of C75 resemble to what was previously reported in association with visceral illness. Our findings suggest that sleep and metabolic effects of C75 in mice are independent of the ghrelin system and may be due to its aversive actions in mice.
    PLoS ONE 02/2012; 7(2):e30651. DOI:10.1371/journal.pone.0030651 · 3.23 Impact Factor
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    • "Several laboratories have attempted to design anti-obesity drugs and modulate fatty acid metabolism to inhibit food intake. C75 is a synthetic inhibitor of fatty acid synthase (FAS) [1] and has been proposed as an anti-obesity agent since its administration decreases food intake and body weight in rodents [2] [3] [4] [5]. C75 can alter the metabolism of neurons in the hypothalamus, where an increase in the level of malonyl-CoA due to FAS inhibition serves as a secondary messenger of nutrient status, thereby mediating the suppression of food intake [6] [7]. "
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    ABSTRACT: Central nervous system administration of C75 produces hypophagia and weight loss in rodents identifying C75 as a potential drug against obesity and type 2 diabetes. However, the mechanism underlying this effect is unknown. Here we show that C75-CoA is generated chemically, in vitro and in vivo from C75 and that it is a potent inhibitor of carnitine palmitoyltranferase 1 (CPT1), the rate-limiting step of fatty-acid oxidation. Three-D docking and kinetic analysis support the inhibitory effect of C75-CoA on CPT1. Central nervous system administration of C75 in rats led to C75-CoA production, inhibition of CPT1 and lower body weight and food intake. Our results suggest that inhibition of CPT1, and thus increased availability of fatty acids in the hypothalamus, contribute to the pharmacological mechanism of C75 to decrease food intake.
    Biochemical pharmacology 12/2008; 77(6):1084-95. DOI:10.1016/j.bcp.2008.11.020 · 5.01 Impact Factor
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    • "Peripheral administration of the natural FAS inhibitor cerulenin (2,3-epoxy-4-oxo-6-dodecadienoylamide) or the synthetic inhibitor C75 (trans-4-carboxy-5-octyl-3-methylenebutyrolactone) causes profound dose-dependent anorexia and weight loss in several rodent models (12,13,15,16). Reduced food intake is also observed with central administration of much lower doses of C75, suggesting that the brain is the key site of action (12). "
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    ABSTRACT: Evidence links the hypothalamic fatty acid synthase (FAS) pathway to the regulation of food intake and body weight. This includes pharmacological inhibitors that potently reduce feeding and body weight. The mammalian target of rapamycin (mTOR) is an intracellular fuel sensor whose activity in the hypothalamus is also linked to the regulation of energy balance. The purpose of these experiments was to determine whether hypothalamic mTOR complex 1 (mTORC1) signaling is involved in mediating the effects of FAS inhibitors. We measured the hypothalamic phosphorylation of two downstream targets of mTORC1, S6 kinase 1 (S6K1) and S6 ribosomal protein (S6), after administration of the FAS inhibitors C75 and cerulenin in rats. We evaluated food intake in response to FAS inhibitors in rats pretreated with the mTOR inhibitor rapamycin and in mice lacking functional S6K1 (S6K1(-/-)). Food intake and phosphorylation of S6K1 and S6 were also determined after C75 injection in rats maintained on a ketogenic diet. C75 and cerulenin increased phosphorylation of S6K1 and S6, and their anorexic action was reduced in rapamycin-treated rats and in S6K1(-/-) mice. Consistent with our previous findings, C75 was ineffective at reducing caloric intake in ketotic rats. Under ketosis, C75 was also less efficient at stimulating mTORC1 signaling. These findings collectively indicate an important interaction between the FAS and mTORC1 pathways in the central nervous system for regulating energy balance, possibly via modulation of neuronal glucose utilization.
    Diabetes 10/2008; 57(12):3231-8. DOI:10.2337/db07-1690 · 8.10 Impact Factor
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