C75 inhibits food intake by increasing CNS glucose metabolism

Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, United States
Nature Medicine (Impact Factor: 27.36). 06/2003; 9(5):483-5. DOI: 10.1038/nm0503-483
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    • "It is noteworthy that the anorexic effects of FAS inhibition via C75 may not be due entirely to alterations in malonyl CoA content; Wortman et al. (2003) showed that the anorexigenic effects of C75 could also be attributed 248 to an increase in glucose metabolism, because C75 did not affect food intake in rats subjected to a ketogenic diet. However, if these animals were supplemented with sucrose (in drinking water), the C75 effect on appetite was restored. "
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    ABSTRACT: The central nervous system mediates energy balance (energy intake and energy expenditure) in the body; the hypothalamus has a key role in this process. Recent evidence has demonstrated an important role for hypothalamic malonyl CoA in mediating energy balance. Malonyl CoA is generated by the carboxylation of acetyl CoA by acetyl CoA carboxylase and is then either incorporated into long-chain fatty acids by fatty acid synthase, or converted back to acetyl-CoA by malonyl CoA decarboxylase. Increased hypothalamic malonyl CoA is an indicator of energy surplus, resulting in a decrease in food intake and an increase in energy expenditure. In contrast, a decrease in hypothalamic malonyl CoA signals an energy deficit, resulting in an increased appetite and a decrease in body energy expenditure. A number of hormonal and neural orexigenic and anorexigenic signaling pathways have now been shown to be associated with changes in malonyl CoA levels in the arcuate nucleus (ARC) of the hypothalamus. Despite compelling evidence that malonyl CoA is an important mediator in the hypothalamic ARC control of food intake and regulation of energy balance, the mechanism(s) by which this occurs has not been established. Malonyl CoA inhibits carnitine palmitoyltransferase-1 (CPT-1), and it has been proposed that the substrate of CPT-1, long-chain acyl CoA(s), may act as a mediator(s) of appetite and energy balance. However, recent evidence has challenged the role of long-chain acyl CoA(s) in this process, as well as the involvement of CPT-1 in hypothalamic malonyl CoA signaling. A better understanding of how malonyl CoA regulates energy balance should provide novel approaches to targeting intermediary metabolism in the hypothalamus as a mechanism to control appetite and body weight. Here, we review the data supporting an important role for malonyl CoA in mediating hypothalamic control of energy balance, and recent evidence suggesting that targeting malonyl CoA synthesis or degradation may be a novel approach to favorably modify appetite and weight gain.
    Pharmacological reviews 06/2010; 62(2):237-64. DOI:10.1124/pr.109.002428 · 17.10 Impact Factor
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    • "Quantitative and temporal changes in glucose concentration are closely monitored and integrated by specific subpopulations of “glucosensing” neurons in the CNS that are crucial to the regulation of feeding (6). A key finding to support the involvement of increased glucose use in mediating the effect of FAS inhibition is that rats on a very low carbohydrate diet, which forces them to produce ketone bodies that neurons use in preference to glucose (33), do not reduce their food intake in response to C75 (13). In accordance with those previous results, we observed that rats maintained on a ketogenic diet but given sucrose to prevent ketosis responded to C75. "
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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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    • "For instance, rats fed a carbohydrate-free diet and considered to be ketotic do not experience the hypophagia usually associated with i.c.v. administration of C75, possibly due to an inability to oxidize glucose (Wortman, et al., 2003). Previous studies in primary cortical neurons demonstrated increases in glucose oxidation upon addition of C75 (Landree, et al., 2004). "
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    ABSTRACT: Understanding the mechanisms that govern neuronal responses to oxidative and metabolic stress is essential for therapeutic intervention. In vitro modeling is an important approach for these studies, as the metabolic environment influences neuronal responses. Surprisingly, most neuronal culture methods employ conditions that are non-physiological, especially with regards to glucose concentrations, which often exceed 20mM. This concentration is a significant departure from physiological glucose levels, and even several-fold greater than that seen during severe hyperglycemia. The goal of this study was to establish a physiological neuronal culture system that will facilitate the study of neuronal energy metabolism and responses to metabolic stress. We demonstrate that the metabolic environment during preparation, plating, and maintenance of cultures affects neuronal viability and the response of neuronal pathways to changes in energy balance.
    Journal of Neuroscience Methods 02/2008; 167(2):292-301. DOI:10.1016/j.jneumeth.2007.08.028 · 2.05 Impact Factor
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