Figuring out how C75 acts

Here's a new article trying to sort out how C75 acts. For those of you who have tried to read any of the medical literature on appetite/feeding/satiety, you have probably realized that there are many hormones and neurotransmitters that influence food intake and energy expenditure.
These neuropeptides are made in the brain and/or in the GI tract. Figuring out how these systems overlap, interact and influence each other is a major focus of research in this area. Specifically, integrating the information to determine the pathways that regulate hunger/satiety is an area of active research. One part of this is to determine which peptides (small proteins) are 'upstream' or 'downstream' of the others, so as to figure out who influences whom. Here, the researchers look at that with respect to C75, a molecule that inhibits the enzyme Fatty Acid Synthase (FAS), and causes animals to stop eating and lose weight. They find that administering C75 causes a decrease in ghrelin release, and they propose that this leads to a change in expression of other neuropeptides (NPY, AgRP, POMC, etc) that ultimately results in less food intake. They propose a model for how this is all integrated. The abstract is below.

As far as I know, levels of Mal-CoA, which they propose as a central part of the 'energy-sensing system' has not yet been studied in PWS -- but several companies are looking at this part of the pathway as a therapeutic target in obesity.

Remember: orexigenic means stimulates food intake (examples: ghrelin, NPY, AgRP), while anorexigenic means inhibits food intake (PYY, orexin, POMC); c-fos expression is just a way these guys look at which neurons get 'turned on'.

Abstract of the article follows:


Effect of centrally administered C75, a fatty acid synthase inhibitor, on ghrelin secretion and its downstream effects Hu Z, Cha SH, van Haasteren G, Wang J, Lane MD. PNAS 102: 3972-77, 2005.

The central administration of the fatty acid synthase (FAS) inhibitor, C75, rapidly suppresses the expression of orexigenic neuropeptides [neuropeptide Y (NPY) and agouti-related protein (AgRP)] and activates expression of anorexigenic neuropeptides [proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART)] in the hypothalamus. The combined actions of these changes inhibit food intake and decrease body weight. Intracerebroventricular injection of C75 appears to rapidly inhibit the secretion of ghrelin by hypothalamic explants ex vivo and by the stomach in vivo. Ghrelin administered intracerebroventricularly reverses the anorexic effect of C75, suggesting that C75 acts upstream of ghrelin. Because ghrelin-producing neurons are known to form synapses onto NPY/AgRP neurons, we suggest that the reversal of C75-induced anorexia by ghrelin may be mediated by NPY/AgRP neurons. This hypothesis is supported by the finding that ghrelin reverses the C75-induced inactivation (assessed by c-Fos expression) of neurons in the arcuate nucleus that express NPY (assessed by immunohistochemical costaining). These effects closely correlate with appropriate changes downstream in the expression of the hypothalamic neuropeptides that regulate feeding behavior, i.e., down-regulation of the expression of NPY and AgRP and up-regulation of the expression of proopiomelanocortin/-melanocyte-stimulating hormone, provoked by C75 and reversed by ghrelin. We propose a model in which ghrelin secretion plays an intermediary role between malonyl-CoA, the substrate of fatty acid synthase, and the neural circuitry regulating energy homeostasis.

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Theresa Strong

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Theresa V. Strong, Ph.D., received a B.S. from Rutgers University and a Ph.D. in Medical Genetics from the University of Alabama at Birmingham (UAB). After postdoctoral studies with Dr. Francis Collins at the University of Michigan, she joined the UAB faculty, leading a research lab focused on gene therapy for cancer and directing UAB’s Vector Production Facility. Theresa is one of the founding members of FPWR and has directed FPWR’s grant program since its inception. In 2016, she transitioned to a full-time position as Director of Research Programs at FPWR. She remains an Adjunct Professor in the Department of Genetics at UAB. She and her husband Jim have four children, including a son with PWS.

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