Fatty acid oxidation rates in the human body may regulate fat intake. Signalling regarding fatty acid oxidation in the liver and abdominal tissues is likely to be transmitted to the satiety centres of the brain including the central nucleus of amygdala, via the vagus and the Nucleus of tractus solitarius to effect a reduction in postprandial meal intake. Nutrition. 1999 Sep;15(9):704-14  A reduction in fatty acid oxidation has been shown to lead to overeating on a high fat diet. Physiol Behav. 2004 Dec 30;83(4):645-51.  by inducing a shortening of intermeal interval rather than  meal size.  Nutrition. 1999 Sep;15(9):704-14    Inhibition of hepatic fatty acid oxidation using mercaptoacetate in rats Am J Physiol. 1986 Jun;250(6 Pt 2):R1003-6. or etomoxir in humans Nutrition. 1999 Nov-Dec;15(11-12):819-28.   leads to increased food intake in the presence of a high fat diet.     Ketone body concentration may also be involved in this signalling to the central nervous system as evidenced by a reduction in fat intake induced by ketone body infusions. Br Poult Sci. 2001 Jul;42(3):405-8.
Fatty acid synthase (FAS) catalyzes the condensation of acetyl-CoA and malonyl-CoA to generate long-chain fatty acids in the cytoplasm.  FAS inhibition has been shown to facilitate weight loss through increased peripheral utilization of fat as well as reduction of food intake. Physiol Behav. 2005 May 3;  FAS  is expressed in various regions of the  brain, including arcuate and paraventricular nuclei (PVN).  FAS is co-localized with NPY in neurons in the arcuate nucleus. Fasting down-regulates liver FAS, but FAS levels remain high in hypothalamus even in the fasting state suggesting different regulatory mechanisms. C75, a specific inhibitor of fatty acid synthase, may alter food intake via interactions within the arcuate-PVN pathway mediated by NPY. Am J Physiol Endocrinol Metab. 2002 Nov;283(5):E867-79.   
 

Rodents:

C75 is a potent and specific inhibitor of fatty acid synthase (FAS) in central neurons that control feeding and also stimulates carnitine palmitoyltransferase-1 (CPT-1) resulting in peripheral energy expenditure. It causes anorexia and profound weight loss in lean and genetically obese mice. A single dose causes a rapid (>90%) decrease of food intake. Chronic C75 treatment decreased food consumption and increased energy expenditure due to increased fatty acid oxidation in both DIO (diet induced obese) and lean mice.

Lean vs. obese mice:

Food intake of lean and obese mice was altered in different ways by C75.  In lean mice, C75 suppressed food intake by 50% and, in obese mice (ob/ob and dietary-induced obesity), by 85-95% during the first day of treatment. Lean mice, however, became tolerant/resistant to C75 over the 2-5th days of treatment, with food intake returning to near normal. Rebound hyperphagia occurred on cessation of treatment.
In contrast, ob/ob obese mice responded to C75 with a >90% suppression of food intake throughout the same period with incipient tolerance becoming evident only after substantial weight loss had occurred. Diet-induced obese mice exhibited intermediate behaviour. In all cases, a substantial loss of body weight resulted.  C75-treated mice lost 24-50% more body weight than pair fed controls, indicating that C75 may increase energy expenditure in addition to suppressing food intake . The decrease in body weight by ob/ob mice was due primarily to loss of body fat. In contrast to the short-term effects of C75 on "fasting-induced" changes of hypothalamic orexigenic and anorexigenic neuropeptide mRNAs, repeated administration of C75 either had the inverse or no effect as tolerance developed. Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):1921-5

In obese mice, C75 rapidly suppressed food intake, reduced body weight, and normalized obesity-associated hyperglycaemia and hyperinsulinaemia. Like its effect in lean mice, C75 prevented the fasting-induced increase of hypothalamic NPY and AgRP mRNAs in obese mice, but had no effect on the expression of POMC and CART mRNAs. The suppressive effect of C75 on food intake in lean mice seems to be mediated both by NPY/AgRP and POMC/CART neurons, whereas in obese mice the effect seems to be mediated primarily by NPY/AgRP neurons.  Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):66-71.In both lean and obese mice, C75 markedly increased expression of melanin-concentrating hormone and its receptor in the hypothalamus.

Acute vs. Chronic Administration:

While acute C75 treatment in lean mice produce changes in neuropeptide Y, the reduced food consumption in chronic C75-treated DIO mice was accompanied by an increase in cocaine and amphetamine-related transcript (CART) expression and not by changes in neuropeptide Y (NPY). Am J Physiol Endocrinol Metab. 2004 Jan 21

A low dose of C75 administered  for 30 days in Ob/Ob mice reduced food intake by 62% and body weight by 43%, whereas body weight of ad lib-fed controls increased by 11%. Decreased food intake correlated with decreased expression of hypothalamic neuropeptide mRNAs for NPY, AGRP, and MCH and an increased expression of neuropeptide mRNAs for alpha-MSH (POMC) and CART. Biochem Biophys Res Commun. 2004 Apr 30;317(2):301-8

Route of administration:

Intraperitoneal injection of C75, causes a decrease in food intake by approximately 95% which may persist for at least 24 hours.C75 blocks the normal, fasting- associated, hypothalamic increases in neuropeptide Y (NPY)/Agouti-related protein (AGRP) expression and the decrease in proopiomelanocortin (POMC)/cocaine and amphetamine regulated transcript (CART) expression.  Intraperitoneal C75 administration seems toe work in two phases, a rapid initial phase via the NTS area postrema of the brainstem and a delayed phase via the Arcuate nucleus, LHA, and PVN of the hypothalamus. The latter phase correlates well with its ability to interfere with the fasting-induced effects on the expression of orexigenic (neuropeptide Y and agouti-related protein) and anorexigenic (POMC (alpha MSH) and CART) messages in the hypothalamus. Proc Natl Acad Sci U S A. 2003 May 13;100(10):5628-33
 

Mechanisms:

C75, an alpha-methylene-gamma-butyrolactone,is postulated to cause significant weight loss through decreased hypothalamic neuropeptide Y (NPY) production. C75 not only inhibits fatty acid synthase, but seems to stimulate CPT-1 enzyme. (carnitine O-palmitoyltransferase-1). C75 treatment of rodent adipocytes and hepatocytes increased fatty acid oxidation and ATP levels by increasing CPT-1 activity. Whole-animal calorimetry shows that C75-treated Diet Induced Obese (DIO) mice had a 50% greater weight loss, and a 32.9% increased production of energy because of fatty acid oxidation, compared with paired-fed controls. Peripherally, C75 reduces adipose tissue and fatty liver, despite high levels of malonyl-CoA. (vide infra)  Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9498-502

The Malonyl Co A connection:
Intracerebroventricular (i.c.v.) administration of C75 to fasted mice rapidly  increased  hypothalamic malonyl-CoA and blocked feeding when the mice were presented with food. Prior i.c.v. administration of an acetyl-CoA carboxylase inhibitor  at least partially  prevented the C75-induced rise of hypothalamic malonyl-CoA and prevented the C75-induced decrease of food intake. These effects correlated closely with the effects of i.c.v. C75 on the expression of hypothalamic orexigenic (reduced NPY and AgRP) and anorexigenic (increased  proopiomelanocortin) neuropeptide mRNA.  Thus the level of hypothalamic malonyl-CoA, which depends on the relative activities of acetyl-CoA carboxylase and FAS, could indicate energy status and mediates feeding behaviour. Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12624-9

C75 blocks the normal fasting-induced rise in blood free fatty acids and ketones. This may be due to either decreased adipose tissue lipolysis and hepatic ketogenesis, or increased fatty acid and ketone utilization by peripheral tissues, especially skeletal muscle. Biochem Biophys Res Commun. 2004 Apr 30;317(2):301-8 

When energy sources are low, AMP-activated protein kinase (AMPK), a sensor of peripheral energy balance, is phosphorylated and activated and increases food intake. AICAR, an activator of AMP-activated protein kinase (AMPK) increases food intake, whereas compound C, an inhibitor of AMPK decreases food intake. C75 decreases AMPK activity possibly by increasing hypothalamic neuronal ATP levels. C75 rapidly reduced the level of the phosphorylated AMPK alpha subunit  in the hypothalamus even in fasted mice. J Biol Chem. 2004 Mar 17  

Regulators:

Lipogenesis in humans, as assessed by glucose incorporation into lipids, was increased by insulin and a  combination of insulin and Dexamethasone. Insulin and Dexamethasone also significantly increased FAS expression, activity, and gene transcription rate . Linoleic acid, a PUFA, attenuated the actions of insulin and Dexamethasone on fatty acid and lipid synthesis as well as FAS activity and expression. The regions  responsible for hormonal regulation of the FAS gene has been localised, within which  an insulin response element has been demonstrated similar to the sequence identified in the rat FAS gene. Thus  lipogenesis in human adipose tissue can be induced by insulin, further enhanced by glucocorticoids, and suppressed by PUFA in a hormone-dependent manner. J Nutr. 2004 May;134(5):1032-1038

Orlistat is a novel inhibitor of the thioesterase domain of fatty acid synthase. Cancer Res. 2004 Mar 15;64(6):2070-5.

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    This page was last updated on: 07/03/2007

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