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

López, Miguel; Lelliott, Christopher J.; Tovar, Sulay; Kimber, Wendy L.; Gallego, Rosalı́a; Virtue, Sam; Blount, Margaret; Vázquez, María J.; Finer, Nick; Powles, Trevor J.; O’Rahilly, Stephen; Saha, Asish K.; Diéguez, Carlos; Vidal-Puig, António

doi:10.2337/db05-1356

Cited by 140 publications

(193 citation statements)

References 50 publications

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“…7C). Consistent with prior reports (10,12,14,24), central infusion of TOFA had no significant effect on the basal (PBS/DMSO) level of food intake (Fig. 3A) or body weight (Fig.…”

supporting

confidence: 81%

“…We expected that the level of malonyl-CoA, the product of ACC, and/or palmitate, a direct product of the pathway, would be elevated. Both metabolites have been suggested to play significant roles in the hypothalamic controls of food intake and energy balance (8,(10)(11)(12)(13)(14)(15). In this report, we provide evidence supporting the hypothesis that ACC plays an important role in the hypothalamic intracellular signaling cascade underlying leptin's controls of food intake and energy balance.…”

supporting

confidence: 73%

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Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake

Gao

Kinzig

Aja

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

184

178

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Hypothalamic fatty acid metabolism has recently been implicated in the controls of food intake and energy homeostasis. We report that intracerebroventricular (ICV) injection of leptin, concomitant with inhibiting AMP-activated kinase (AMPK), activates acetyl-CoA carboxylase (ACC), the key regulatory enzyme in fatty acid biosynthesis, in the arcuate nucleus (Arc) and paraventricular nucleus (PVN) in the hypothalamus. Arc overexpression of constitutively active AMPK prevents the Arc ACC activation in response to ICV leptin, supporting the hypothesis that AMPK lies upstream of ACC in leptin's Arc intracellular signaling pathway. Inhibiting hypothalamic ACC with 5-tetradecyloxy-2-furoic acid, a specific ACC inhibitor, blocks leptin-mediated decreases in food intake, body weight, and mRNA level of the orexigenic neuropeptide NPY. These results show that hypothalamic ACC activation makes an important contribution to leptin's anorectic effects. Furthermore, we find that ICV leptin up-regulates the level of malonyl-CoA (the intermediate of fatty acid biosynthesis) specifically in the Arc and increases the level of palmitoyl-CoA (a major product of fatty acid biosynthesis) specifically in the PVN. The rises of both levels are blocked by 5-tetradecyloxy-2-furoic acid along with the blockade of leptinmediated hypophagia. These data suggest malonyl-CoA as a downstream mediator of ACC in leptin's signaling pathway in the Arc and imply that palmitoyl-CoA, instead of malonyl-CoA, could be an effector in relaying ACC signaling in the PVN. Together, these findings highlight site-specific impacts of hypothalamic ACC activation in leptin's anorectic signaling cascade.carnitine palmitoyltransferase ͉ long-chain fatty acyl CoA ͉ malonyl CoA ͉ oleic acid ͉ malonyl CoA decarboxylase E nergy balance is maintained by hypothalamic systems responding to hormonal and neural signals that sense body energy status (1). Leptin is an anorexigenic hormone secreted mainly from adipocytes that controls food intake and energy homeostasis primarily by acting at hypothalamic nuclei such as the arcuate nucleus (Arc) (1, 2). The Arc, the primary nucleus in the hypothalamus in mediating leptin's control of energy balance, contains first-order neurons that express leptin receptors and a variety of feeding-related neuropeptides such as neuropeptide Y (NPY), agouti-related peptide (AgRP), and ␣-melanocyte stimulating hormone (␣-MSH) (1). Leptin exerts its anorectic effects by modulating the levels of these neuropeptides. Activation of signal transducer and activator of transcription 3 (STAT3) and activation of phosphatidylinositol 3-kinase have been shown to play critical roles in leptin's hypothalamic intracellular signaling pathways (3, 4).Further aspects of leptin's hypothalamic intracellular signaling have been identified. Minokoshi et al. (5) have demonstrated that exogenous administration of leptin inhibits AMP-activated kinase (AMPK) in the Arc, and, based on the finding that constitutive activity of AMPK in the Arc prevents leptin's anorectic acti...

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“…7C). Consistent with prior reports (10,12,14,24), central infusion of TOFA had no significant effect on the basal (PBS/DMSO) level of food intake (Fig. 3A) or body weight (Fig.…”

supporting

confidence: 81%

supporting

confidence: 73%

Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake

Gao

Kinzig

Aja

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

184

178

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“…After 1 week of postsurgical recovery, cannula placements were verified by assessing a feeding response to ghrelin [20]. I.c.v.…”

Section: Treatmentsmentioning

confidence: 99%

C75 is converted to C75-CoA in the hypothalamus, where it inhibits carnitine palmitoyltransferase 1 and decreases food intake and body weight

Mera

Bentebibel

López-Viñas

et al. 2009

Biochemical Pharmacology

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runathan, et al.. C75 is converted to C75-CoA in the hypothalamus, where it inhibits carnitine palmitoyltransferase 1 and decreases food intake and body weight. Biochemical Pharmacology, Elsevier, 2009, 77 (6) 20-11-2008 Please cite this article as: Mera P, Bentebibel A, López-Viñas E, Cordente AG, Gurunathan C, Sebastián D, Vázquez I, Herrero L, Ariza X, Gómez-Puertas P, Asins G, Serra D, García J, Hegardt FG, C75 is converted to C75-CoA in the hypothalamus, where it inhibits carnitine palmitoyltransferase 1 and decreases food intake and body weight, Biochemical Pharmacology (2008Pharmacology ( ), doi:10.1016Pharmacology ( /j.bcp.2008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 3 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.

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“…All of the enzymes of the fatty acid synthesis pathway are expressed in the ventromedial nuclei of the hypothalamus. These include acetyl-CoA carboxylase, fatty acid synthase and malonyl-CoA decarboxylase (118,119) . Additionally, it has been demonstrated that nutritional status regulates hypothalamic malonyl-CoA levels and fatty acid synthase expression in a nucleus-specific manner, with fatty acid synthase and acetyl-CoA carboxylase levels downregulated by fasting and up-regulated by refeeding (119) .…”

Section: Hypothalamic Fatty Acid Metabolismmentioning

confidence: 99%

“…These include acetyl-CoA carboxylase, fatty acid synthase and malonyl-CoA decarboxylase (118,119) . Additionally, it has been demonstrated that nutritional status regulates hypothalamic malonyl-CoA levels and fatty acid synthase expression in a nucleus-specific manner, with fatty acid synthase and acetyl-CoA carboxylase levels downregulated by fasting and up-regulated by refeeding (119) . The extensive role of lipid metabolism in the hypothalamus has recently been revealed in mediating responses to both fasting (120) and peripheral hormones, particularly ghrelin (119,121,122) , with elevation of the long-chain fatty acyl Co-A in the ARC decreasing food intake and whole body glucose metabolism (19) .…”

Section: Hypothalamic Fatty Acid Metabolismmentioning

confidence: 99%

Hypothalamic dysfunction in obesity

Williams

2012

Proc. Nutr. Soc.

113

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A growing number of studies have shown that a diet high in long chain SFA and/or obesity cause profound changes to the energy balance centres of the hypothalamus which results in the loss of central leptin and insulin sensitivity. Insensitivity to these important anorexigenic messengers of nutritional status perpetuates the development of both obesity and peripheral insulin insensitivity. A high-fat diet induces changes in the hypothalamus that include an increase in markers of oxidative stress, inflammation, endoplasmic reticulum (ER) stress, autophagy defect and changes in the rate of apoptosis and neuronal regeneration. In addition, a number of mechanisms have recently come to light that are important in the hypothalamic control of energy balance, which could play a role in perpetuating the effect of a high-fat diet on hypothalamic dysfunction. These include: reactive oxygen species as an important second messenger, lipid metabolism, autophagy and neuronal and synaptic plasticity. The importance of nutritional activation of the Toll-like receptor 4 and the inhibitor of NF-kB kinase subunit b/NK-kB and c-Jun amino-terminal kinase 1 inflammatory pathways in linking a high-fat diet to obesity and insulin insensitivity via the hypothalamus is now widely recognised. All of the hypothalamic changes induced by a high-fat diet appear to be causally linked and inhibitors of inflammation, ER stress and autophagy defect can prevent or reverse the development of obesity pointing to potential drug targets in the prevention of obesity and metabolic dysfunction.Hypothalamus: Obesity: High-fat diet: Inflammation: Neuronal and synaptic plasticityThe developed world is currently facing an epidemic of obesity. Diseases associated with obesity, particularly type 2 diabetes, CVD, cancer, stroke and mental health issues, including dementia (1,2) are provoking a crisis in health care, adversely affecting health and life expectancy and increasing health care costs, estimated to be up to £45 billion by 2050 in the UK alone (3) . Direct and indirect costs of type 2 diabetes, for example, one of the major health consequences of obesity, are currently £21 . 8 billion and set to rise to £35 . 6 billion by 2035-36 in the UK (4) .Obesity is the result of a disproportionately high energy intake compared to energy expenditure and is a complex interaction between environmental and genetic factors (5) with monogenic defects being relatively rare (6) . It seems obvious that an energy-dense diet, high in saturated fat and sugar, should cause weight gain and increased adiposity; nonetheless it appears that these diets cause a profound change in energy balance that does not result from a simple increase in energetic intake. Diet composition, particularly the presence of long-chain saturated fats, results in metabolic dysfunction and increased adiposity and body weight, Abbreviations: AgRP, agouti-related peptide; ARC, arcuate nuclei; CART, cocaine and amphetamine-regulated transcript; CNTF, ciliary neurotrophic factor; ER, endoplasmic reticulum; I...

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

Cited by 140 publications

References 50 publications

Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake

Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake

C75 is converted to C75-CoA in the hypothalamus, where it inhibits carnitine palmitoyltransferase 1 and decreases food intake and body weight

Hypothalamic dysfunction in obesity

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