Tài liệu Báo cáo khoa học: Hypothalamic malonyl-CoA and CPT1c in the treatment of obesity pptx

MINIREVIEW Hypothalamic malonyl-CoA and CPT1c in the treatment of obesity Michael J. Wolfgang and M. Daniel Lane Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, USA Introduction All living organisms must maintain a homeostatic energy balance to survive fluctuations in environmental conditions such as the scarcity of food. For higher organisms, this involves storing energy as fat during periods of an abundant food supply to hedge against periods of food shortage. Today, humans have pushed storage too far, to the point of widespread obesity. Although obesity is preferable to starvation, this state frequently leads directly or indirectly to serious pathol- ogies including diabetes and heart disease. Interven- tions to diminish adiposity beyond diet and exercise would be greatly advantageous. The central and peripheral nervous systems play cru- cial roles in the regulation of metabolism, both glob- ally and in various organ systems. Even in organisms lacking a brain, such as Caenorhabditis elegans, the nervous system plays a key role in maintaining energy balance [1–4]. In more advanced, mammalian systems there is compelling evidence for the control of energy metabolism via the central nervous system (CNS), notably through the regulation of feeding behavior and satiety [5,6]. Furthermore, efferent neural signals to peripheral sites have been shown to directly and ⁄ or indirectly control diverse processes including beta-cell Keywords acetyl-CoA carboxylase; AMPK; carnitine palmitoyl-transferase-1c; diabetes; fatty acid; fatty acid synthase; malonyl-CoA; neurometabolism; nutrient sensing; obesity Correspondence M. J. Wolfgang, Department of Biological Chemistry, Johns Hopkins University School of Medicine, Center for Metabolism and Obesity Research, 475 Rangos Building, 725 N. Wolfe St., Baltimore, MD 21205, USA Fax: +1 410 614 8033 Tel: +1 443 287 7680 E-mail: mwolfga1@jhmi.edu (Received 10 August 2010, revised 29 Octo- ber 2010, accepted 3 December 2010) doi:10.1111/j.1742-4658.2010.07978.x Metabolic integration of nutrient sensing in the central nervous system has been shown to be an important regulator of adiposity by affecting food intake and peripheral energy expenditure. Modulation of de novo fatty acid synthetic flux by cytokines and nutrient availability plays an important role in this process. Inhibition of hypothalamic fatty acid synthase by pharma- cologic or genetic means leads to an increased malonyl-CoA level and sup- pression of food intake and adiposity. Conversely, the ectopic expression of malonyl-CoA decarboxylase in the hypothalamus is sufficient to pro- mote feeding and adiposity. Based on these and other findings, metabolic intermediates in fatty acid biogenesis, including malonyl-CoA and long- chain acyl-CoAs, have been implicated as signaling mediators in the central control of body weight. Malonyl-CoA has been hypothesized to mediate its effects in part through an allosteric interaction with an atypical and brain- specific carnitine palmitoyltransferase-1 (CPT1c). CPT1c is expressed in neurons and binds malonyl-CoA, however, it does not perform the same biochemical function as the prototypical CPT1 enzymes. Mouse knockout models of CPT1c exhibit suppressed food intake and smaller body weight, but are highly susceptible to weight gain when fed a high-fat diet. Thus, the brain can directly sense and respond to changes in nutrient availability and composition to affect body weight and adiposity. Abbreviations ACC, acetyl-CoA carboxylase; AMPK, 5¢ AMP-activated protein kinase; CNS, central nervous system; CPT, carnitine palmitoyltransferase; FAS, fatty acid synthase. 552 FEBS Journal 278 (2011) 552–558 ª 2010 The Authors Journal compilation ª 2010 FEBS function [7], adipose tissue lipolysis [8,9], muscle fatty acid oxidation [10,11] and hepatic gluconeogenesis [12], among others. Although much has been learned con- cerning the molecular mechanisms underlying how the brain senses and responds to nutrients, suitable targets for intervention in the nervous system–metabolism axis are still lacking. Metabolic sensing Endocrine signals from the pancreas, adipose tissue and gastrointestinal tract, as well as other sites, are known to reach the CNS to effect changes in feeding behavior and energy expenditure. Thus, insulin, leptin and ghrelin, as well as other hormones ⁄ cytokines, interact with their cognate receptors on neurons within the CNS that project to higher brain centers and to peripheral tissues to affect energy intake and expendi- ture. It has become apparent that certain regions of the brain, notably the hypothalamus, are also respon- sive to circulating nutrients that reflect the energy sta- tus of the animal. These nutrients too can provoke changes in feeding behavior and energy expenditure. For example, the hypothalamus can sense and respond to fluctuations in the levels of blood glucose [13], fatty acids [12,14,15] and certain amino acids [16]. A linkage between fatty acid synthesis in the CNS and feeding behavior was uncovered with the finding that systemic or intracerebroventricular administration of fatty acid synthase (FAS) inhibitors causes a dra- matic decrease in food intake and body weight, con- comitant with an increase in the level of its substrate, malonyl-CoA [17]. Consistent with these findings, genetic disruption of hypothalamic FAS was found to elicit similar effects [18]. Thus, it was postulated that malonyl-CoA may be the responsible signaling metab- olite that mediates the weight loss associated with FAS inhibition. Additional support for the direct involve- ment of malonyl-CoA is derived from the following: (a) food deprivation ⁄ fasting, which provokes the drive to eat, leads to lowered hypothalamic malonyl-CoA, whereas refeeding, which suppresses appetite, gives rise to elevated malonyl-CoA [13,19]; (b) the administra- tion of an inhibitor of acetyl-CoA carboxylase (ACC) that blocks malonyl-CoA formation reverses the weight-reducing phenotype induced by FAS inhibitors [17]; (c) exogenous delivery of a malonyl-CoA decar- boxylase expression vector to the ventral hypothala- mus, which lowers malonyl-CoA, reverses the effects of FAS inhibition [20] and results in obese rodents [21]; (d) changes in malonyl-CoA level in the hypothal- amus correlate closely and rapidly with reciprocal changes in the levels of the orexigenic and anorectic neuropeptide expression in the hypothalamus [22]. Thus an increase in malonyl-CoA promotes a decrease in neuropeptide Y and agouti related peptide in hypo- thalamic malonyl-CoA while promoting an increase in proopiomelanocortin and cocaine and amphetamine regulated transcript. Taken together, these findings provide a compelling argument for the role for malo- nyl-CoA in regulating feeding behavior. The question arises, what drives the changes in hypothalamic malonyl-CoA that affect feeding behav- ior under physiological conditions? Because glucose is the primary fuel for the CNS and blood glucose and hypothalamic malonyl-CoA levels fall and rise together during food deprivation and refeeding, it was reasoned that glucose metabolism per se may be a primary dri- ver for these responses. A substantial body of evidence supports this view. First, hypopthalamic malonyl-CoA is suppressed during fasting and increases upon refeed- ing [13,19]. This is not true for other areas of the brain such as the cortex, which is indicates that the hypotha- lamic region may specifically nutritionally control malonyl-CoA levels. Consistent with this is the close correlation with the hypothalamic levels of orexigenic and anorexigenic neuropeptide expression during fast- ing and refeeding. A detailed kinetic analysis of hypo- thalamic malonyl-CoA has shown that glucose is necessary and sufficient to alter malonyl-CoA concen- tration [13]. Furthermore, blood glucose concentra- tions peak  15 min before the increase in malonyl- CoA is observed. Moreover, the activity of 5¢ AMP- activated protein kinase (AMPK) correlates closely with malonyl-CoA concentration (see below) [23]. Therefore, we have suggested that malonyl-CoA, an intermediate in fatty acid biosynthesis, acts as a glucose-sensing mechanism in the hypothalamus [24]. During periods of nutritional surplus, carbon flux from carbohydrate, i.e. primarily glucose, is directed into the fatty acid synthesis pathway. Glucose metabo- lism in the CNS en route to fatty acids gives rise to ATP and NADH, and inhibits isocitrate dehydroge- nase, thereby increasing the level of citrate which is in equilibrium with isocitrate. Citrate exits the mitochon- dria and undergoes cleavage by cytoplasmic ATP: citrate lyase producing acetyl-CoA – the sole precursor of fatty acids. The initial and committed step of de novo fatty acid synthesis is the carboxylation of acetyl-CoA to form malonyl-CoA, catalyzed by ACC – the key reg- ulatory enzyme in the pathway. Malonyl-CoA serves as the basic chain-elongating substrate for the formation of long-chain saturated fatty acids catalyzed by FAS. It should be noted that cytoplasmic citrate is not only a precursor of acetyl-CoA, but also functions as a ‘feed- forward’ allosteric activator of ACC. M. J. Wolfgang and M. D. Lane Signaling mediators in the treatment of obesity FEBS Journal 278 (2011) 552–558 ª 2010 The Authors Journal compilation ª 2010 FEBS 553 In certain cell types, notably heart and skeletal myo- cytes, where little de novo fatty acid synthesis occurs, malonyl-CoA serves primarily as a regulator of fatty acid oxidation. As discussed below, malonyl-CoA reg- ulates fatty acid oxidation by inhibiting carnitine pal- mitoyltransferase-1 (CPT1) – an outer membrane enzyme required for entry of fatty acid into mitochon- dria. Thus, the steady-state level of malonyl-CoA in these tissues is determined by the relative activities of ACC and malonyl-CoA decarboxylase. Role of the AMP-dependent protein kinase AMPK, a nutrient-sensitive kinase, plays a pivotal role in mammalian energy metabolism [25,26]. AMPK was initially identified as the kinase responsible for inhibit- ing ACC and 3-hydroxy-3-methyl-glutaryl-CoA reduc- tase, the rate-setting enzymes of de novo fatty acid and cholesterol synthesis, respectively, thereby linking energy accessibility to energy-depleting biosyntheses. AMPK is now known to regulate a multitude of bio- logical processes [25,26]. Global energy status is monitored in the CNS by AMPK, which senses the [ATP] ⁄ [AMP] ratio [26]. When the [ATP] ⁄ [AMP] ratio in the hypothalamus is lowered due to reduced nutrient ⁄ glucose availability, AMPK is activated [23,27–29]. Phosphorylation of ACC by AMPK suppresses ACC activity and thereby lowers hypothalamic malo- nyl-CoA, which provokes an increase in food intake [13,23,30]. The AMPK system provides a rapid means of detecting energy status not dependent directly upon endocrine signals, although endocrine factors can impinge on its activity. Thus, the activity of ACC is an indicator of energy surplus and is thought to be one of the mechanisms by which energy homeostasis is mediated. Endocrine signals also impinge on hypothalamic AMPK because leptin, leptin-like hormones, ghrelin and adiponectin alter hypothalamic AMPK and malo- nyl-CoA levels [13,23,28,30–33]. The genetic evidence for the role of AMPK in the hypothalamus is less clear because the loss of the AMPKa2 subunit in specific hypothalamic cell types resulted in the opposite pheno- type to what was expected [34] and needs to be explored further. Other areas of the brain have also been shown to regulate feeding via AMPK [35,36]. Of interest is the extensive use of fructose as a sweetener in the human diet [37]. Glucose and fructose are isocaloric, however, there are important differences in their metabolism that inversely affect nutrient sig- naling pathways [27]. Whereas centrally administered glucose inhibits food intake [13], fructose increases food intake [38]. The ultimate catabolic fates of glu- cose and fructose are similar, however, fructose is tran- siently ATP depleting because fructose bypasses the rate-limiting regulatory step of glycolysis catalyzed by phosphofructokinase, which is used by glucose, but not fructose. This rapidly activates AMPK rather than inhibiting AMPK as glucose does. Therefore, fructose and glucose have opposing effects on malonyl-CoA concentration in the short-term [27]. Aside from the public health aspects of the affects of fructose on food intake, these findings lend further support to the mech- anism by which malonyl-CoA participates in the regu- lation of feeding behavior. Role of carnitine acyltransferases The brain and neurons in particular rely heavily on glucose as a primary energy source at all times [39]. During times of food deprivation, liver-derived ketones can be used by the brain to supplement glucose utiliza- tion, however, sustained blood glucose is required for the brain to function even in the face of high concen- trations of energy-rich blood ketones and fatty acids [39]. The oxidation of long-chain fatty acids for energy has long been thought to play a minor role in brain energetics. Although most cells containing mitochon- dria maintain some ability to beta-oxidize long-chain fatty acids, adult neurons do not robustly oxidize long-chain fatty acids [40]. The rate-setting step in long-chain fatty acid catabo- lism is the translocation of long-chain fatty acyl-CoAs from the cytoplasm, where they are made de novo or imported from the extracellular space, to the mito- chondrial matrix where the oxidative machinery is located [41–45]. This translocation is made possible via two transacylation reactions. The first is mediated by a malonyl-CoA-sensitive carnitine acyltransferase that is embedded in the outer mitochondrial matrix, CPT1. CPT1 enzymes transfer the acyl chain from coen- zyme A to carnitine. Acyl-carnitines can then traverse the mitochondrial membranes via organic cation trans- porters. Once in the matrix, the acyl chain is trans- ferred back to coenzyme A via the malonyl-CoA insensitive CPT2 [41–45]. There are at least six carnitine acyltransferases in mammals [46]. Carnitine acetyltransferase and carni- tine octonyltransferase mediate the transfer of acetyl and short- to medium-chain fatty acyl-CoAs. There are three long-chain carnitine fatty acyltransferases with different properties and tissue distribution. CPT1a is enriched in the liver and has been heavily studied due to the key role of beta-oxidation in gluconeogenesis Signaling mediators in the treatment of obesity M. J. Wolfgang and M. D. Lane 554 FEBS Journal 278 (2011) 552–558 ª 2010 The Authors Journal compilation ª 2010 FEBS and patients with hypomorphic mutations. CPT1b is enriched in muscle. Muscle, including cardiomyocytes, is a major user of fatty acids and CPT1b is an impor- tant regulatory step in that process. The most enig- matic carnitine acyltransferase has been the neuron- specific acyltransferase CPT1c [47]. As stated previ- ously, the brain is not a major user of long-chain fatty acids making a brain-specific isoform intriguing. CPT1c was identified and cloned from in silico sequences as a highly homologous member of the CPT1 class of enzymes and was shown to bind malo- nyl-CoA [47]. Interestingly, its tissue distribution was restricted to the brain. Being a malonyl-CoA binding protein that is restricted to neurons made it a tantaliz- ing effecter for the actions of malonyl-CoA [24]. Although it retains a high primary amino acid similar- ity, no laboratory has been able to demonstrate CPT1 enzymatic activity [47–50] although some have shown that it alters cellular acylcarnitine levels [50]. Clearly, it can not enhance fatty acid oxidation in heterologous systems as other members can. Two groups have produced mouse knockouts of CPT1c using independent strategies. Both knockouts show essentially identical phenotypes [49,51]. Under normal chow feeding, the mice have a small but signifi- cant suppression of feeding and body weight. This is the phenotype that was predicted, i.e. CPT1c controls food intake and is allosterically inhibited by malonyl- CoA. Given their decreased food intake, CPT1c knockout mice were also predicted to have decreased weight gain when fed a high-fat diet. When CPT1c knockout mice were fed a high-fat diet, paradoxically, they became obese although maintaining a lower food intake. This is accompanied by a suppression in energy expenditure. These data suggest that CPT1c can integrate carbohydrate and lipid nutrient sensing in the brain and is an example of an enzyme that can sense and respond to the nutritional environment. The major challenge to understanding the role of CPT1c is to determine its enzymatic activity and regulation and how this ultimately leads to complex behavioral phenotypes. Some groups have shown a role for CNS fatty acid oxidation in food intake and body weight largely attributed to CPT1a [14,15,52,53]. Many of these stud- ies rely heavily on inhibitors that may affect the newly identified and structurally similar CPT1c. Therefore, some of these studies need to be re-evaluated in light of the discovery of CPT1c. CPT1a is localized mainly in astrocytes and is upregulated in reactive astrocytes. CPT1c is expressed in neurons so CPT1c and CPT1a largely do not localize to the same cells in the brain, suggesting that they are functionally distinct. Although CPT1c is highly expressed in the hypothalamus, it is ubiquitously expressed in neurons throughout the body so its role is most likely broader than controlling body weight. Future directions Clearly, there is much left to be learned about neuro- nal nutrient sensing. A model is proposed whereby glu- cose and lipid flux in nutrient-sensitive neurons alters intermediary metabolites that ultimately lead to changes in the neural electrical or chemical potential (Fig. 1). Because the knockout of hypothalamic FAS and CPT1c do not fully phenocopy, either the knock- out of CPT1c is complicated by compensatory mecha- nisms or CPT1c is not the only effector in this pathway. Does malonyl-CoA have other neuronal spe- cific targets? It remains possible that malonyl-CoA could allosterically or even covalently alter other enzymes in neurons. Alternatively, the inhibition of neuronal long-chain fatty acid oxidation could contrib- ute to body weight control. The roles of long-chain fatty acyl-CoAs and long-chain fatty acid oxidation, which are both affected by the loss or inhibition of FAS, have been more difficult to understand in a phys- iologic context. Fig. 1. Model of how glucose and malonyl-CoA regulate body weight in hypothalamic neurons. Glucose flux through glycolysis and the tricarboxylic acid cycle provides the carbon substrate for malonyl-CoA as well as the NADH and ATP that is required to (a) inhibit isocitrate dehydrogenase to increase citrate concentrations and (b) inhibit AMPK thus derepressing ACC. The increase in mal- ony-CoA is thought to allosterically inhibit CPT1c to mediate changes in feeding behavior and body weight. ACC, acetyl-CoA car- boxylase; AMPK, 5¢ AMP kinase; CPT, carnitine palmitoyltransfer- ase; FAS, fatty acid synthase; MCD, malonyl-CoA decarboxylase; OAA, oxaloacetate; TCA, tricarboxylic acid. M. J. Wolfgang and M. D. Lane Signaling mediators in the treatment of obesity FEBS Journal 278 (2011) 552–558 ª 2010 The Authors Journal compilation ª 2010 FEBS 555 One of the biggest challenges to the field is the lack of experimental tools to investigate intermediary metabolites and lipids in general [54]. The application of ultrasensitive mass spectrometry techniques and metabolomics is exciting and has garnered interesting new avenues of research. Large-scale metabolite analy- sis, however, is far behind protein and nucleic acid techniques. Even with a technological leap in analysis (which is rapidly occurring), metabolites are short lived and it remains impossible to measure most metabolites or lipids at the single cell level. This is ever more important in the brain because it has an extraordi- narily diverse population of cells. The role of malonyl-CoA and other intermediary metabolites is an exciting area of research and poten- tially a therapeutic avenue to treat obese and diabetic people. 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Daniel Lane Department of Biological Chemistry, The. pro- mote feeding and adiposity. Based on these and other findings, metabolic intermediates in fatty acid biogenesis, including malonyl-CoA and long- chain acyl-CoAs,