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:
(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. Manipulating metabolic pathways for the treat-
ment of disease has once again placed basic metabo-
lism research at the forefront of biomedical science.

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