SCIENCE CHINA

Life Sciences
•REVIEW•.
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An overview of energy and metabolic regulation

*
Song Wen, Chaoxun Wang, Min Gong & Ligang Zhou

Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai 201399, China

Received July 5, 2018; accepted August 23, 2018; published online October 18, 2018

The physiology and behaviors related to energy balance are monitored by the nervous and humoral systems. Because of the
difficulty in treating diabetes and obesity, elucidating the energy balance mechanism and identifying critical targets for treatment
are important research goals. Therefore, the purpose of this article is to describe energy regulation by the central nervous system
(CNS) and peripheral humoral pathway. Homeostasis and rewarding are the basis of CNS regulation. Anorexigenic or orexigenic
effects reflect the activities of the POMC/CART or NPY/AgRP neurons within the hypothalamus. Neurotransmitters have roles
in food intake, and responsive brain nuclei have different functions related to food intake, glucose monitoring, reward pro-
cessing. Peripheral gut- or adipose-derived hormones are the major source of peripheral humoral regulation systems. Nutrients or
metabolites and gut microbiota affect metabolism via a discrete pathway. We also review the role of peripheral organs, the liver,
adipose tissue, and skeletal muscle in peripheral regulation. We discuss these topics and how the body regulates metabolism.
hedonic, POMC/CART, NPY/AgRP, neurotransmitter, brain nuclei, gut-derived hormone, gut microbiota, BAT

Citation: Wen, S., Wang, C., Gong, M., and Zhou, L. (2018). An overview of energy and metabolic regulation. Sci China Life Sci 61, https://doi.org/10.1007/
s11427-018-9371-4

INTRODUCTION tabolism. Specialized neurons in the hypothalamus and

Bodily functions and activities require fuel from intake of brainstem can sense the messages of energy intake and en-
food and nutrients. Food intake is influenced by conditions, ergy stores in the body. For many decades, researchers have
such as starvation, frequency of eating, and stress. Morbid focused predominantly on physical energy homeostasis, the
hyperphagia and obesity refer to the body’s inability to activities of which are governed predominantly by the nuclei
competently control energy homeostasis. An increasing within the hypothalamus, such as the arcuate nucleus (ARC)
amount of data has pointed to the role of key components in and paraventricular nucleus (PVN) (Schneeberger et al.,
both the central nervous systems (CNS) and peripheral hu- 2014). Various receptors of nutrient and hormonal signals
moral systems governing energy balance. In this review, we distributed to hypothalamic nuclei can be bound by their
discuss the roles of the CNS and humoral systems, micro- ligands derived during or immediately after a meal
biota, liver, brown adipose tissue (BAT) as well as the muscle (Adamska et al., 2014). For instance, the ARC can respond to
regulation to show how the body regulates metabolism. energy balance signals, such as leptin or GLP-1 (Baver et al.,
2014; Secher et al., 2014). However, the reward mechanisms
influencing our intake behaviors are also indispensable for
ENERGY AND METABOLIC REGULATION BY energy balance regulation. It is common that palatable food
THE CNS attracts increased intake even though an individual feels
Homeostatic and reward system sated. Thus, this hedonic behavior that overrides homeostatic
The brain has a central role in the regulation of energy me- eating if continued long term may contribute to over-
consumption and obesity (Zheng and Berthoud, 2008).
*Corresponding author (email: zhouligang@yahoo.com)
The reward system involves a hedonic and incentivized

© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2018 . . . . . . . . . . . . . . . . . . . . . . . life.scichina.com link.springer.com
2. . . . . . . . . . . . . . . . . . . . . . . . . . . Wen, S., et al. Sci China Life Sci ............................................ 2

motivational mechanism. A reward is an attractive and mo-
tivational property of a stimulus that induces pleasure, and in
the case of eating, it can cause inappropriate consumption
behavior (Schultz, 2015). The reward system wields distinct
actions through dissimilar brain regions and neural path-
ways, such as the corticolimbic (e.g., the hippocampus,
amygdala, prefrontal cortex) and mesolimbic structures (e.g.,
the ventral tegmental area (VTA), nucleus accumbens
(NAc), and striatum) (Figure 1). The corticolimbic system
represents the “liking” zone, whereas the mesolimbic system
represents “wanting” areas (Berridge et al., 2010; Egecioglu
et al., 2011). The mesolimbic dopamine system, especially
from the midbrain VTA to the forebrain NAc, is thought to
be the major rewarding pathway (Wise and Bozarth, 1987).

Figure 1 The illustration shows the reward system which contains links between midbrain and forebrain. Mesolimbic pathway contains contacts among
NAc, VTA, and Striatum whereas corticolimbic pathway contains links among the hippocampus, amygdala, and prefrontal cortex. DLPFC, dorsal lateral
prefrontal cortex; ACC, anterior cingulate cortex; Hippo, hippocampus.
3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
This pathway exerts a food intake promoting effect via do-
pamine signaling. The morbid obesity phenomenon may be
underlain by a reduction in dopamine receptor 2 (D2r) ex-
pression due to prolonged exposure to excessive palatable
food intake (Wang et al., 2001; Volkow et al., 2008). Another
finding suggested that hyperphagia in obese individuals may
reflect an altered balance between the “liking” and “wanting”
aspect of food rewards. Motivated actions to obtain palatable
food may increase to compensate for decreased pleasure for
food, which is similar to the mechanism underlying drug
addiction (Egecioglu et al., 2011). In addition to the genes
that encode similar feeding-related peptides (Olszewski et
al., 2008), these two systems can respond to similar per-
ipheral signals.
Anorexic and orexigenic effects
It is well known that food intake can be strongly driven by
two opposite behaviors: the anorexic effect inhibits feeding,
and the orexigenic effect stimulates food intake. Anatomical
and physiological evidence supports two main distinct series
of cells within the hypothalamus: orexigenic neurons that
express neuro-peptide Y (NPY) and agouti-related peptide
(AgRP) and anorexigenic neurons that express proopiome-
lanocortin (POMC) and cocaine- and amphetamine-regu-
lated transcript (CART) (Figure 2) (Sohn, 2015).
POMC neurons by post-transcriptional processing of
POMC express the peptide α-MSH, which has an anorexic
effect on food intake. Binding to the MC3R and MC4R on
second-order neurons influences metabolism and thereby
induces the anorexigenic effect (Fan et al., 1997). One study
showed that MC4R knockout mice or human individuals
with acquired MC4R mutants were associated with early
onset severe obesity (Huszar et al., 1997; Srisai et al., 2011).
CART is co-expressed with POMC within the ARC
(Chronwall, 1985) and suppresses food intake and con-
currently modulates energy expenditure (Wang et al., 2000).
CART can encourage satiety when presented to hypotha-
lamic second-order neurons (Lau and Herzog, 2014). Injec-
tion of CART can reduce feeding in rodents, and treatment
with CART antiserum reduces hypophagia (Kristensen et al.,
1998). Similarly, mutants or polymorphisms of the CART
gene have been associated with an increased incidence of
obesity (Challis et al., 2000).
Our previous studies demonstrated that POMC neurons
expressing the 5-HT2C receptor (5-HT2CR) can be activated
by serotonin (5-HT), which improves glucose metabolism.
The activation can trigger increased production of α-MSH
derived from precursor POMC. α-MSH acts on MCR4 dis-
tributed within the intermediolateral nucleus of the spinal
cord, which contains sympathetic preganglionic neurons.
Through this action, the function of pancreas islet endocrine
or GI tract hormone secretion could be improved, which
Wen, S., et al. Sci China Life Sci ............................................ 3
improves insulin resistance. Glucose utilization and insulin
sensitization will be improved in the liver and skeletal
muscle. A selective 5-HT2CR agonist was shown to induce
significant insulin-induced protein kinase B phosphorylation
and a decrease in glucose neogenesis enzymes, such as
phosphoenolpyruvate carboxykinase and glucose 6-phos-
phatase peripherally (Zhou et al., 2007). Activation of the 5-
HT1B receptor can also mediate the role of MC4R in both
POMC neurons and NPY/AgRP neurons, which can reduce
production of AgRP and inhibit GABA fibers projecting to
POMC/CART neurons from NPY neurons (Heisler et al.,
2006).
AgRP neurons are restricted to the ARC of the hypotha-
lamus, with most (~90%) expressing NPY (Anderson et al.,
2016). Administration of NPY centrally induces increased
food intake through binding to the Y1 or Y5 receptor (Beck,
2006; Nguyen et al., 2012) distributed within the ARC, PVN,
and ventromedial hypothalamus (VMH). NPY gene expres-
sion and the release of its product can be induced by fasting
condition accompanied by the observable c-fos expression
(Liu et al., 2012). Central administration of AgRP promotes
hyperphagia and weight gain, which concurrently blocks the
MC3R/MC4R (Schwartz et al., 2000).
Circulating nutrients and hormones may also have con-
current effects on the two subtype neurons. Elevated extra-
cellular glucose level activates POMC neurons, whereas
NPY/AgRP neurons are provoked in glucose-deprived con-
ditions. Long-chain fatty acids may also induce decreased
hypothalamic AgRP and NPY expression (Obici et al., 2002).
Increased malonyl CoA can also inhibit intake (Lane et al.,
2005). Leptin and CCK may enhance the action of POMC or
CART (Cowley et al., 2001).
Critical neurotransmitters or peptides related to central
regulation
Neurotransmitters act as central signals that coordinate the
activities of the homeostatic and reward systems. They act on
different correspondent receptors to induce effects on food
intake, energy expenditure, and body weight. Indeed, some
current medications available for obesity treatment are de-
signed to target certain neurotransmitters that effect energy
regulation through the CNS (Table 1).
Dopamine
Dopamine is the primary neurotransmitter related to rewards.
Dopamine-producing neurons in the substantia nigra (SN) of
the brainstem and the VTA in the midbrain project to the
brain nuclei or areas related to food reward (Levey et al.,
1993; Björklund and Dunnett, 2007; Taber et al., 2012).
Dopamine signaling pathway activation increases the
“wanting” property in the reward system (Peciña et al., 2003)
and can interact with a satiety signal, such as those associated
4. . . . . . . . . . . . . . . . . . . . . . . . . . . Wen, S., et al. Sci China Life Sci ............................................ 4

Figure 2 The two subtype neurons related to food intake locate in the ARC. One subtype neurons express POMC/CART. It acts on melanocortin receptor
(MCR) by α-melanocyte stimulating hormone (α-MSH), which generates anorexigenic effect. In contrast, NPY/AgRP expressed neurons may lead to
orexigenic effect via either NPY binding to Y1R and Y5R or AgRP indirectly blocking the activation of α-MSH on MCR. 3rd V, the third ventricle; VMN,
ventromedial nucleus; MC3R/MC4R, melanocortin receptor 3/4; Y1R/Y5R, neuropeptide receptor 1/5.

with leptin and GLP-1 (Hommel et al., 2006; Mietlicki-
Baase et al., 2013). Binding to the D1 receptor (D1r) in-
creased palatable food intake and decreased normal chow
intake, whereas activation of the D2r or D3 receptor showed
the opposite outcome in rodents (Cooper and Al-Naser,
2006). It is thought that evaluation of the reward process
relies on activation of the dopamine D2r (Baik, 2013). As
referred to previously, a deficit in D2r signaling may con-
tribute to excessive intake to compensate for reduced plea-
sure during eating (van de Giessen et al., 2014). However,
pharmacological intervention targeting the dopaminergic
(DA) system has shown various outcomes in human and
animal studies (Bojanowska and Ciosek, 2016), which sug-
gests that targeting of the DA system may be a promising
approach but currently needs further investigation to unravel
the complicated effects of the DA system on food intake.
Endocannabinoids
Two major endocannabinoids affecting fat intake are ana-
ndamide (N-arachidonoylethanolamide) and 2-arachidonoyl
glycerol produced from cell membrane phospholipids fol-
lowing cell stimulation. Generated centrally and periph-
erally, both eventually bind to the cannabinoid receptor 1
(CB1) predominantly distributed in the CNS, which affects
food intake. CB1 exerts its orexigenic effect mainly by ac-
tivating the cells of the NAc and interacting with the leptin,
ghrelin, DA, and opioidergic signaling pathways within or
beyond the hypothalamus (Pagotto et al., 2006). When in-
fused in rats, which were randomly provided a 3-component
diet containing carbohydrates, protein, and fat, the rats in-
creased their carbohydrate intake; this suggests that en-
docannabinoids may selectively influence the appetite for
macronutrients (Escartín-Pérez et al., 2009). The CB1 an-
tagonists showed a tendency to selectively reduce appetizing
food intake, such as of sucrose or chocolate-flavored pellets
(Arnone et al., 1997; Droste et al., 2010). Consistent with
these findings, normal human subjects who had received
CB1 antagonist therapy showed decreased responses in
certain neural areas related to rewarding observed by func-
tional magnetic resonance imaging (fMRI) (Horder et al.,
2010). Therefore, utilization of antagonists of CB1 may at-
tenuate appetizing food intake and be useful for obesity and
type 2 diabetes mellitus (T2DM) therapy.
Orexin
Orexin A and B act as orexigenic neuropeptides. The neu-
rons that produce these neuropeptides are located within the
lateral hypothalamic area (LHA), perifornical area, dor-
5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Wen, S., et al. Sci China Life Sci ............................................ 5

a)
Table 1 Summary on neurotransmitters in relation to energy balance regulation

Categorizes Neurotransmitter Derivations Projection Receptor Food intake Energy Body weight
expenditure
NAc, striatum, VTA,
Anandamide hypothalamus, *
Endocannabinoids (AEA) brainstem, In situ (presynaptic) CB1r Orexigenic Decrease Increase
hippocampus, medulla
NAc, striatum, basal
ganglia, amygdala,
2-Arachidonoyl hypothalamus, In situ (presynaptic)
*
CB1r Orexigenic Decrease Increase
glycerol (2-AG) brainstem,
hippocampus, medulla
Perifornical area, LH, VTA, ventromedial pre-
Orexins Orexin DMH, posterior frontal cortex, hypotha- OXR1, OXR2 Orexigenic Increase Decrease
hypothalamus lamus, brainstem

Hypothalamus, Hypothalamus, singu-

Opioids Endorphins pituitary gland, late cortex, hippocam- μ-Opioid recptor Orexigenic Decrease Increase
brainstem pus, locus coeruleus,
NAc
Hypothalamus,
Enkephalin neurohypophysis, Nac, VP, Nac, hypothalamus μ-, δ-Opioid Orexigenic Decrease Increase
receptor
amygdala
Hypothalamus, VTA, Hypothalamus, VTA,
Dynorphin Nac Nac, brainstem κ-Opioid recptor Orexigenic Decrease Increase

Biogenic amines Dopamine VTA, SN Prefrontal cortex, Nac, D1r,D2r, D3r, Orexigenic/ Decrease Increase
striatum D4r anorexigenic
Locus coeruleus, Hypothalamus,
Noradrenaline lateral tegmental prefrontal cortex, Nac, α, β receptor Orexigenic/ Decrease/
#
Decrease/#
field amygdala anorexigenic increase increase

Hypothalamus, Nac, 5-HT1A, 5-HT1B,

Caudal nuclei, rostral VTA, SN, hippocampus,
Serotonin nuclei amygdala, prefrontal 5-HT1D, 5-HT2C, Anorexigenic Increase Decrease
cortex 5-HT4, 5-HT6

Hypothalamus, NAc,
Histamine Tuberomammillary VTA, hippocampus, H1r Anorexigenic Increase Decrease
nucleus amygdala, prefrontal
cortex
Forebrain nuclei, Orexigenic/ #
Acetylcholine Acetylcholine brainstem nuclei, Hypothalamus, VTA M3, α3, α7, β4 anorexigenic Increase Decrease
hypothalamus
Hypothalamus, VTA, Hypothalamus, VTA,
Amino acids Glutamate striatum, brainstem Nac, hippocampus mGlu 5 Orexigenic Increase Decrease

Gamma-Amino- Hypothalamus, VTA, Hypothalamus, VTA, Orexigenic/ Decrease/# Decrease/#

butyric acid striatum Striatum GABA A, GABA B anorexigenic# increase increase
(GABA)
Peptides CRF PVN Neurohypophysis CRF2 receptor Anorexigenic Increase Decrease
AgRP ARC Hypothalamus MC3R/MC4R Orexigenic Decrease Increase
NPY PVN Hypothalamus Y1/Y5 receptor Orexigenic Decrease Increase

Oxytocin PVN, amygdala, Hypothalamus, VTA, Oxytocin receptor Anorexigenic Increase Decrease
BNST Nac, brainstem
a) *, This type of neurotransmitter acts as a retrograde signal released from postsynaptic and bind to receptor localized on presynaptic. #, The effect of this
neurotransmitter depends on activation on the certain subtype of receptor.

somedial hypothalamus (DMH), and posterior hypothala-
mus. The orexins bind to orexin receptor 1 and 2 (OXR1 and
OXR2). Within the hypothalamus, OX1R is most highly
expressed in NPY neurons within the VMN, whereas OXR2
is predominantly expressed in the PVN (Trivedi et al., 1998).
Central administration of an orexin antibody or an OX1R
antagonist has been shown to decrease food intake (Haynes
et al., 2000; Yamada et al., 2000). Injection of orexin led to
enhanced motivation for food seeking (Borgland et al.,
2009). Orexins can simultaneously increase food intake and
energy expenditure eventually to decrease body weight.
Endogenous opioid peptides
There are opioid peptides (e.g., enkephalins, endorphins,
dynorphins) and receptors (κ (KOR), δ (DOR), μ (MOR)
opioid receptors) that extensively exist in the CNS. Espe-
cially, β-endorphins are derived from the POMC. Increases
in hypothalamic endocannabinoid expression have been
shown to lead to orexigenic feeding accompanied by upre-
gulated expression of POMC, which seems paradoxical at
6. . . . . . . . . . . . . . . . . . . . . . . . . . . Wen, S., et al.
first sight; however, an increase in POMC reflects the en-
hanced expression of β-endorphins, which can be attenuated
by opioid receptor blockade (Koch et al., 2015). These
findings suggest an interaction between the opioid system
and endocannabinoid system. Previous studies support that
stimulating μ-opioid receptors by opioid agonists can cause
an increased desire for appetizing foods, which suggests that
use of opioid antagonists can prevent morbid energy intake
predisposing to obesity (Peciña and Smith, 2010). However,
μ-receptor antagonists in rodent studies have shown ambig-
uous results, whereas in human studies, treatment with μ-
receptor antagonists showed a decrease in the response to
palatable food in reward areas reflected by fMRI (Rabiner et
al., 2011; Murray et al., 2014; Yeomans and Gray, 1996;
Langleben et al., 2012).
Oxytocin
In addition to regulation of reproductive functions and its
effect on social behaviors, oxytocin has also been referred to
as a hypothalamic neuropeptide that has an anorexigenic
effect on palatable food intake (Onaka et al., 2012). Rodent
studies have shown that endogenous oxytocin selectively
suppressed carbohydrate intake (Olszewski et al., 2010).
Peripherally injected oxytocin also has been shown to reduce
food intake both in humans and rodents (Morton et al., 2012;
Ott et al., 2013).
Noradrenaline
Noradrenaline either enhances or inhibits food intake by
acting on different receptors. Activation of α1-, β2-, and β3-
adrenoceptors decreased food intake, whereas stimulation of
the α2-adrenoceptor increased food intake (Adan et al.,
2008). The related pathway is via the prefrontal cortex,
which affects decision making in rodents through dopamine
release derived from NAc in the presence of appetitive food.
This finding suggests that the DA and noradrenergic systems
share the same target for controlling food intake (Ventura et
al., 2007). Otherwise, noradrenaline can be involved in
regulation through a connection from the brainstem to the
hypothalamus (Wellman, 2000) and amygdala (Savard et al.,
1983).
Serotonin
Serotonin (5-HT)-producing neurons in the CNS extend
projections to the area known to be involved in reward, such
as the NAc, VTA, SN, hippocampus, amygdala, and pre-
frontal cortex (Hensler, 2006; Lechin et al., 2006; Ikemoto,
2010). Seven receptor families and multiple subtypes are
distributed in the CNS (Lam et al., 2010; Hayes and
Greenshaw, 2011). The central 5-HT1A, 5-HT1B or human
counterpart 5-HT1D, 5-HT2C, 5-HT4, and 5-HT6 receptors
have been determined to have distinct roles in food intake
regulation (Garfield and Heisler, 2009; Voigt and Fink,
Sci China Life Sci ............................................ 6
2015). As previously shown, 5-HT can be involved in me-
tabolism regulation via melanocortin circuits that lead to
improved metabolism.
Histamine
Histamine induces an anorexigenic effect after it activates
the histamine receptor (H-1r) in the VMN (Teff and Kim,
2011; Torrealba et al., 2012). Activation of H-1r has also
been determined to affect anticipatory food reward behavior.
However, given that histamine is primarily released from the
tuberomammillary nucleus, especially during the appetitive
phase of feeding in rats, it only induces transient anorexia
rather than a sense of satiety (Valdés et al., 2010). Another
study also found that histamine in the combination of ser-
otonergic and cholinergic medication may regulate food in-
take, whereas respective activation by antagonists had no
effect on food intake (Hartfield et al., 2003).
Acetylcholine
Acetylcholine is colocalized with POMC within the hy-
pothalamus and can bind to muscarinic M3, nicotinic β4, and
probably α7 receptors to influence food intake (Yamada et
al., 2001; Mineur et al., 2011; McFadden et al., 2014). An-
other study demonstrated that application of α3 and β4 ni-
cotinic receptor antagonists reduced food intake and
prevented weight gain in rats (Taraschenko et al., 2011).
Studies have shown that nicotine can enhance energy ex-
penditure and affect food preferences (Audrain-McGovern
and Benowitz, 2011; Geha et al., 2013), which in turn results
in sweeter flavors of ingested food than sensed by non-
smokers, but it also lowers body weight in active smokers
and is associated with weight gain after cessation of smoke
(Allen et al., 2005; Chiolero et al., 2008; Stadler et al., 2014).
Glutamate
As an excitatory neurotransmitter, glutamate can affect me-
tabolism regulation via metabotropic glutamate receptor 5
(mGlu 5) (Bradbury et al., 2005). The VTA can be an origin
site where glutamate is produced. Peripheral glutamate in-
jection can affect feeding centers, such as the ARC or lateral
hypothalamus (LH) by either direct infiltration through the
blood-brain-barrier (BBB) or indirect activation of vagal
afferent neurons (Torii et al., 2013). Recent data has shown
that variations in the genes related to glutamate action or
alteration of glutamatergic receptor expression in regions
related to rewards could affect food intake or be responsible
for obesity (Brownley et al., 2015; Locke et al., 2015). In-
jection of mGlu 5 antagonists has been shown to suppress
food intake (Bisaga et al., 2008).
GABA
GABA acts as an inhibitory neurotransmitter and binds to
GABA A and GABA B receptors to influence food intake. At
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the ARC level, GABA neurons receive input from AgRP
neurons and attenuate the anorexic effect induced by POMC
neurons (Cansell et al., 2012). Similarly, GABA can act on
the VTA dopamine system to affect reward feeding (van
Zessen et al., 2012). When binding to the GABA A receptor
within the VMN, GABA induces an orexigenic signal (Ka-
matchi and Rathanaswami, 2012), whereas utilization of
GABA A receptor antagonists leads to increased perception
of sweetness in milk and selective fat intake when separately
infused into the anterolateral hypothalamus and the medial
ventral pallidum (Kelly et al., 1977; Covelo et al., 2014).
Peripheral administration of a GABA B receptor agonist was
shown to suppress food intake and to possibly selectively
reduce motivation or appetite for certain palatable food both
in rodents and humans (Sato et al., 2007; Arima and Oiso,
2010).
Corticotropin releasing factor
Corticotropin releasing factor (CRF) has been shown to play
a pivotal role in stress and eating disorders. Food restriction,
commonly known to be a stressor, has been determined to
cause altered CRF expression in the hypothalamus (Lenglos
et al., 2013). CRF can be a functional antagonist to NPY and
AgRP expression under stress. Substantial evidence has
pointed to the role of CRF2 receptor in reduced feeding.
Infusion of a CRF2 receptor agonist in the lateral septum
reduced intake and encouraged anxiety-like behavior in rats
(Bakshi et al., 2007). Administration of urocortin (UCN)-1,
an endogenous CRF2 receptor agonist, was found to induce
anorexic behavior in rats, which was blocked by 5-HT2cR
activation. This result suggests that 5-HT signaling activation
regulates the CRF system in stress-related eating disorders
(Harada et al., 2014). These studies demonstrated that the
CRF system is an indispensable signal in both stress and
energy balance regulation.
Critical brain nuclei for homeostasis and food rewarding
Compiled data have suggested that nuclei can be classified
into the following three categories: (i) brain nuclei related to
food intake, (ii) brain nuclei related to blood-glucose reg-
ulation, and (iii) brain nuclei related to food-rewarding be-
havior.
Brain nuclei related to food intake
The ARC. The ARC is located beneath the third ventricle and
near the median eminence. Studies have shown that the BBB
here may not be completely impermeable. Therefore, the
ARC may provide easy access to circulation and early de-
tection of nutrients and hormones (Re´thelyi, 1984). Satur-
able glucose transporter isoform-1 (GLUT1) mediates the
entry of glucose, which has a predominant distribution in the
BBB (Cardoso et al., 2010).The hypothalamic ARC ex-
Wen, S., et al. Sci China Life Sci ............................................ 7
presses receptors, such as leptin, GLP-1, and insulin, which
can activate POMC neurons and inhibit NPY/AgRP neurons
to mediate food intake (Maejima et al., 2011; Patterson et al.,
2011; Baggio and Drucker, 2014). The AgRP neurons within
the ARC are mainly distributed homogeneously throughout
the rostrocaudal axis, whereas POMC neurons are located in
the anterior and medial areas (Anderson et al., 2016). Neu-
rons within the ARC can then be activated to influence
downstream second-order neurons, such as PVN or DMH.
Nucleus of solitary tract (NTS). The NTS is anatomically
not far from the area postrema (AP). The NTS and AP as well
as the dorsal motor nucleus of the vagus constitutes the
dorsal vagal complex. The DVC is a critical neural con-
nection between the gut and brain. Signals of metabolism,
such as leptin, ghrelin, and glucagon-like peptide-1 (GLP-1)
as well as GIGI satiation signals relayed by the vagal nerve
were found to be eventually processed by neurons within the
NTS (Grill and Hayes, 2012). The NTS is also a major site
from which endogenous GLP-1 is derived. Preproglucagon
neurons located in the NTS synthesize endogenous GLP-1
that spreads throughout the CNS (Trapp and Cork, 2015).
The NTS has been shown to have extensive relationships
with other nuclei related to food intake in CNS. Current
research found that the majority of NTS neurons are glucose
responsive and can be specifically targeted by α-MSH, which
implies a link with the ARC (Mimee and Ferguson, 2015).
The norepinephrine neurons here were shown to link with the
mesolimbic area, such as the VTA and NAC (Richard et al.,
2015). Some studies have implicated the noradrenergic A2
population of DBH-expressing cells in the NTS’ role in sa-
tiety (Rinaman, 2003; Kreisler et al., 2014), which is in ac-
cordance with subsequent research results showing that
dopamine b-hydroxylase- and cholecystokinin (CCK)-ex-
pressing neurons within the NTS can spread to the lateral
PBN and suppress orexigenic eating (Roman et al., 2016).
Additionally, oxytocin signaling in the medial NTS leads to
food intake inhibition, and this effect was partly mediated by
GI satiation signals within the NTS that cause an NTS in-
teraction with the PVN on food intake (Ong et al., 2015).
Parabrachial nucleus (PBN). PBN neurons within this re-
gion mainly express the calcitonin gene-related peptide
(CGRP), and activation of CGRP PBN neurons or their
projections in the central nucleus of the amygdala (CeA) can
decrease feeding (Roman et al., 2016). Studies have con-
sistently shown that stimulation of GLP-1 receptors ex-
pressed here reduced intake and decreased body weight in
rats, which suggests a role of PBN in the GLP-1 anorexic
effect (Richard et al., 2014).
PVN. The PVN is located next to the dorsal horn of the
third ventricle. The PVN neurons act as second-order neu-
rons in the melanocortinergic neuronal circuit innervated by
the POMC and NPY/AgRP neurons from the ARC (Cone,
2005). Several critical peptides released in the PVN, such as
8. . . . . . . . . . . . . . . . . . . . . . . . . . . Wen, S., et al.
oxytocin, thyrotropin-releasing hormone, corticotrophin-
releasing hormone, and nesfatin, have roles in food intake.
Additionally, the PVN is indispensable in mediating the
anorexic effect of GLP-1, which has a downstream effect on
the hypothalamic-ituitary-drenal axis or hypothalamic-itui-
tary-hyroid axis related to energy balance (Katsurada et al.,
2014).
Brain nuclei related to blood-glucose regulation
VMN. The VMN is located in the upper ARC, receives in-
puts from the ARC, and extends its axons to the diverse
neurons related to energy metabolism, such as the PVN, LH,
NTS, or dorsomedial hypothalamic nucleus.
Neurons within the VMN synthesize steroidogenic factor 1
and release brain-derived neurotrophic factor (BDNF) (Par-
ker and Schimmer, 1997; Unger et al., 2007). Selective de-
letion of the BDNF gene in the VMN of mice induced
hyperphagia and obesity. Similarly, genetic function muta-
tion of the BDNF receptor tropomyosin receptor kinase B
leads to a morbid intake effect and severe obesity both in
humans and rodents, which suggests that BDNF possesses a
satiety trait (Yeo et al., 2004).
Studies have shown that the VMH, which contains the
ARC and VMN, contains a high density of glucose-sensing
neurons called “glucose-excited” (GE) or “glucose-
inhibited” (GI) glucose-sensing neurons (Figure 3). GE
neurons depolarize in the presence of elevated plasma glu-
cose levels, and the activity of GI neurons is enhanced with
decreasing glucose level (Dunn-Meynell et al., 2002). Stu-
dies have shown that GE neurons express peptides that exert
an anorexic effect, whereas GI neurons in this area release
orexic peptides, which counter-regulate hypoglycemia
(Murphy et al., 2009).
AMPK has been shown to involve both GE and GI activity
(Routh et al., 2014). As a type of cellular fuel sensor, acti-
vated AMPK due to the elevated ratio of ADP/ATP or AMP/
ATP is regarded as the key component in the process of
glucose sensing. AMPK promotes feeding behavior by in-
creasing energy intake and glucose production, and reduces
thermogenesis. Particular hormones, such as adiponectin,
ghrelin, leptin, and GLP-1, have been shown to interact with
AMPK to mediate energy regulation (Huynh et al., 2016).
The mechanism underlying GE neuronal function is si-
milar to that of β-cells within the pancreatic islet. GK is the
crucial component in GE sensing (De Backer et al., 2016).
When transported into the neurons via glucose transporter 2
(GLUT2), glucose is phosphorylated by glucokinase and
leads to a series of downstream effects. GLUT2 has been
shown to play the vital role of glucokinase in glucose sen-
sing. If GLUT2-mediated glucose detection is inhibited, food
intake will be augmented (Stolarczyk et al., 2010). The role
of GE neurons in reaction to changed glucose levels is to
stress the hyperglycemia under regulation of insulin, which
Sci China Life Sci ............................................ 8
may be disturbed under pathological conditions. This effect
was demonstrated by a study that showed peripheral insulin
resistance in db/db mice and fa/fa Zucker rats also led to GE
neurons resistant to insulin action (Cotero et al., 2010). GK is
also a crucial component in GI sensing which is similar to
GE (Kang et al., 2006). Besides GK, GI neurons also depend
on nNOS and AMPK. The VMN nNOS-GI mechanism is
clearly regulated by changes in AMPK activity, which results
in a series of activities, including chloride channel closure,
membrane depolarization, and intensified action potential
frequency (Fioramonti et al., 2010). Studies have shown that
the role of GI cells is to counter-regulate hypoglycemia
through glucagon and epinephrine.
Medial amygdalar nucleus (MAN). The MAN is a limbic
area that possesses another group of glucose-sensing neu-
rons. It is well acknowledged that hypoglycemia causes a
series of responses involving activation of the sympathetic
nervous system and release of hormones, including gluca-
gon, epinephrine, and growth hormone (Cryer et al., 2003).
Our study found that the glucose-sensing neurons in the
medial amygdala nucleus could be responsive to hypogly-
cemia via UCN3 acting on the CRF2 receptor. Neurons of
MAN have a reciprocal link with the VMH in the hypotha-
lamus, and UCN3 neuronal fibers have been shown to be the
main input to the VMH. One third of UCN3 neurons can be
activated in hypoglycemia to regulate blood sugar by in-
itiating food intake. Hypoglycemic glucoprivic of MAN or
VMH did not elicit a hypoglycemic counter-regulation hor-
monal response immediately; however, glucoprivation
combined with mild to moderate systemic hypoglycemia can
cause a counter-regulation hormonal response in normal
mice. This finding suggests that MAN or VMH has a central
role in initiation of a hypoglycemic counter-regulation re-
sponse (Zhou et al., 2010).
Brain nuclei related to food-rewarding behavior
The primary brain nuclei related to food rewarding constitute
the DA system from the midbrain to the forebrain. Two
noticeable DA pathways exist: one from the VTA to the
ventral striatum, termed the “Satiety” pathway related to
satiety in food-rewarding behavior and another from the SN
to the dorsal striatum, termed the “Hedonistic” pathway for
promoting rewarding behavior in addition to its previous role
in the motor regulation (Figure 4). It has recently been de-
termined that the dorsal and ventral striatum can receive
discrete nutrient information from intestinal segments. Stu-
dies have found that the duodenum can convey a heightened
sense of sweet to the dorsal striatum, which leads to in-
creased intake of sugars, whereas jejunum signals commu-
nicate with the ventral striatum that has a role in food satiety
signaling to terminate a meal.
Projection from the VTA to the ventral striatum. The VTA
lies along the midline of the midbrain near the SN and red
9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Wen, S., et al. Sci China Life Sci ............................................ 9

+
Figure 3 The activation of GE neuron involves elevated ATP/ADP ratio due to increased glucose consumption which results in the K ATP channel’s
closure and depolarization. However, the GI neurons are activated via either metabolism dependent or independent way in a low glucose background.
Metabolism dependent GI neuron is mainly a nNOS-GI neuron due to the nNOS which catalyze the NO production being detected in this type of neuron. The
−
activation requires AMPK and closure of Cl channel, whereas independent GI mainly express Orexin or AgRP, and may be evoked by glucose structure itself
rather than its metabolite. This process may require K2P and Twik-related acid-sensitive potassium-like (TASK) 1/3 channels. SGLT, sodium-dependent
glucose transporters; GLUT4, glucose transporter type 4; TCA, tricarboxylic acid cycle; GK, glucose kinase; AMPK, AMP-activated protein kinase; NO,
nitric oxide; nNOS, nitric oxide synthase 1 (neuronal); sGC, soluble guanylate cyclase; K2P channel, two pore potassium channel; TASK1/3 channel, TWIK-
related acid sensitive potassium channel1/3; TWIK, tandem of P domains in a weak inwardly rectifying potassium channel.

nucleus and is rich in dopamine neurons. The VTA is widely from distal intestines, project their axons to the ventral
implicated in drug and natural reward addiction. Recent striatum, and terminate at the neurons within the ventral
studies have shown that VTA neurons can receive signals striatum, which may lead to enhancement of satiety during a
10 . . . . . . . . . . . . . . . . . . . . . . . . . . Wen, S., et al.
Figure 4 There are two major DA pathways involved in food rewarding
manner, one originates from the VTA, and targets the ventral striatum,
which is related to feeding satiety to end the eating; another pathway
derives from the SN and terminates on the dorsal striatum, which is a
hedonistic pathway promoting food intake.
meal to terminate further intake.
Projection from the SN to the dorsal striatum. Recent
findings showed that the dorsal striatum may play a role in
food-rewarding behavior. Nutrients in the duodenum may
convey “hedonistic or enjoyable” signals to the neurons in
the SN, which interacts with the dorsal striatum to promote
further intake. Duodenal-jejunal bypass surgery can curb
sugar cravings in mice by decreasing sugar intake-induced
dopamine release specifically in the dorsal striatum. In ad-
dition to the energy restriction foregut or hindgut hypothesis
of this surgery, Han et al. stated that recurrent exposure to
sugar may postpone the satiety of sugar intake, whereas
bariatric surgery may perturb this effect via blocking of the
link to the dorsal striatum. They found that duodenal glucose
infusions induced significantly greater dopamine release in
the dorsal striatum than did equivalent jejunal infusions, and
activation of dopamine D1r expression neurons by in-
tracerebral laser stimulation can mimic the glucose influx in
the duodenum, which can reverse the duodenal-jejunal by-
pass surgery effect on energy metabolism (Figure 4) (Han et
al., 2016).
LH. The LH is in the hypothalamic region and serves to
incorporate and process metabolic and reward-related in-
formation. Some LH neurons rightly link with midbrain DA
neurons that act on the forebrain. The studies that adopt
lesion, stimulation, and anatomical methodologies have re-
cognized that the LH has a powerful influence on the desire
for eating, drinking, and moving.
The LHA is composed of a narrow line of tissue upon the
whole length of the rostral-caudal hypothalamus. Three main
subpopulations of LHA neurons exist that coordinate dis-
crete energy cues and behavioral responses: melanin-con-
Sci China Life Sci ........................................... 10
centrating hormone, orexins/hypocretins, and neurotensin-
expressing cells (Brown et al., 2015). The last one possesses
anorexigenic attributes that have been shown to involve the
major neurotensin receptor (NtsR) type 1 (Feifel et al.,
2010). Binding to NtsR-1 facilitates the inhibitory effect on
feeding induced by leptin (Sahu et al., 2001); however, a
deficiency in NtsR-1 in mice may affect the response to
leptin, which suggests that leptin acts on the LH to affect
energy balance regulation (Kim et al., 2008).
Overlap and interaction between homeostatic and hedonic
nuclei
Although we classified three categories of major critical
brain nuclei and areas, these structures are not completely
independent from the others given the basis of multiple
complicated interconnections among them and simultaneous
functions. Evidence suggests that these two systems, in fact,
interact with each other (Williams, 2014). First, the GLP-1
projections from the NTS to the NAc and VTA have a role
through which meal-related gut signals may influence pa-
latability, motivation for food, and meal size. Second, orexin
projections from the LHA to the NTS and AP act as a
pathway through which cues that predict food rewarding
may respond to increased motivation for food and suppress
satiation. Moreover, studies have also revealed that leptin-
sensitive neurons (not the GLP-1 neurons) in the NTS in-
fluence motivation and food-seeking behavior. Infusion of a
ventricle subthreshold dose of leptin into the medial NTS
suppressed responses to sucrose and reversed high-fat food-
conditioned preferences (Kanoski et al., 2014). Similar to
GLP-1 neurons, leptin-sensitive neurons in the NTS respond
to meal-related GI signals, such as gastric distention (Huo et
al., 2007). Finally, an increasing body of knowledge suggests
that PVN oxytocin neurons simultaneously affect both
homeostatic and hedonic systems. Oxytocin neurons can be
activated by leptin and CCK and have been proposed to
mediate at least some aspects of GI nutrient-induced satia-
tion (Olszewski et al., 2010). These neurons also project to
the VTA (Sofroniew, 1983; Vaccari et al., 1998) In conclu-
sion, it is suggested that the circuitry of energy homeostasis
and that of food rewarding are, in fact, mutually affected.
ENERGY AND METABOLISM REGULATION
BY PERIPHERAL BIO-SUBSTANCES
Peripheral hormone regulation
Peptides released from the gut send energy signals to the
brain. These signals are delivered mainly through activation
of the afferent vagus nerve, which in turn can inform the
brainstem and hypothalamus. On the other hand, peptides
from the gut or adipose tissue can travel by circulation and
infiltrate the BBB through the corresponding transporters in
11 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Wen, S., et al. Sci China Life Sci ........................................... 11

the hypothalamus or near the brainstem (Table 2; Figure 5).
CCK
CCK is a type of intestinal peptide hormone, and its structure
is very similar to that of gastrin. It is secreted by the I-cells in
the first segment of the intestine (Moran, 2000). CCK re-
ceptors are G protein-coupled receptors, termed CCK-A or
CCKB. CCK can also act as a neurotransmitter in CNS and
mostly exerts a satiation effect via the CCK-A receptor
(Lieverse et al., 1995; Beglinger et al., 2001). Administration
of selective agonists and antagonists has proved the anor-
exigenic trait of CCK; however, the anorexigenic effect does
not have a long-term effect on caloric intake in rodents (West
et al., 1984).
PYY
PYY is released from L cells of the intestine. It is a member
of the pancreatic polypeptide family. PYY3–36 is the active
isoform in circulation postprandially (Grandt et al., 1994).
Activation of the Y2 receptor in the CNS has an impact on
energy regulation (Batterham et al., 2002). A defect in PYY
signaling may be implicated in the development of obesity,
and its concentration in circulation may become normalized
after bariatric surgery (le Roux et al., 2006). The activation
site of PYY covers the ARC, brainstem, and corticolimbic
pathway, such as the orbitofrontal cortex, which can be ac-
tivated to make food less rewarding (D’Agostino and Small,
2012).
GLP-1
GLP-1 is the expression product of the proglucagon gene in
L cells of the ileum and proximal colon or hindbrain in the
CNS (Drucker, 2006; Trapp and Cork, 2015), and gut-
derived GLP-1 is secreted postprandially. The two biologi-
cally active isoforms are GLP-1 (7–37) and GLP-1 (7–36)
NH2, and the latter is the major active isoform in the cir-
culation. GLP-1 can suppress food intake via activation
neurons within the hypothalamus, brainstem, and rewarding
pathways as well as via activation of the vagal afferent
neurons and other involved mechanisms, such as delaying of
gastric emptying.
Ghrelin
Ghrelin is encoded by the preproghrelin gene from the GI
tract. GOAT is the enzyme responsible for ghrelin acylation
and has a role in ghrelin’s physiological activity (Yang et al.,
2008). Ghrelin can induce hunger and weight gain in both
rodents and humans when it acts on vagal afferent neurons,
which in turn affects CNS areas related to energy home-
ostasis (Date et al., 2002). The orexigenic effect centrally
involves activation of GHSR1a receptors in the ARC of the
hypothalamus, which affects NPY/AgRP neuronal activity
(Kamegai et al., 2001). Ghrelin can also activate food reward
areas in response to food stimuli, as reflected by fMRI,
which suggests a role in the reward mechanism (Kroemer et
al., 2013; Goldstone et al., 2014). The critical role of ghrelin
is to prevent hypoglycemia because ablation of ghrelin-
producing cells in adults induce profound hypoglycemia
after prolonged caloric restriction (McFarlane et al., 2014).
Insulin
Insulin enters the brain from the circulation via the BBB to
activate hypothalamic neurons, which induces an anorexi-
genic effect. By binding to receptors highly expressed in
POMC/CART and NPY/AgRP neurons, it decreases NPY
and stimulates POMC expression (Porte et al., 2005).
Otherwise, insulin was determined to affect the VTA DA
concentration via upregulation of DA transporters to depress
DA reuptake, which suggests that insulin has a role in reward
regulation (Mebel et al., 2012).

Table 2 Summary on major peripheral hormone involved in energy regulation

Categories Hormone Derivation Effective form Target Receptor Pathway action Food intake
Gut-peptide Pancreas, hypothalamus, G13-RhoA-PLD/
hormone CCK I-cell, duodenum CCK-58 vagus nerve CCK-A/B r β-arrestin Anorexigenic

PYY L-cell, Ileum, colon PYY3–36 Pancreas, Y2r PI3K/PLC-ERK Anorexigenic

gastrointestine, brain
GLP-1 (7–36) amide, Pancreas, brain, cAMP-PKA-AMPK/
GLP-1 L-cell, Ileum, colon GLP-1 (7–37) vagus nerve GLP-1r p44 42MAPK Anorexigenic

Ghrelin Ghrelinergic cells, Ghrelin Hypothalamus, vagus GHS-r1a mTORC1-S6K1 Orexigenic

gastrointestine nerve, mesolimbic
Pancreatic
hormone PP PPcell, pancreas PP Brain, vagus nerve Y4/5r PI3K/PLC-ERK Anorexigenic

IRS-PI3K-AKT-FoxO1/
Insulin β-cell, pancreas Insulin Whole body IR mTOR Anorexigenic

Adipose-peptide Leptin Adipose cell, adipose Leptin Hypothalamus, adipose OB-R PI3K-AKT-FoxO1/ Anorexigenic
hormone tissue (WAT) tissue JAK-STAT3
Hypothalamus, adipose
Adiponectin Adipose cell, WAT Adiponectin tissue, muscle Adipo-R AMPK/PPARα Anorexigenic
12 . . . . . . . . . . . . . . . . . . . . . . . . . . Wen, S., et al. Sci China Life Sci ........................................... 12

Figure 5 The illustration above displays the interaction between gut, adipose tissue and brain in rodents. The signals derived from adipose tissue or GI tract
either have impact upon hypothalamus via infiltrating a leaky BBB, or link the NTS in the brainstem via acting on receptors within vagal afferents. These
signals induce activities of nuclei such as ARC and NTS, which may in turn affect second order neurons within PVN or VMN; other nuclei related to reward
such as VTA or NAc may also be involved in. GLP-1, glucagon like peptide-1; PYY, peptide YY; PP, pancreatic peptide; GI tract, gastrointestinal tract.

Leptin
Leptin is derived from adipose tissue. It is also known as the
“satiety hormone”. As an anorexigenic hormone in circula-
tion, its concentration fluctuates with feeding and increases
postprandially to suppress further intake (Leibowitz et al.,
2006). Moreover, the leptin concentration in the body re-
flects the fuel status because a higher concentration of leptin
has been found under obese conditions, which suggests that
leptin resistance exists. Activation of the leptin receptors
results in increased POMC transcription and suppressed
transcription of AgRP (Villanueva and Myers, 2008; Morris
and Rui, 2009).
Adiponectin
Adiponectin is also derived from adipose tissues; its role in
energy regulation is to promote energy consumption and its
signaling has been determined to improve insulin sensitivity,
reduce insulin resistance, and reduce atherosclerosis (Ya-
mauchi et al., 2014). There are two types of receptors: adi-
ponectin receptor 1 (AdipoR1) and AdipoR2 (Yamauchi et
al., 2007). The metabolic effect of liver AdipoR1 may be
involved in activating AMPK, whereas AdipoR2 is involved
in activation of PPARα, which leads to increased insulin
sensitivity (Yamauchi et al., 2002; Yamauchi et al., 2003).
There is evidence suggesting adiponectin activity in the
brain, such as in the ARC and PVN (Hoyda et al., 2009;
Psilopanagioti et al., 2009; Sun et al., 2016).
Nutrient regulation
Nutrient-related signals may have an effect on CNS. Besides
glucose, lactate, referred to as a metabolic waste previously,
has also been shown to regulate metabolism, such as by
promoting insulin secretion, and mostly acts by signaling via
the CNS (Sola-Penna, 2008). It has been proposed that the
enhanced hypothalamic lactate metabolism alters signaling
13 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
to the brain and to the whole body, which results in decreased
liver glucose production (Chari et al., 2008). Free fatty acids
(FFAs) bind to FFA receptors and can affect metabolism
(Hara et al., 2014). Infusion of FFA centrally affects insulin
secretion and insulin sensitivity via altering the activity of
GE or GI within the VMH (Le Foll et al., 2013). A recent
study determined the signaling pathway of ketone body β-
hydroxybutyrate, which is involved in the starvation re-
sponse during nutrient deprivation and ensures energy
homeostasis (Rojas-Morales et al., 2016). The branched
chain amino acid (BCAA) L-leucine, suppresses food intake
when administered into the third ventricle. This effect may
involve action on hypothalamic mammalian target of rapa-
mycin (Cota et al., 2006). Studies have also shown that
elevated BCAA concentrations in plasma are associated with
obesity and insulin resistance (Newgard et al., 2009; Adams,
2011; Adeva et al., 2012). This finding suggests that BCAA
acts as a satiety signal. β-Aminoisobutyric acid, which is a
small-molecule metabolite of BCAA, has been shown to
increase browning of white WAT in response to physical
activity and is inversely associated with cardiometabolic
risks (Roberts et al., 2014).
Gut microbiota
Multiple studies have identified the role of gut microbiota.
Short-chain fatty acid (SCFA) metabolites generated by gut
microbiota can regulate gut hormones, such as CCK, GLP-1,
PYY, and leptin. Food rich in plant fibers can influence the
microbiota, and their metabolites, such as acetate, propio-
nate, and butyrate, have an effect on host energy homeostasis
(Schwiertz et al., 2010). These SCFAs act as key signaling
molecules, with activation of both FFAR2 and FFAR3 to
modulate host adiposity or GLP-1 secretion (Samuel et al.,
2008; Tolhurst et al., 2012). Butyrate activates intestinal
gluconeogenesis (IGN) gene expression through a cAMP-
dependent mechanism, whereas propionate, itself a substrate
of IGN, activates IGN gene expression via the gut-brain
neural circuit involving FFAR3 (De Vadder et al., 2014).
Studies have found a distinction between the microbiota of
normal individuals and obese individuals or patients with
T2DM (Qin et al., 2012; Karlsson et al., 2013). Additionally,
these pre-clinical studies also proved that using fecal trans-
plantation of modifying rodents’ microbiota may improve
metabolism (de Clercq et al., 2017). Transfer of intestinal
microbiota from obese mice resulted in significantly greater
adiposity in recipients than did transfer of microbiota from
lean donors (Bäckhed et al., 2007). Microbiota-related dys-
function creates a predisposition toward a range of disorders,
including metabolic syndrome, neurodevelopmental dis-
orders, autoimmune diseases, and allergic diseases (Shana-
han, 2012).
Wen, S., et al. Sci China Life Sci ........................................... 13
CRITICAL ORGANS OR TISSUES IN
PERIPHERAL METABOLIC REGULATION
Role of the liver in energy balance regulation
With the advent of an increased incidence of nonalcoholic
fatty liver disease (NAFLD), it is time to re-examine the role
of the liver in energy metabolism. Although there are cur-
rently various attribution theories on this disease, such as
mitochondrial hyperfunction, it is accepted that the patho-
physiology is related to energy dysregulation in the liver. In a
physiological state, the liver acts as a hub involved in mac-
ronutrients (e.g., glucose, lipid, protein) and small molecules
(e.g., vitamin, peptide, iron) metabolism essential for
homeostasis and affects various metabolic tissues, including
skeletal muscle and adipose tissue. Food and small mole-
cules can be digested and taken up by GI cells and absorbed
into the circulation of the liver, which facilitates further
processing. The liver acts as a producer of chemicals that can
convert multiple nutrients or metabolites into substances that
benefit the body’s discrete metabolic needs. For instance,
glucose can be synthesized into glycogen or other substances
and stored by the liver in the presence of insulin after a meal,
whereas in the starvation state, it can be produced increas-
ingly through the glycogenolysis or gluconeogenesis pro-
cesses de novo. These processes are affected by regulators,
such as hormone milieus (e.g., insulin, glucagon, gluco-
corticoids) and metabolic states (e.g., post-meal, fasted, ex-
ercise), which have effects on the activity of critical
enzymes, such as phosphoenolpyruvate carboxylase cata-
lysis in gluconeogenesis.
The liver also communicates with the CNS, skeletal
muscles, adipose tissue, and the gut. First, the CNS directly
innervates the liver and modulates energy metabolism via
either the sympathetic or parasympathetic nervous system.
The sympathetic system generally increases hepatic glucose
production by promoting glycogenolysis and mobilizing the
other forms of fuel for gluconeogenesis, whereas the para-
sympathetic system counteracts it. Multiple hormones can
indirectly influence liver activity via activation of the re-
ceptors of hypothalamus cells, such as insulin, which sti-
mulates the PI 3-kinase/Akt pathway in the brain (Ramnanan
et al., 2011). Second, skeletal muscles consume energy and
produce lactate and amino acids, which are eventually de-
livered to the liver, thus providing the gluconeogenic sub-
strates for hepatocytes to synthesize glucose that can be
utilized by muscle. A study also revealed that IL-6 can be
generated by skeletal muscle as a myokine that has an effect
on the liver to increase hepatic glucose production during
exercise (Febbraio et al., 2004). Third, crosstalk between the
liver and adipose tissue has been shown by the finding that
adipocytokines, such as adiponectin generated by adipo-
cytes, can influence hepatic metabolism and fibroblast
growth factor 21 (a hormone mainly derived from the liver in
14 . . . . . . . . . . . . . . . . . . . . . . . . . . Wen, S., et al.
the fasted state), can affect the adipocyte response to lipo-
lysis, and release adiponectin (Xu et al., 2003; Lin et al.,
2013). Finally, given that the liver port vein system linked
the liver and the gut, this connection allows for nutrients, gut
hormones, and metabolites (especially derived from gut
microbiota) to access the liver and thus directly regulate the
liver metabolism (Henao-Mejia et al., 2012). On the other
hand, the gut-brain axis can be an indirect method of gut-
liver cross talk that requires an intact vagal nerve pathway to
modulate liver metabolism. In conclusion, the liver is an
essential nutrient metabolism producer and is metabolically
linked with both the CNS and multiple insulin-sensitive
peripheral organs or tissues, such as skeletal muscle, adipose
tissue, and gut. Therefore, in addition to pharmacological
targeting of intracellular key molecules, rearrangement of the
proper links of these organs and tissues may be important for
curing obesity, insulin resistance, NAFLD, and T2DM, in
future therapeutic strategies.
BAT in peripheral metabolic regulation
Peripheral BAT thermogenesis regulation is dependent on
sympathetic outflow to it. The adipocytes accumulated in
BAT provide the binding receptors involved in metabolism
(the β3-adrenergic receptors). After binding to receptors,
adrenaline triggers cyclic adenosine monophosphate, which
activates mitochondrial uncoupling protein-1 (UCP-1) re-
sulting in greater thermogenesis. The preoptic area (POA)
has been shown to directly affect sympathetic premotor
neurons derived from the rostral raphe pallidus to regulate
sympathetic outflow to the BAT (Morrison, 2004). Other-
wise, POA neurons may mediate thermoregulatory responses
via the projection to DMN neurons (Yoshida et al., 2009).
Sympathetic outflow to the BAT can be adjusted by certain
nutrient signals or hormones, such as glucose or GLP-1
(Rahmouni et al., 2004; Lockie et al., 2012). Administration
of an MC3R/MC4R agonist centrally evokes BAT through
sympathetic outflow, which suggests that the melanocortin
system can regulate BAT thermogenesis (Brito et al., 2007).
Brown-like fat adipocytes, also named “beige” or “brite”
adipocytes, are located across the inguinal subcutaneous area
of rodents as well as the supraclavicular, pericardial, para-
aortic, and suprarenal areas as well as areas surrounding the
trachea, pancreas, or kidney in humans. Although UCP-1 is
weakly expressed in beige adipocytes under basal conditions,
higher expression can be induced under extreme conditions,
such as cold temperatures (van Marken Lichtenbelt et al.,
2009). The browning of WAT in a rodent study was shown to
encourage energy consumption and improve diet-induced
obesity (Seale et al., 2011). Therefore, regulation of WAT
browning is an ideal methodology for obesity and metabo-
lism dysregulation treatment.
Sci China Life Sci ........................................... 14
ROLE OF SKELETAL MUSCLE IN PERIPH-
ERAL METABOLISM REGULATION
As the major energy-consuming motor organ in the body,
skeletal muscle can also release hormones or small proteins
that affect systemic metabolism. These substances are known
as myokines, which are similar to but distinct from adipo-
cytokines from adipose tissue. These proteins exert bene-
ficial effects on peripheral and remote organs. The TGF-β
superfamily and related factors released by the muscles un-
der exercise-like conditions are myokines, such as myostatin
and activins. Myostatin and activins act to limit muscle mass
and inhibition that can induce significant muscle growth
(Lee et al., 2005; Kollias and McDermott, 2008). Another
myokine, follistatin, which does not belong to the TGF-β
superfamily, acts to inhibit myostatin and activins, similar to
irisin.
In general, myostatin, leukemia inhibitory factor, and IL-6
and IL-7 are involved in muscle hypertrophy and myogen-
esis, whereas BDNF and IL-6 are involved in AMPK-
mediated fat oxidation. IL-6 also appears to have systemic
effects on the liver, adipose tissue, and the immune system
and mediates crosstalk between intestinal L cells and pan-
creatic islets (Pedersen and Febbraio, 2012). Chronic ex-
ercise as a lifestyle intervention can improve overall
metabolism and benefit the health of individuals for not only
energy expenditure but also for adjusting systemic functions.
CONCLUSION
In this review, we initially investigated metabolic regulation
of CNS not only as a homeostatic system, but also as a
reward system that maintains energy balance both metabo-
lically and motivationally. We described the anorexigenic
and orexigenic mechanisms and regulation of food intake by
hypothalamic POMC/CART and NPY/AgRP neurons.
Moreover, we summarized the role of essential neuro-
transmitters coordinated within the CNS. Critical brain re-
gions or nuclei operate spatially and temporally and are
responsible for the three kinds of central regulation of energy
balance. We then reviewed energy regulation by peripheral
mechanisms. First, the crosstalk between the gut or adipose
tissue and the brain involves a variety of signals derived from
the GI tract and adipocytes that respectively act as humor
signals to inform the CNS or to affect the metabolism of
peripheral organs. In addition, nutrients or metabolites act
synergistically with the humor signals to affect metabolic
control. On the other hand, gut microbiota with their SCFA
metabolites have been determined to influence intestinal
activity and improve metabolism, and their constitutional
alteration has been associated with various diseases. Finally,
regulation by the liver, BAT and skeletal muscle demon-
15 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Wen, S., et al.
strates their comprehensive role and interactions with other
parts of the body. Accordingly, a living organism’s energy
balance requires accurate and precise control at the mole-
cular, cellular, and organ levels as well as the systemic level
through nervous and humor system mechanisms. Drug tar-
gets in these areas may lead to disruption of unhealthy me-
tabolic activity or prevent development of T2DM or morbid
obesity, which are increasingly prevalent in modern society.
Compliance and ethics The author(s) declare that they have no conflict
of interest.
Acknowledgements This work was supported by the National Natural
Science Foundation of China (81370932), the United States MERCK IISP
Fund (40313, 40309), Outstanding Leaders Training Program of Pudong
Health Bureau of Shanghai (PWR12014-06), Integrative Medicine special
fund of Shanghai Municipal Health Planning Committee (ZHYY-ZXYJHZX-
2-201712) and the Key Studies (Special) Department Fund of the Pudong
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