The Obese Brain—Effects of Bariatric Surgery on Energy Balance Neurocircuitry
Curr Atheroscler Rep
The Obese Brain-Effects of Bariatric Surgery on Energy Balance Neurocircuitry
José Carlos de Lima-Júnior 0 1
Lício A. Velloso 0 1
Bruno Geloneze 0 1
0 Laboratory of Investigation in Metabolism and Diabetes-LIMED, University of Campinas, UNICAMP , 13084-970 Campinas , Brazil
1 Laboratory of Cell Signaling, Department of Internal Medicine, University of Campinas-UNICAMP , Campinas , Brazil
Obesity is a highly prevalent disease in the world and with a major impact on global health. While genetic components are also involved in its pathogenesis, in recent years, it has shown a critical role of the innate and adaptive immune cell response in many tissues triggered by excess of nutrients such as lipids and glucose. Free fatty acids and other nutrientrelated signals induce damage such as insulin resistance in the peripheral tissues but also in the brain. Specifically in the hypothalamus, these metabolic signals can trigger significant changes in the control of energy balance. Recent studies have shown that saturated fat disrupts melanocortin signaling of hypothalamic neuronal subgroups pivotal to energy control. Bariatric surgery is a treatment option for obesity when other tools have failed, because it is more effective than pharmacotherapy concerning of weight loss itself and in improvement of obesity-related comorbidities. Here, we review the mechanisms by which Roux-en Y gastric bypass (RYGB) can change peripheral signals that modulate melanocortin circuits involved in the regulation of energy balance.
Obesity; Bariatric surgery; Roux-en Y gastric bypass; Brain; Hypothalamus
The central nervous system (CNS) orchestrates energy
homeostasis. Adiposity signals, as leptin and insulin,
gastrointestinal signals, and other stimuli feed itself reflect the body fat
store, shuttling information to the brain, particularly the
neuropeptidergic system in the arcuate nucleus (ARC) of the
hypothalamus, which has been reported to modulate energy
balance through melanocortinergic second-order neurons .
Food reward circuits act parallely with melanocortinergic
circuitry in the management of the coordination of the energy
requirements outputs that maintain a stable balance between
spending and energy consumption .
Regardless of the intricate regulatory system of body fat
reserves, more than one-third of adults in the United States are
obese , resulting in an obesity pandemic that is reaching
catastrophic proportions, impacting the incidence of a burden
chronic disease and global mortality . The hypothalamic
alterations that result from exposure to high-fat diets and
low-grade inflammation contribute to the pathogenesis of
obesity and reorganization in the energy balance [5, 6 ]. Thus,
the brain changes that result from diet-induced obesity (DIO)
affect brain programming to promote rescheduling in food
intake, food interest, satiety signals response, and energy
expenditure, and these changes contribute to a new energy
balance set point in the obese brain [7, 8]. This new phenotype,
which is characterized by a modified balance, implies a new
defended level of adiposity that somehow contributes to the
maintenance of obesity through the ARC. Signals from the
ARC will deliver outputs to modulate the current adipose
tissue stores and adjust to the obesity pattern through
physiological and behavioral adaptations . Increased adiposity is
supported through decreased leptin/insulin signaling in the
obese brain, which reduces the negative feedback of these
adipostatic peripheral signals [1, 9]. As expected, the central
administration of leptin has not been able to influence caloric
intake . Similarly, the anti-obesity drugs that are currently
available mostly target the brain, but they are not optimally
effective . Therefore, bariatric surgery, which can be more
effective to enhance the cerebral effects, is more effective as
obesity therapy .
We herein will discuss the factors that are known to be
involved in the neurobiological modifications are promoted
by Roux-en Y gastric bypass (RYGB), and contribute to the
reversal of the damage to the homeostasis neuronal circuitry,
decreased food intake, and/or increased energy expenditure.
An understanding of how the surgery is able to change the
energy homeostasis set point in the obese brain of humans and
rodents and partially modify the neuronal programming
defense system of adiposity body is still incipient and will
contribute greatly to the search for new therapeutic targets.
Overview of the Hypothalamic Neuronal Systems
for Energy Homeostasis
The central melanocortin system exerts control of expenditure
and energy intake through neurons of the brainstem and two
first-order neurons subpopulations located in the arcuate
nucleus (ARC) of the hypothalamus, which transmit information
on metabolic status—pro-opiomelanocortin (POMC) and
neuropeptide Y/agouti-related protein (NPY/AgRP) neurons
. POMC neurons comprise two distinct γ-aminobutyric
acid (GABA)-ergic and glutamatergic neuronal
subpopulations that express the anorexigenic peptides POMC
[α-melanocyte stimulating hormone (MSH)] and cocaine- and
amphetamine-related transcript (CART), whereas AgRP
neurons express the orexigenic peptides NPY, AgRP, and
neurotransmitter GABA, although the existence of these
neurotransmitters is controversial [13, 14]. Other system components are
second-order neurons that express the melanocortin receptors
MCR3 and MCR4 and that receive ARC inputs  (see 
for a review). POMC- and CART-positive neurons and NPY/
AgRP, respectively, send projections within the hypothalamus
to the periventricular nucleus, paraventricular nucleus (PVN),
perifornical area (PFA), and lateral nucleus (LH), as well to
the brainstem [16, 17]
These two neural ARC subpopulations are targeted by
several signaling peptides, including insulin, leptin, and
gastrointestinal hormones, such as CCK, peptide YY, ghrelin, and
glucagon-like peptide-1 (GLP), which, except for the unique
gastrointestinal orexigenic hormone, ghrelin, have
anorexigenic effects on POMC [18, 19]. During the fed state, there
is an increase in leptin and insulin levels in proportion to fat
store, in order to stimulate the transcription of anorexigenic
POMC peptides and decrease the expression of orexigenic
peptides NPY and AGRP in order to reduce food intake and
increase energetic expenditure, this mechanism makes up the
peripheral adipostatic system [15, 20, 21].
How Fatty Acids Affect the Hypothalamus
and Deregulates Energetic Homeostasis
Insulin resistance is the main metabolic change that is
associated with obesity and the chronic inflammation of adipose
tissue, and macrophage activation in this tissue plays a crucial
role in this disease mechanism . These findings illustrate
the interconnection between the lipid signaling, inflammation,
and energy homeostasis . Saturated fatty acids, which
derive from the diet and are crucial components in the
proinflammatory response, activate inflammatory signaling in
various tissues through TLR4 activation and the subsequent
stimulus of the inhibitor of Kβ (IKKβ) and nuclear factor κβ
(NFκβ) pathways, such that this process culminates in
blocking the transduction of the insulin and leptin signals in
these tissues . It is not surprising that this process also
occurs in the hypothalamus and affects energy homeostasis
. Because leptin and insulin have a central role in
adipostatic signaling, a deterioration in their action in the
hypothalamus could initiate a new set point for energy in an
adaptive process that favors energy intake and subsequent
weight gain . High fat feeding has been involved in
several important processes that affect the neural physiology of
the melanocortin system . Thus, the state of insulin and
leptin can affect the firing of the neuronal subpopulations that
are crucial in energy balance . Likewise, in rats fed with
saturated fatty acids, the Toll-like receptor 4 acts as a
molecular trigger for inflammatory signaling in the hypothalamus,
thus impairing the anorexigenic signals that maintain the
energy balance . Additionally, high-fat feeding triggers
apoptosis and major changes in synaptic plasticity in
hypothalamic neurons .
Evidence from Human Observational Studies That
RYGB Affects the Hypothalamus
The unavoidable question is whether the surgical weight loss
causes regression of the neuronal damage that is induced by
obesity and if such hypothalamic changes alter the neural
control and reset the set-point energy balance.
A number of neuroimaging studies of the effects of RYGB
on eating behavior have shown the involvement of the brain’s
the reward system. A reduction in the activation of these areas
in response to food cues after RYGB has mapped the changes
in limbic circuitry of hedonic drive. However, in addition to
the impact on the mesolimbic system, other studies have
demonstrated that RYGB results in major changes in the regulation
of energy expenditure and that these changes are fundamental
for maintaining the negative balance [31 ].
The hypothalamus plays a central role in regulating this
homeostasis. Matsuda et al. demonstrated for the first time
in humans an anomaly in the hypothalamus and a difference
between lean and obese individuals that could correspond to
central damage that is caused by obesity. They performed
functional magnetic resonance imaging (fMRI) after oral
glucose intake and demonstrated that obese individuals exhibit an
attenuation and delay of the fMRI signal in the ventromedial
nucleus (VMH) and PVN in the hypothalamus . Similarly,
Thaler et al. showed that obese subjects had evidence of
gliosis in their mediobasal hypothalamus (MBH), which was
associated with body mass index (BMI). Interestingly, the
correlation between BMI and signal intensity was restricted
to the hypothalamus . Additional studies have been
published that support these findings and that shed light on the
effects of RYGB on neural control (Table 1). Frank et al. 
demonstrated in a cross-sectional study that changes in
corporal weight after RYGB are capable to induce changes within
the hypothalamus. Severely obese women presented greater
activation during the presentation of low-calorie food and
lower hypothalamic activation during the presentation of
high-calorie food compared with normal-weight women and
RYGB women. In contrast, the RYGB women exhibited a
hypothalamic response that was analogous to those of
normal-weight women and distinct from those of severely
obese women, thus demonstrating a normalization of
hypothalamic brain activity after RYGB.
In another study, Rachid et al.  explored the central
regulation of brown adipogenesis in humans based on the
finding that brown adipose tissue (BAT) in rodents is
controlled by hypothalamic sympathetic outputs. They evaluated
the hypothalamic response in humans after a cold stimulus,
because brown/beige adipose tissue is mainly recruited in this
situation. They wondered how weight loss that was induced
by RYGB would affect the activation of BAT and if the
recruitment was due to changes in the hypothalamic neural
activation . Their results showed that significant weight loss
resulted in greater activation of BAT, which was not
accompanied by changes in hypothalamic neuronal activity. These
findings suggested that the damage that was induced by
obesity in the brain region that controls whole-body energy
homeostasis might be irreversible or only partially reversible in
humans. The same group demonstrated the partial reversibility
of hypothalamic damage after surgical weight loss with fMRI
of brain activity after glucose ingestion. Thus, the structural
changes that occur in the postsurgical obese brain bring it
closer to the template of a lean brain. Another important
finding was an increase of interleukin (IL)-6 and IL-10 in the
cerebrospinal fluid (CSF) of these obese individuals after
surgery . Interestingly, these findings have suggested that the
attenuation of inflammation markers in the CSF correlated
with the changes in brain activity as well as the increase in
the levels of anti-inflammatory cytokines, thus suggesting a
route for mechanistic investigations in humans .
Mechanistic Insights Underlying the Effects
of RYGB on the Hypothalamic Circuitry
RYGB is an effective option for treatment of obesity, type 2
diabetes, and insulin resistance. However, which mechanisms
are involved is still not very clear, and these may also cause
changes in the energy expenditure in the central nervous
system or in the gut-brain communication (Fig. 1) .
Leptin and Insulin as Protagonists
As mentioned previously, leptin and insulin signaling in the
hypothalamus is crucial for the regulation of energy balance
on the melanocortin system [38, 39]. In obesity, the serum
levels of these hormones are increased in parallel with the
resistance to receptor-mediated signaling . Defective
insulin and leptin signaling in the hypothalamus prevents input to
the anorexigenic areas by adiposity negative feedback, thus
enhancing the food intake .
Because RYGB induces profound changes in several
factors that are involved in energy homeostasis signaling, it has
been hypothesized that such changes will be able to partially
restore the lean set point of energy balance. However, such
beneficial changes that would cause weight loss are extremely
difficult because the physiological compensatory changes
occur in energy expenditure in order to oppose the variation in
the weight to maintain the usual weight. 
Recently, it was described in human BAT activity, which is
located primarily on cervical and supraclavicular depot.
Brown fat produces heat though thermogenesis induced by
mitochondrial UCP1 and is important for energy expenditure
in the defense against cold and obesity [42, 43]. Recently,
BAT has emerged as a potential therapeutic opportunity
. These functions suggest that low or no function of
brown/beige adipose tissue could cause a propensity to DIO
The central route for the control of metabolorregulatory
thermogenesis could be confused with feeding behavior and
the thermoregulatory pathway . Signals in the blood, such
as insulin, leptin, CCK, enterostatin, GLP1, adenosine,
serotonin, endocannabinoids, angiotensin, α-MSH, and ghrelin
can act in nutrient-sensing areas, such as the ARC, or directly
in VMH to regulate BAT activation . For instance, leptin
and insulin act together on POMC neurons to drive browning
of white adipose tissue, which culminates in weight loss and
increased energy expenditure . Thus, the hypothesis that
the enhancement of brown/beige adipose tissue activity after
RYGB occurs through hypothalamic regulation, as
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Fig. 1 The effects of RYGB on the main hypothalamic circuitry that
controls energy balance. On the left, first-order neurons in the ARC
nucleus in an obese state. This panel shows a simplified circuit of these
neuronal sensing of peripheral signals that regulate energy balance.
During the obese state, hypothalamic leptin and insulin resistance occur.
Thus, downstream activation of second-order neurons (PVN, LHA/PFA)
to reduce food intake and lead to higher energy expenditure is impaired.
On the right, RYGB results in a possible change in central regulation by
adipostatic signals leptin and insulin, in a higher secretion of anorexigenic
peptides, such as PYY and GLP-1, and bile acids. Such modifications
through mechanisms not fully demonstrated have targeted the
hypothalamic center of energy regulation
demonstrated by Rachid et al.  may be a result of
improved insulin and leptin sensitivity on the hypothalamus after
weight loss is plausible.
To assess the importance of improving insulin sensitivity in
hypothalamic signaling after RYGB, it was obtained a
knockdown animal model for the insulin receptor kinase domain in
the VMH (VMH IRkd). After RYGB, these Sprague-Dawley
rats exhibited significant impairments in hepatic glucose
production during hyperinsulinemic-euglycemic clamp versus
sham RYGB. These data suggest that an improved sensitivity
to insulin in the VMH might be one of the mechanisms
underlying the amelioration of glucose homeostasis after
surgery, which was modulated in the liver. The observation that
the postsurgical insulin-induced glucose disposal was not
completely improved in the knockdown rats suggested that
other pathways and regions might be involved in the
metabolic benefits of the procedure [50 ].
The effects of insulin action on neuronal activity in the
brain can be investigated by fMRI in humans by using
blood-oxygen-level-dependent (BOLD) contrast imaging or
cerebral blood flow (CBF) after insulin or glucose injection
. Using this method, van de Sande-Lee et al. demonstrated
changes in neuronal activity in the hypothalamus after RYGB
with an fMRI protocol that evaluated hypothalamic
connectivity after the oral ingestion of 50 g D-glucose .
In addition to insulin levels, leptin levels decrease after
RYGB . This also suggests the central question: does
RYGB able to reset the leptin/insulin adipostatic set point in
the hypothalamus?  As mentioned above, the weight loss
changes occur in order to defend the level of adiposity prior to
weight loss. After the surgery, leptin levels decrease over time
, which could stem from the improvement in leptin
signaling in the body or an energetic adjustment that is made to
maintain pre-weight loss state through reduced energy
expenditure and increased food consumption. This seems more
reasonable in view of the weight regain rate after dieting  or
even after surgery [56, 57]. We will not be able to exactly
answer the question about the resetting of the set point.
Although the neuronal cells are endowed with plasticity and
evidence of the reversibility of the brain damage has been
reported, even in humans (Table 1) , leptin continues
working to keep it that way once the individual is obese
. This relative leptin insufficiency that occurs in parallel
with the weight reduction induces weight regain because its
central action is mirrored in key areas of eating behavior and
energy homeostasis, and this action is therefore reversible
when the weight loss is accompanied by replacement leptin
. In leptin deficient ob/ob mice, RYGB does not produce
weight loss. Initial weight loss is soon followed by restoration
of the weight to presurgical levels, and this is partially
corrected with replacement leptin . This reversibility of
l e p t i n r e s i s t a n c e i s d u e t o p l a s t i c i t y i n t h e A R C
melanocortinergics neurons, which is promising for the
maintenance of the profound changes that are caused by RYGB.
When extrapolating to knifeless weight loss in mice, an
energy-restricted diet simultaneously promotes decreased
levels of leptin and simultaneously promotes increased
expression of neurons NPY/AgRP and does not enhance the
activation of POMC neurons, which puts this neural recovery
in check [62, 63]. In humans, a clinical trial of the
administration of leptin after RYGB in women with relative
hypoleptinemia after surgery did not have beneficial effects on
body composition or energy expenditure [64 ].
The current knowledge about whether this set point is
resettable or not comes from animal models, and absolute
studies are lacking. Sprague-Dawley rats that underwent RYGB
showed 10 days after surgery decreased NPY-immunoreactive
neurons and increased α-MSH-immunoreactive neurons in
the ARC, parvocellular PVN, and magnocellular PVN .
A decrease in NPY receptors in the PVN indicates increased
NPY signaling activity as opposed to decreased POMC
signaling. These findings indicate that the restriction of energy
intake results in a hungry obese brain rather than in a newly
satiated thin brain . Apparently, when we compare
Sprague-Dawley rats’ DIO with a successful RYGB
(RYGB-S) and those with a failed bypass (RYGB-F),
RYGB-S rats exhibit increased expression of the leptin
receptor in the hypothalamus compared to the other group, which
exhibits reduced serum leptin levels, most notably in the
RYGB-S. The most logical explanation is that there is no
change in the set point hypothalamic leptin, insofar as the
greatest weight loss might have occurred due to compensatory
catabolic changes that were promoted by the increase of PYY
in these rats. PYY expression was also increased in the
hypothalamus, followed by an inhibition of NPY/AgRP and
POMC/CART expression was increased. This study of the
characteristics of the underlying mechanisms also noted some
changes in other candidates that are involved in
gutbrain axis .
Candidate Signals Operating in the Gut-Brain Axis
The obvious candidates for involvement in the new regulation
of energy balance after RYGB are peptides that are secreted by
the enteroendocrine cells in the gastrointestinal tract, are
involved in the regulation of food intake, have nutrient-sensing
mechanisms, and act in the hypothalamus or hindbrain.
Thereby, an anatomical change in the gastrointestinal tract must
change their secretion, and why not optimize its
signaling in the hypothalamus to enhance the satiety? (See
 for a review).
Most studies have reported an increase in the secretion of
anorexigenic peptides after RYGB—such as PYY, GLP-1,
amylin, oxyntomodulin, CCK, and total bile acids (TBA),
and the only one with orexigenic effect, ghrelin, exhibits more
complex behavior but with generally reduced levels [66–71].
This enhanced response is persistent and supports weight loss,
despite the presurgical-defended level of adiposity controlled
by leptin .
Currently, other factors have been shown to be involved in
the mechanistic roles underlying RYGB’s effects on the brain,
such as changes in the intestinal microbiota and signaling by
bile acids through the farsenoid-X receptor (FXR) and TGR5
receptor membrane [53, 73]. Although there is an
abundant negative correlation between body weight after
RYGB and postoperatively increased levels of
gastrointestinal peptides, the literature is more saturated when it
comes to GLP-1 and PYY, and direct mechanistic
evidence is partially missing. The central signaling of
GLP-1R does not seem to have a pivotal role in
downstream cascade that results in postsurgical weight loss,
which is a phenomenon that was confirmed by the
similar amounts of weight loss between GLP-1R-knockout
(KO) mice and wild-type mice that underwent RYGB
[74 ]. Similarly, although the GLP-1 leads to BAT
thermogenesis after its central administration , its
peripheral levels are not able to increase energy
expenditure after RYGB in rats . After performing a
modified gastric bypass in PYY-KO mice, the effects of
weight loss were lost, thus establishing a critical role
of this hormone in weight loss mechanisms. 
Recently, Fang S et al. demonstrated that
administration of gut-restricted agonist FXR leads to weight loss,
browning, and increased thermogenesis through an
increase in fibroblast growth factor 15 (FGF15) .
Thus, if the control of BAT thermogenesis and
browning occurs centrally and involves GLP-1R signaling in
the brain  and if there are TGR5 receptors for bile
acids in the brain , crosstalk between GLP-1R and
TGR5 brain receptor signaling is possible. This
crosstalk would contribute to greater energy expenditure
through RYGB-induced thermogenesis because this
surgery involves changes in the delivery of bile acids into
the modified gastrointestinal tract.
In recent years, the increase in obesity has led to substantial
increase in the study of its important clinical and
pathophysiological aspects, and scientific efforts have more recently
tried to clarify the molecular mechanisms underlying the
changes in energy balance and, particularly, the changes in
hypothalamic circuitry, which are key to the evolution of
pharmacotherapy. These scientific advances have contributed to a
description of the installation of the hypothalamic injury as
well as to how the surgery can modify the programming brain
and drive it to a favorable energy balance. However, there are
still many gaps in the understanding, and new avenues are
opening up every day. Although RYGB has important effects
on the population, including reduction in cardiovascular
mortality, an in-depth understanding of how and why the surgery
causes such profound changes, particularly in this
hypothalamic neuronal group that regulates energy
homeostasis, is lacking.
Compliance With Ethics Guidelines
Conflict of Interest José Carlos de Lima Júnior and Bruno Geloneze
declare that they have no conflict of interest.
Lício A. Velloso has received grants from Fundação de Amparo a
P e s q u i s a d o E s t a d o d e S ã o P a u l o , C o n s e l h o N a c i o n a l d e
Desenvolvimento Cientifico e Tecnologico, and Trust in Science
Initiative from GlaxoSmithKline, UK.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
Open Access This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License (http://
creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a link to the
Creative Commons license, and indicate if changes were made.
Papers of particular interest, published recently, have been
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