Neural Control of Energy Balance: Translating Circuits To Therapies
Neural Control of Energy Balance: Translating Circuits To Therapies
Neural Control of Energy Balance: Translating Circuits To Therapies
Review
Neural Control of Energy Balance:
Translating Circuits to Therapies
Laurent Gautron,1,* Joel K. Elmquist,1,2 and Kevin W. Williams1,3,*
1Division
Recent insights into the neural circuits controlling energy balance and glucose homeostasis
have rekindled the hope for development of novel treatments for obesity and diabetes. However,
many therapies contribute relatively modest beneficial gains with accompanying side effects,
and the mechanisms of action for other interventions remain undefined. This Review summarizes
current knowledge linking the neural circuits regulating energy and glucose balance with current
and potential pharmacotherapeutic and surgical interventions for the treatment of obesity and
diabetes.
Introduction
Obesity, diabetes, and associated disorders represent a major
public health challenge for North America, Europe, and increasingly the rest of the world. Both obesity and diabetes inflict
health and economic burdens that require coordinated strategies to both prevent and treat these disorders. Indeed, a major
barrier in the management and prevention of obesity is that
weight loss due to lifestyle changes alone is inherently difficult.
For many, this means that dieting-induced weight loss initially
results in tangible beneficial effects but is often followed by a
return to previous energy intake and consequently a rebound
weight gain.
Numerous neurobiological and physiological mechanisms
that regulate energy balance exist. In particular, it has become
increasingly evident that the brain plays an important role in
sensing energy demands and storage in order to maintain/
defend body weight within a rather tight range. Studies ranging
from worms, flies, and mice to humans have identified key
conserved genes and neural pathways that are critical in regulating energy balance and glucose homeostasis. Moreover, the
identification of human mutations in these or analogous pathways has led to hope that it may be possible to develop rational
strategies based on animal model studies that may ultimately
lead to successful therapeutic intervention in humans. In this
Review, we will highlight how advances in understanding the
neurophysiology underlying metabolism, including an increased
understanding of neural circuits, may hold promise for development of adjunct therapies in the treatment of obesity and associated co-morbidities, including diabetes. Several recent Reviews
have provided more detailed information and review of the primary literature regarding the respective circuits and approaches
highlighted here (Barsh et al., 2000; Cone, 2005; Deisseroth,
2012; Farooqi and ORahilly, 2005; Heisler et al., 2003; Myers
and Olson, 2012; Powley et al., 2005; Schwartz and Porte,
2005; Wikberg and Mutulis, 2008).
dependent upon melanocortin receptors within the paraventricular hypothalamus (PVH), a hypothalamic nucleus that is a direct
target of arcuate melanocortin neurons. Stimulation of arcuate
AgRP neurons elicited feeding behavior via projections to the
thalamus, the hypothalamus, and the basal forebrain (Atasoy
et al., 2012). Interestingly, either the neurotransmitter GABA or
NPY is required for the rapid stimulation of feeding, whereas
the neuropeptide AgRP, through action on Mc4 receptors, is sufficient to induce feeding over a delayed yet prolonged period
(Krashes et al., 2013). GABA from NPY/AgRP neurons of the hypothalamic arcuate nucleus may also play an important role in
the regulation of feeding behaviors via direct actions within the
hindbrain (Wu et al., 2009). Moreover, neurons of the nucleus
of the solitary tract in the caudal medulla might counterbalance
this activity (Wu et al., 2012). Neurons of the PVH also reciprocally innervate arcuate NPY/AgRP neurons, providing a regulatory loop in the control of feeding behavior (Krashes et al.,
2014). Collectively, these data suggest that in addition to a
core circuit, AgRP neuron projections and reciprocal innervations may reveal key modulatory circuit nodes that are gated
or otherwise regulated by AgRP neuron projections (Atasoy
et al., 2012). Importantly, its currently unclear which circuits
are acutely involved in other complex metabolic processes
such as energy expenditure and glucose metabolism. Undoubtedly, similar parallel and redundant mechanisms involved in
regulating feeding behavior will be intertwined with various aspects of metabolism.
Both NPY/AgRP and Pomc neurons are also sensitive to metabolic status (Cone, 2005; Yulyaningsih et al., 2011). In particular,
NPY/AgRP neurons are activated during fasting, whereas Pomc
neurons are activated following feeding and inhibited during fasting. NPY/AgRP and Pomc neurons are also well positioned to
sense and integrate numerous nutrient and humoral signals
(Schwartz and Porte, 2005). Indeed, many of these signals in
the periphery and/or the central nervous system (CNS) have
been attributed to regulating feeding behavior and energy expen134 Cell 161, March 26, 2015 2015 Elsevier Inc.
Table 1. Select List of Current and Potential Future Therapeutics for the Treatment of Obesity and Diabetes
Pharmacology
Drug/Compound
Trade/Brand Name
Receptors/Molecular
Pathways
FDA Approval
Applications(s)
Lorcaserin
Belviq
5ht2cr agonist
yes2012
obesity
hypothalamus, cortex,
midbrain, and brainstem
Liraglutide
Victoza
GLP-1r agonist
yes2012
obesity and
diabetes
hypothalamus
Topiramate/
Phentermine
Qysemia
yes2012
obesity
Buproprion/
Naltrexone
Contrave
dopamine and
norepinephrine reuptake
inhibitor/opioid receptor
antagonist
yes2014
obesity
hypothalamus
D-fenfluramine
5ht2cr agonist
withdrawn
obesity
Orlistat
yes1999
obesity
gut
Sibutramine
Meridia
withdrawn
obesity
Ribonamant
Zimulti
CB1R antagonist
withdrawn
obesity
Mc4R agonists
N/A
Mc4R
no
obesity
Exenatide
Byetta, Bydureon
GLP-1r agonist
yes 2005
T2DM
hypothalamus
Metformin
Glucophage, Glumetza,
Glucophage XR, Fortamet
suppress gluconeogenesis
pathways
yes1995
T2DM
liver
Pramlintide
Symlin
yes2005
T2DM
Leptin
Metreleptin
LepRB agonist
nob
type 1 and 2
diabetes
hypothalamus
Device-Assisted
Device
Receptors/Molecular
Pathways
FDA Approval
Application(s)
hfDBS
neuronal excitability
noa
obesity
hypothalamus
tDCs
neuronal excitability
noa
obesity
cortex
VNS
neuronal excitability
noa
obesity
VBLOC
neuronal excitability
yes2015
obesity
Lap-bandlaparoscopic
adjustable gastric band
unknown
yes2001
obesity
gut-brain communication
unknown
N/A
gut-brain communication
unknown
N/A
gut-brain communication
(Astrup et al., 2004). Naltrexone is an antagonist of opioid receptors with little effect on food intake when administered
alone (Greenway et al., 2009). Although Naltrexone may act by
increasing the firing rates of Pomc neurons (Greenway et al.,
2009), the exact mechanisms of action of Naltrexone and Topiramate on energy balance are unclear. Importantly, the FDA has
recently approved the drug combinations Contrave and Qysemia as an adjunct for chronic weight management (Table 1)
with both medications promoting weight losses of 8% to 10%
of initial body weight (Allison et al., 2012; Garvey et al., 2012;
Greenway et al., 2009). Interestingly, another combination medication called Empatic (trade name) that contains both Bupropion
and Zonisamide (another anti-convulsant) is currently under
phase 2 clinical trial (Jackson et al., 2014). Thus, with the recent
FDA approval and/or promising clinical trial results, combination
therapies show promise for therapeutic efficacy in the treatment
of obesity.
Novel Paradigms in Anti-Obesity Pharmacotherapy
Although many compounds acting on neural pathways controlling appetite, glucose metabolism, and energy expenditure
were found to induce marked body-weight loss in animal models
and human clinical trials, leading to FDA approval, many of these
simultaneously affect energy expenditure, appetite, cardiovascular function, and glucose metabolism makes them particularly
relevant for the treatment of the metabolic syndrome. In summary, the brain should be (re)-considered as a prime target in
designing therapeutics for diabetes, especially in individuals
with multiple comorbidities.
Is the Brain Involved in the Metabolic Outcomes of
Bariatric Surgery?
A number of different approaches to bariatric surgery, also
known as gastric bypass, have been described (for review, see
Lutz and Bueter, 2014; Stefater et al., 2012). Roux-en-Y gastric
bypass is the most efficacious and frequently performed
weight-loss surgery (Buchwald, 2014; Lo Menzo et al., 2014;
Schauer et al., 2003). However, the use of sleeve gastrectomy
has been gaining in popularity in recent years since the approval
of laparoscopic sleeve gastrectomy in 2005. Patients eligible for
either sleeve gastrectomy or Roux-en-Y gastric bypass can
reasonably expect a near normalization of their body mass index
and reversal of most co-morbidities within 2 years. Despite their
remarkable efficacy, these surgeries remain costly procedures
associated with many complications. Perhaps weight-loss surgeries could be simplified and their complications avoided if
the biological mechanisms underlying their effects were understood. Thus, many investigators acknowledge that identifying
the mechanisms underlying the beneficial effects of gastric
bypass is an important challenge. There is now ample evidence
that neither the mere physical restriction of the stomach nor
nutrient malabsorption is sufficient to explain weight loss and
glucose-metabolism improvement after bariatric surgery (Lutz
and Bueter, 2014; Stefater et al., 2012). At the physiological level,
a combination of modified parameters, including reduced appetite, modified food preference, and augmented energy expenditure, may collectively mediate weight loss after bariatric surgery.
At the cellular level, numerous non-exclusive factors have been
implicated in the benefits of bariatric surgery, including, but not
limited to, elevated levels of gut peptides and bile acids secretion, enhanced intestinal growth, and changes in the microbiome
composition (Lutz and Bueter, 2014). At the molecular level, farsenoid-X receptor (FXR), a nuclear receptor for bile acids, has
been recently demonstrated to play a key role in mediating weigh
loss after Roux-en-Y gastric bypass (Ryan et al., 2014). Interestingly, a recent study further demonstrated that intestinal FXR agonism is sufficient to attenuate diet-induced obesity and insulin
resistance in the mouse (Fang et al., 2015).
The role played by the brain in mediating the benefits of bariatric surgery remains open to discussion. At the phenomenological
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