This review focuses on the control of appetite by food intake-regulatory peptides secreted from the gastrointestinal tract, namely cholecystokinin, glucagon-like peptide 1, peptide YY, ghrelin, and the recently discovered nesfatin-1 via the gut-brain axis. Additionally, we describe the impact of external factors such as intake of different nutrients or stress on the secretion of gastrointestinal peptides. Finally, we highlight possible conservative—physical activity and pharmacotherapy—treatment strategies for obesity as well as surgical techniques such as deep brain stimulation and bariatric surgery also altering these peptidergic pathways.
The control of food intake is well balanced in healthy individuals with mostly peptidergic regulators stimulating the feeling of hunger to initiate food intake or satiety to terminate food intake when the necessary amount of externally delivered energy is reached. A dysregulation of this system can lead to obesity.1 For a better understanding of the control of food intake it is necessary to understand the interaction of peripheral and central signals that regulate energy homeostasis. Briefly, several peptides are derived from the gastrointestinal tract, most of which inhibit food intake, namely cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), peptide tyrosine tyrosine (PYY),2 and the recently discovered nesfatin-1,3 while only one peripherally produced and centrally acting peptide is known to stimulate food intake, ghrelin.2 These peptides affect brain centers involved in the central control of hunger and satiety via the gut-brain axis that involves crossing of the blood-brain barrier and targeting the arcuate nucleus (ARC) of the hypothalamus, or an action via the vagus nerve to reach the nucleus of the solitary tract (NTS) of the brainstem.4 It is of note that these 2 pathways are not separated from each other but rather intertwined by neuronal networks; ie, the NTS and the paraventricular nucleus (PVN) of the hypothalamus are connected by nerve fibers.
When anorexigenic signals reach the ARC they activate proo-piomelanocortin (POMC)- and cocaine- and amphetamine-related transcript- (CART) containing neurons, and deactivate neuropeptide Y (NPY)- and Agouti-related peptide (AgRP)- containing neurons.4 POMC/CART leads to an activation of melanocortin receptors 3 and 4 in the PVN and the lateral hypothalamic area (LHA), which causes a reduction of food intake.4 The melanocortin receptor 4 is expressed in the NTS as well, which also contains POMC neurons. In contrast, ghrelin as an orexigenic peptide activates NPY/AgRP-containing neurons and deactivates POMC/CART-containing neurons in the ARC.5 NPY stimulates food intake by activating the Y1 receptor in the PVN, whereas AgRP increases food intake as an antagonist of the melanocortin receptor 3 and 4.5 Additionally, NPY can also act in the NTS to stimulate food intake. Taken together, peripheral and central signals are involved in the orchestration of food intake. While peripheral transmitters reach the brain via the blood-brain barrier or the vagus nerve and modulate brain neuronal activity, brain nuclei also release peptidergic transmitters such as oxytocin or corticotropin-releasing factor that affect peripheral binding sites eg, at the level of the enteric nervous system to modulate food intake.4,5
In the present review, we focus on gastrointestinal peptides mainly involved in the regulation of hunger and satiety. In comparison to other excellent reviews on gut peptides with a main focus on the reward system,6,7 pharmacological treatment,6,8 bariatric surgery9 or the gut microbiota,10 in the present review we comprehensively describe the main effects and routes of peptide signaling, the regulation by nutrients, and also external stressors increasingly recognized to affect gastrointestinal peptides. Lastly, we highlight strategies to modulate peptidergic signaling in the treatment of obesity: here, conservative (physical activity and pharmacological treatment) as well as surgical options will be highlighted (bariatric surgery and the rather novel method of deep brain stimulation).
Ghrelin stimulates food intake after central and peripheral administration and subsequently also increases body weight.11 These effects are blunted after vagotomy pointing towards this route of gut-brain signaling.12 However, ghrelin can also pass the blood-brain barrier bidirectionally.13 The main source of circulating ghrelin is the stomach, as indicated by a massive reduction of circulating ghrelin levels following gastrectomy.14 Ghrelin is produced in gastric endocrine X/A-like cells (in humans termed P/D1 cells)15 and requires an acylation on its third serin residue necessary for the binding to and activation of the ghrelin receptor, the growth hormone secretagogue receptor 1a (GHSR1a, today often also called ghrelin receptor).16 The enzyme that catalyzes this acylation is the ghrelin-
Besides the direct effect after central injection, ghrelin also increases food intake following intraperitoneal administration in rats22 and intravenous infusion in humans23 likely reaching the hindbrain via the vagus nerve (or directly, since it is known that the NTS expresses the GHSR1a in humans),24 and the ARC also expressing the GHSR1a25 via crossing the blood-brain barrier. In the ARC the GHSR1a is co-localized in neurons expressing NPY/AgRP26 and ghrelin increases NPY/AgRP activity, while POMC is inhibited.27 In NPY/AgRP knockout (KO) mice ghrelin failed to increase food intake pointing towards the important role of NPY/AgRP to mediate ghrelin’s orexigenic effect.28 In addition to ghrelin’s food intake-stimulatory effects, peripherally injected ghrelin increases abdominal white adipose tissue in rodents.29 Ghrelin is also involved in the regulation of thermogenesis in brown adipose tissue with GHSR1a KO mice showing an increased thermogenesis in brown adipose tissue giving rise to an energy expenditure-reducing effect of ghrelin.30 Moreover, ghrelin stimulates gastric acid secretion as well as gastric motility in rats31 and humans,32 while often supraphysiological doses are needed in order to enhance motility.31 Both effects are blunted by cervical vagotomy indicating a vagal mediation.31 Lastly, ghrelin is also involved in glucose homeostasis with a decrease of insulin secretion following intravenous administration of ghrelin, while insulin sensitivity was not altered in humans.33
Over the last years, there has been increasing knowledge on desacyl ghrelin, the major circulating form of ghrelin34 that for long was thought to be an inactive deactivation product of ghrelin without any endogenous activity due to the lack of binding to the GHSR1a.16 However, desacyl ghrelin might also play a role in the modulation of hunger and satiety based on the finding that co-injection of desacyl ghrelin and ghrelin greatly blunts the orexigenic effect of ghrelin in rats.35 In line with this finding, a recent study showed that desacyl ghrelin antagonizes the orexigenic effect of peripherally administered ghrelin in mice.36 This points towards a counteracting function of desacyl ghrelin to modulate/balance ghrelin’s food intake-stimulating effect. This antagonism was also observed on colorectal motility: desacyl ghrelin reduced the motility-stimulating effect of ghrelin after intrathecal co-injection in rats.37 This interesting interplay of ghrelin and desacyl ghrelin warrants further investigation; moreover, the receptor mediating desacyl ghrelin’s effects is yet to be identified.
Nesfatin-1 is a recently discovered peptide derived from the precursor protein nucleobindin2 (NUCB2) and was initially described to be expressed in the rat hypothalamus.38 Early on it was shown that nesfatin-1 reduces food intake following central injection in rats,38,39 mice40 or goldfish.41 Subsequent research showed a more widespread distribution of NUCB2/nesfatin-1 in the rat brain42 and a prominent expression in the rat stomach with 10-fold higher expression levels in the gastric oxyntic mucosa compared to the brain.43 It is important to note that nesfatin-1 was co-localized with ghrelin in gastric X/A-like cells in rats43 and P/D1 cells in humans20 leading to the hypothesis that the peptide products of the X/A-like cell can stimulate food intake in both directions: either stimulate via ghrelin or inhibit via nesfatin-1.
Peripherally injected nesfatin-1 activates the NTS as indicated by increased Fos expression which might be involved in the satiety signaling.44 Moreover, nesfatin-1 can cross the blood-brain barrier bidirectionally in a non-saturable manner45,46 possibly leading to an activation of food intake-regulatory nuclei such as the PVN of the hypothalamus, a nucleus recently suggested to express the yet unknown nesfatin-1 receptor in a study using autoradiography.47 However, it is of note that although one study reported a reduction of food intake following intraperitoneal injection of nesfatin-1 at high doses in mice,44 other studies in rats39 or mice40 were unable to show this anorexigenic action of peripheral nesfatin-1. Also chronic peripheral administration of the peptide provided inconsistent results: while a reduction of food intake was observed in rats,48 no effects were described in mice.49 Whether species differences play a role remains to be further investigated. In summary, current data clearly point towards a role of central nesfatin-1 in the regulation of food intake, whereas peripheral nesfatin-1 seems to be rather involved in the reduction of gastric motility in dogs,50 increase of hepatic β-oxidation49 and glucose homeostasis with an increase of glucose-stimulated insulin release from the pancreas in rats51 and humans.52
Cholecystokinin (CCK) is mainly secreted from I cells of the upper small intestine;53 however, expression has also been detected in the enteric nervous system encompassing the myenteric and submucosal plexus.54 Various forms of CCK were detected since its discovery (CCK-5, -7, -8, -18, -22, -25, -33, -39, -58, or post-translationally sulphated forms), while only CCK-8 and CCK-58 have been observed in the central nervous system.53 The anorexigenic effect of CCK was discovered in 1973 in rats55 and confirmed in different species including rabbits, monkeys, pigs, sheep and humans.53 CCK-8 is the most studied form; however, when blood processing was optimized and degradation inhibited using the RAPID method, only CCK-58 was detectable suggesting that the shorter CCK forms represent fragments derived from enzymatic degradation.56 Although both forms reduce dark phase food intake following intraperitoneal injection in rats, CCK-58 exerts a different effect on the underlying food intake microstructure with a reduction of meal size, while the inter-meal interval following this meal was not shortened, a finding observed after injection of CCK-8.57
Originally, CCK was described as a stimulator of gallbladder contraction, pancreatic secretion, and synthesis of pancreatic enzymes as well as a modulator of gastric motility.53 Part of these actions are different between species with CCK being an inhibitor of gastric motility in humans58 and rats59 and a stimulator in guinea pigs.60 CCK’s actions are mediated by binding to 2 G protein-coupled receptors, the CCKA and CCKB receptors. CCKA (alimentary) is expressed in several tissues including the gastrointestinal tract, liver, pancreas and on vagal afferents,53 whereas the CCKB (brain) is the predominant form in the central nervous system.61
In addition to the functions described above CCK reduces food intake.57,62 The peptide is released from intestinal I cells after food intake with the most potent stimulation by lipids and proteins,63,64 binds to the CCKA on vagal afferents and leads to an activation of cells in the NTS that ultimately induce a reduction of food intake.65,66 In humans, stimulation of the CCKA with the orally-active CCKA agonist, GI181771X did not induce a reduction of body weight, while gastrointestinal side effects and effects on gallbladder and bile duct were observed.67 Therefore, CCKA monotherapy does not seem to be a promising anti-obesity strategy. While other feeding-regulatory peptides affect food intake by crossing the blood-brain barrier, for CCK vagal mediation is the predominant pathway.68 This is further underlined by the finding that CCK’s anorexigenic actions are attenuated by capsaicin treatment68,69 or blocked by abdominal vagotomy.66
Glucagon-like peptide 1 (GLP-1) is best known for its in-cretin effect with analogs used in the treatment of type 2 diabetes mellitus.70 The most famous analogs of GLP-1 are exendin-4 and liraglutide that also reduce food intake in animals71 and humans.72,73 Therefore, besides its incretin effects, GLP-1 mimetics are promising targets in the treatment of obesity.70 GLP-1 is produced in endocrine L cells of the intestine and posttranslationally cleaved from the gene encoding
Besides its expression in the gastrointestinal tract, GLP-1 is also expressed in neurons of the NTS which project to the PVN86 and are activated by several factors that decrease food intake (bacterial components like lipopolysaccharide or hormones such as CCK, leptin or oxytocin).70 Furthermore, the GLP-1 receptor (GLP-1R) is expressed on vagal afferents87 and the peripheral satiety effect of GLP-1 is blocked by vagotomy.88 Taken together, these data point towards a mediation of GLP-1’s food intake-reducing effect by the vagus nerve and hindbrain circuits rather than crossing the blood-brain barrier. This is further supported by lesion experiments showing that disruption of the projections from the brainstem to the hypothalamus reduce the appetite-suppressing effect of peripherally injected GLP-1 in rats.88 Moreover, peripheral as well as central injection of GLP-1 induces Fos, a marker for neuronal activity, in the PVN, while only central injection of GLP-1 induces Fos in the ARC.89 Furthermore, knockdown of the proglucagon gene in the NTS results in an increase of food intake and body weight gain.90 Lastly, microinjection of GLP-1 into the ARC affected glucose metabolism and insulin release, whereas food intake was only affected by injection of GLP-1 into the PVN.91 This points towards a mediation of the peripheral anorexigenic GLP-1 effect by activation of vagal afferents and a subsequent hindbrain (NTS) to forebrain (PVN) signaling.
However, GLP-1 has also been shown to cross the blood-brain barrier by simple diffusion92 and the GLP-1R is expressed in the hypothalamus as well.93 In line with this expression, peripheral injection of liraglutide was shown to directly stimulate POMC/CART-containing neurons and to inhibit NPY/AgRP-containing neurons in the ARC resulting in a decrease of body weight.94 However, it is of note that after reaching the circulation endogenous GLP-1 is rapidly degraded by the enzyme dipeptidyl peptidase IV.95 Therefore, the vagal signaling pathway following paracrine receptor activation is likely to predominate.
A recent study in Sprague Dawley rats showed that knockdown of the GLP-1R in vagal afferents affects food intake by increasing meal size and meal duration, whereas the number of meals was reduced and overall food intake not altered compared to controls.96 Whether all these changes encompass GLP-1’s effects or reflect compensatory mechanisms will have to be further investigated.
Two native forms of human PYY are known, PYY1-36 and PYY3-36, with PYY3-36 (hereafter termed as PYY) being the major circulating form resulting from cleavage of PYY1-36 by DPP IV.97,98 PYY is primarily produced in L cells of the small intestine but also the colon.97 It is important to note that it took 20 years following its discovery in the porcine intestine99 to identify PYY as a peripheral inhibitory regulator of food intake postprandially acting via the Y2 receptor in the central nervous system,100 an effect blunted by central injection of the Y2 antagonist, BIIE0246.101 Microinjection of PYY into the ARC inhibited electrical activation of NPY-containing nerve terminals and activated adjacent POMC-containing neurons.100 Taken together, these results give rise to PYY as a peripheral and central regulator of food intake in animals100,102 and humans.102
Interestingly, Y2 are localized on NPY-containing neurons in the ARC suggesting a direct action of PYY on hypothalamic neurons.103 This hypothesis is supported by the finding that peripheral PYY can cross the blood-brain barrier by a non-saturable mechanism.104 However, current data also point towards a vagal route of PYY signaling since the food intake-reducing effect of PYY following intraperitoneal injection was blocked by vagotomy in rats.105 Moreover, vagotomy also greatly decreased the PYY-induced expression of Fos in the ARC.105 Therefore, peripheral PYY is likely to signal to the brain both via the vagus nerve and via direct interaction with hypothalamic nuclei after crossing the blood-brain barrier. The peptidergic regulation of hunger and satiety is summarized in Figure 1.
The release of gastrointestinal food intake-regulating peptides is greatly affected by ingested nutrients. The early release of CCK has been well described when nutrients reach the duodenum, while GLP-1 and PYY are released later when nutrients further proceed through the intestine.106 This points towards a direct contact of nutrients with enteroendocrine cells to trigger the release of anorexigenic peptides.106 CCK is mainly stimulated by digested lipids and proteins,107,108 while intraduodenal glucose load exerted only a small increase of circulating CCK in healthy subjects.109 Further investigation of lipids and proteins showed that especially fatty acids with more than 12 carbons (oleate) or non-hydrolyzed and partially hydrolyzed proteins (casein or soybean trypsin inhibitors) stimulate CCK release.110 A number of G protein-coupled receptors has been described that can sense oral lipids in the gastrointestinal tract including FFAR1, PPR120 or GPR119 or a G protein-coupled receptor for bile acids, GPBAR1. A recent study showed that lipid superfusion on human duodenal biopsies increased GPR119 expression but not FFAR1 or FFAR4 and stimulated the secretion of CCK and GLP-1.111 Therefore, these receptors might be localized on the surface of I and L cells to trigger CCK and GLP-1 release following lipid sensing.
In contrast to CCK, GLP-1 is mainly triggered by glucose,109,112 which is sensed by the same sweet taste receptors on GLP-1-expressing L cells that are also expressed on the tongue, namely T1R2 and T1R3.113 Apart from the nutrients, the amount of energy also seems to play a role in gastrointestinal peptide release. PYY levels were shown to increase in response to nutrients proportionally to the amount of calories ingested114 and to decrease during fasting.115
Moreover, oral administration of glucose, lipids, and proteins in male and female healthy subjects showed that levels of the orexigenic peptide ghrelin decreased after glucose and lipid meals, whereas proteins did not affect circulating ghrelin.116 Interestingly, desacyl ghrelin can be directly acylated by GOAT using medium chain fatty acids or medium chain triacylglycerols of ingested foods.117 In vitro studies of cultured stomach ghrelinoma cells (MGN3-1) showed that oleic acids increase the expression of orexigenic ghrelin and simultaneously decrease the expression of NUCB2 (the precursor protein of the anorexigenic peptide nesfatin-1)118 also expressed in gastric X/A-like cells. Interestingly, L-tryptophan increased both NUCB2 expression and nesfatin-1 release as well as ghrelin expression, while glucose only stimulated NUCB2 expression.118 Since both peptides are derived from the same cell, different downstream signaling is likely to mediate this differential regulation. This has to be further investigated in future studies.
The impact of psychological diseases and stress on food intake-regulatory peptides is well investigated for ghrelin and also for nes-fatin-1, whereas studies for CCK, GLP-1, and PYY mostly focused on the impact of these peptides on the development of psychological disorders or stress.
Besides its orexigenic effect, ghrelin (subcutaneously injected or endogenously increased under conditions of caloric restriction) was shown to induce anxiolytic and antidepressant behavior in mice.119 These effects are ghrelin-specific and mediated by the GHSR1a as GHSR1a KO mice do not display these behaviors following ghrelin injection.119 In line with these acute findings, Wistar Kyoto rats which show more anxious behavior than Sprague Dawley rats have 2-fold lower fasting ghrelin levels.120 Taken together, these data give rise to the assumption that ghrelin might have beneficial effects in disorders involving anxiety or depression.
Chronic social defeat stress, representing a model of depression, increased circulating ghrelin levels.119 In this model the upregulation of ghrelin seems to play an adaptive/counter-regulatory role as mice lacking the GHSR1a showed even greater social avoidance.119 In line with these results, previous studies showed that acute stress resulted in increased circulating levels of ghrelin in mice121 and rats.122 In humans the results are divergent. A cold pressor test (a physiological laboratory stressor) increased circulating ghrelin levels in overweight women with and without night eating123 and obese women with binge eating disorder,124 while another study did not detect a correlation of plasma ghrelin with perceived stress in overweight and obese women125 or showed that acute stress did not affect ghrelin levels in obese women.126 Whether confounding factors such as comorbidities contribute to these inconsistent results remains to be further investigated. However, since intravenous administration of ghrelin reduced blood pressure and sympathetic nerve activity in response to mental stress,127 ghrelin might still hold therapeutic potential under these conditions.
NUCB2/nesfatin-1 is involved in the stress response as initially described by Goebel and colleagues in 2009.128 Abdominal surgery as a model for physical stress129 and restraint stress as a psychological stressor128 activated NUCB2/nesfatin-1-containing neurons in the forebrain (including the hypothalamus) as well as the hindbrain (including the NTS) in rats which was confirmed in a subsequent study.130 Human studies showed increased circulating NUCB2/nesfatin-1 levels in depressed patients compared to healthy individuals.131 Additionally, NUCB2/nesfatin-1 levels correlate positively with anxiety, depression and perceived stress in female obese patients.132,133 Interestingly, in obese men an inverse correlation of NUCB2/nesfatin-1 and anxiety scores has been described133 giving rise to a sex-specific regulation of the peptide.
CCK seems to be involved in the mediation of anxiety-like behaviors. CCK-8S and CCK-8N increase anxiety-like behavior, an effect likely mediated by the CCKB as shown by decreased freezing behavior following injection of a CCKB receptor antagonist, LY225910, and increased freezing behavior by injection of the CCKB receptor agonist, CCK-4.134 Moreover, CCKB antagonism using LY288513 blunts conditioned fear stress induced by electric footshock in rats.135 In line with these findings, CCKB KO mice showed an anxiolytic phenotype.136 Since mice lacking the CCKB display an increased body weight,137 brain CCK signaling seems to be involved in both, the modulation of anxiety as well as food intake. In humans, CCK has the most prominent role in panic disorder with exogenous CCK being able to provoke panic attacks and genetic variants of the CCK ligand and CCKB being potentially involved in the pathogenesis of panic disorder.138 Whether these alterations are also directly linked to alterations of food intake and body weight remains to be further addressed.
Similar to CCK, studies are lacking that investigate changes of peripheral GLP-1 expression due to stress, anxiety or depression. However, central GLP-1R stimulation acutely induces anxiety-like behavior in rats, while chronic administration of exendin-4 reduces depression-like behavior.139 These interesting differential effects of acute
Lastly, mice lacking the Y2 showed a suppression of anxiety and stress-related behavior140 suggesting that the PYY-mediated reduction in food intake might also be associated with or be secondary due to a modulation of anxiety and stress. These data show that food-intake regulatory peptides often exert multiple, if not pleiotropic, actions and especially effects related to anxiety and stress may be associated with an acute or chronic modulation of food intake.
Since it is known that long-term physical activity is able to reduce body weight,141,142 an impact on gastrointestinal peptide hormones has been assumed as well. Exercise leads to a reduction of hunger, an effect observable shortly after performing sports.143 In line with this finding, the concentration of ghrelin is reduced following aerobic sports,144,145 as well as resistance exercise,145 likely contributing to the exercise-induced reduction of food intake. However, the exact role of ghrelin under these conditions needs to be further investigated as a correlation of hunger and circulating ghrelin was not detected,144,145 likely suggesting an indirect effect of ghrelin and/or additional (peptidergic) mechanisms.
This hypothesis is underlined by the fact that the decrease of ghrelin levels during exercise is accompanied by reciprocal changes of anorexigenic hormones. Various studies reported that PYY concentrations rise during exercise in lean144,146,147 as well as obese148 individuals. Interestingly, one study showed that plasma concentrations of PYY increased at 5 hours after aerobic exercise, whereas anaerobic exercise did not affect PYY levels.144 Similar results were found for the impact of aerobic exercise on GLP-1 levels, which where elevated during and up to 1 hour after exercise.146–148 CCK concentrations were elevated in men performing 30-minute cycling but did not change after chronic training over a period of 4 weeks.149 These results were confirmed by a 12-week individually designed and supervised exercise program in overweight and obese individuals without changes in CCK concentrations at the end of the treatment period.150 Additionally, cumulative food intake was not altered after 12 weeks,150 which might point towards a rather acute effect of exercise on CCK. Taken together, these results show that acute exercise might affect food intake regulation by changes of the secretion of food intake-regulatory peptides from the gastrointestinal tract, whereas long-term exercise might lead to adaptive changes also blunting the effects on food intake.
Interestingly, different from other anorexigenic peptides, circulating NUCB2/nesfatin-1 decreased after acute exercise at the individual anaerobic threshold.151 In contrast to this acute regulation, aerobic exercise for a period of 8 weeks in overweight and obese females as well as a 6-week high-intensity interval training in overweight men increased circulating NUCB2/nesfatin-1 levels.152,153 These results were confirmed in women with type 2 diabetes mellitus who performed a 10-week resistance training.154 Since current data rather point to a central effect of nesfatin-1 on food intake, the observed peripheral changes of NUCB2/nesfatin-1 after acute and chronic exercise might impact on other regulatory processes such as glucose homeostasis.
Despite the fact that our knowledge on the peptidergic regulation of food intake greatly increased during the past years, only few drugs targeting these hormones are on the market or are tested for the market. Nonetheless, several candidates are in the preclinical pipeline.
While several GHSR1a agonists such as ipamorelin155 or BIM-2831156 are known and able to stimulate food intake, body weight gain, and gastrointestinal motility,155 there is a paucity on ghrelin antagonists. Intraperitoneal and intracerebroventricular administration of [D-Lys-3]-GHRP-6, a GHSR1a antagonist decreased food intake.157 However, GSK1614343, another GHSR1a antagonist, was not able to reduce ghrelin-stimulated food intake and unexpectedly itself stimulated food intake and body weight in rats and dogs158 likely due to GHSR1a-stimulating activity. It is also important to note that the ghrelin receptor GHSR1a displays considerable constitutive signaling activity,159 therefore blockade by classical agonists cannot fully abolish ghrelin signaling. In line with this assumption, central administration of a substance P derivate, an inverse agonist of the ghrelin receptor, was able to reduce food intake and body weight by decreasing the expression of NPY in the hypothalamus.160 Another possibility to reduce food intake is to inhibit the acylation of ghrelin. The most established GOAT inhibitor is GO-CoA-Tat, a peptide-based bisubstrate analogue that was shown to acutely reduce food intake in Siberian hamsters161 and rats162 as well as body weight following repetitive intraperitoneal injections in mice.163 Whether these data can be translated to humans will have to be further investigated.
The food intake-reducing effect of nesfatin-1 is more readily observed after central injection164 hampering the potential therapeutic use as a target in the treatment of obesity. However, one study described the use of an intranasal application of nesfatin-1 in rats inducing an acute reduction of food intake.165 Whether this holds true over a longer period of time and also in humans warrants further investigation.
As described above, a soybean trypsin inhibitor stimulates CCK release from duodenal I cells, an effect mimicked by the non-nutrient trypsin inhibitor, Camostat following oral administration in rats.166 It is known that CCK-8 reduces food intake in healthy volunteers.167 However, no data exist so far on the food intake-modulating effect of the endogenous form, CCK-58 in humans which has a longer half-life in the circulation and might be more effective in the reduction of food intake.53 While several CCK antagonists such as devazepide have been established to increase the amount of food intake or attenuate the anorexigenic effect of CCK in rats,168 there is a paucity on CCK analogs. The use of native CCK is difficult and hampered by the rapid endogenous degradation resulting in a short half-life.169 Amino terminal glycation of CCK-8 prolongs its half-life169 and might therefore be a potential target for short-time therapeutic reduction of food intake. However, longer application may be limited by the development of tolerance as observed after a 2-week intraperitoneal infusion of CCK in rats.170 A recently developed CCK-8 analogue showed more promising results: (pGlu-Gln)-CCK-8 did not result in the development of an adaptation over a period of 28 days as reflected in a sustained decrease in food intake and body weight.171 Moreover, this compound is not subject to rapid degradation and was shown to be stable for 180 minutes post injection.171 Therefore, (pGlu-Gln)-CCK-8 as well as its poly-ethylene glycol-conjugated (PEGylated) form are promising targets in the treatment of obesity and deserve further testing.
Most of the studies investigating the effect of GLP-1 use the synthetic analogs exendin-4 and liraglutide, which are not degraded by dipeptidyl peptidase IV and able to cross the blood-brain barrier as active compounds to bind to the GLP-1R.70 Exendin-4 injected intraperitoneally reduced cumulative food intake in mice by activating sensory afferent pathways due to binding to the GLP-1R, an effect attenuated by co-injection of capsaicin.172 These results were confirmed in rats, where intraperitoneal as well as subcutaneous injection of exendin-4 and liraglutide reduced cumulative food intake after acute injection.71 The same study investigated the effect of subacute intraperitoneal and subcutaneous administration of exendin-4 and liraglutide in diet-induced obese (DIO) rats over a period of 7 days. Both GLP-1 analogs reduced intake of a high fat/sucrose diet and led to a decrease of body weight.71 Taken together, these results show that exendin-4 and liraglutide might be potential targets in the treatment of obesity. A recent meta-analysis comparing 21 studies investigating the effects of GLP-1 analogs on body weight changes in humans confirmed the results observed in rodents, and concluded that exenatide and liraglutide reduce body weight compared to controls.173 These compounds are therefore already used—lira-glutide was recently approved for the drug treatment of obesity—in the clinic.
Although PYY levels are reduced in obese patients, its anorexic effect is still visible after exogenous administration.174 Therefore, PYY analogs and Y2 agonists were suggested as possible targets in the treatment of obesity. The injection of PYY reduces food intake, an effect absent in mice lacking the Y2.100 Also, the use of a selective neuropeptide Y2 PEGylated peptide agonist consisting of a peptide core corresponding to residues 13 to 36 of human PYY and a non-peptidic moiety (2-mercaptonicotinic acid) at the peptide N-terminus reduced food intake and body weight in lean rodents as well as in DIO rats.175 This anorexigenic effect was blocked by co-administration of the Y2 agonist, BIIE0246,175 giving rise to direct competition at the Y2. Recently, a group developed a strategy to create dual target peptides intended to inhibit the GHSR1a while stimulating the Y2.176 While the first results are promising in vitro,176 more research is needed in vivo under acute and chronic conditions in experimental animals and ultimately in humans.
For patients suffering from severe obesity, bariatric surgery is the most effective treatment to reduce body weight.177 The most common procedures are Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), whereas gastric banding (GB) is not frequently performed anymore, and biliopancreatic diversion/duodenal switch (BPD/DS) often reserved as a second option.178 While our knowledge on the effectiveness of these techniques mentioned above (with the exception of gastric banding which does not result in a long-lasting reduction of body weight179) greatly increased over the past years, our knowledge on the underlying mechanisms is still incomplete. Besides the proposed restrictive and malabsorptive components of these techniques,180 an altered gastrointestinal peptide signaling very likely plays a role as well.
While GB had no effect on circulating ghrelin levels,181,182 SG183 and BPD/DS184 led to a pronounced and long-lasting decrease of circulating ghrelin. This regulation seems different under conditions of RYGB with an early decrease of ghrelin184 followed by a later increase to reach preoperative levels,183,185 which may be associated with retained vagal signaling in these patients.185
In type 2 diabetic rats, NUCB2/nesfatin-1 levels initially decreased after RYGB, but increased again at 2 months after the procedure, whereas SG did not affect nesfatin-1 levels.186 In patients with type 2 diabetes mellitus, both RYGB and SG reduced nesfatin-1 levels after surgery with a positive correlation with decreasing BMI,187 an adaptation possibly involved in the postoperative improvement of glucose control. A recent study showed that NUCB2/nesfatin-1 levels were decreased at 12 months following BPD/DS,188 which positively correlated with weight loss. This might be an adaptation process as well, since it is known that peripheral nesfatin-1 is rather involved in hepatic lipolysis49 or glucose homeostasis51 than in body weight control.
The postprandial release of CCK, GLP-1, and PYY was increased following both RYGB189 and SG,183,190 a finding not observed after GB for GLP-1 and pancreatic polypeptide,181 while the regulation of CCK after GB is unknown so far. This increased postprandial release of CCK, GLP-1, and PYY might be due to faster delivery of nutrients to the distal intestinal tract following surgery and contribute to the improvement of glucose control as well as the reduction of food intake and subsequently body weight. Additionally, combined blockade of GLP-1 and PYY in type 2 diabetic patients following RYGB increased food intake, supporting the hypothesis that these 2 peptides play a role in the postoperative attenuation of food intake.191
Taken together, these results show that bariatric surgery greatly affects signaling of food intake-regulatory gastrointestinal peptides that likely contributes to the body weight-reducing effect of these procedures. The impact of bariatric surgery on gastrointestinal peptides is summarized in Figure 2.
Since obesity still is an increasing threat to global health, new approaches have been tested to reduce body weight and food intake. One of the most promising and interesting approaches—besides the well-established use in Parkinson’s disease192,193 and depression194—is the application of deep brain stimulation (DBS), which is a minimally invasive and reversible method to modulate the central neuronal network.195 Interesting regional targets of the brain encompass the LHA, ventromedial hypothalamus (VMH) and the core and shell of the nucleus accumbens (NAc).196
Recently, a study investigated the effects of bilateral DBS in the LHA in 3 morbidly obese patients. The authors did neither report any serious side effects nor effects on body weight gain with the DBS settings used for movement disorders.197 However, when DBS stimulation was performed in the monopolar mode, the resting metabolic rate increased in 2 out of 3 patients and all 3 patients reported a decreased urge to eat.197 The follow-up investigations under monopolar settings showed a weight loss ranging from 12.3–16.4% in 2 of the 3 patients (and 0.9% in the third patient).197 Interestingly, food intake-regulatory peptides such as insulin, insulin-like growth factor, ghrelin, leptin, NPY, AgRP, and PYY were not altered under these conditions197 giving rise to local mechanisms. These results on food intake and body weight are extended by animal studies investigating the effects of bilateral DBS of the LHA in obese Zucker rats, which decreased food intake after 15 days of stimulation associated with a slight reduction of body weight that did not reach statistical significance.198 Taken together, monopolar stimulation seems to be necessary in order to induce weight loss. Although the LHA might be a promising target area, more research investigating larger patient populations over a longer follow-up period is needed to better characterize these effects.
Application of DBS to the VMH of a morbidly obese patient produced several unexpected side effects affecting memory or recollection.199 No weight changes were seen during the first 6 months using monopolar stimulation at 130 Hz.199 However, after lowering the frequency to 50 Hz the patient lost 12 kg in 5 months and reported a reduced desire to eat.199 Subsequent studies were performed in female Göttingen minipigs, which were fed a restricted diet for one month after surgery without stimulation, followed by a 2-months period with twice the amount of food and half of the animals receiving DBS 50 Hz within the VMH, while the other half was not stimulated.200 No motoric or behavioral side effects were monitored and all animals consumed the increased amount of food; however, the DBS-treated animals showed a reduced cumulative weight gain compared to non-stimulated pigs.200 This points towards a DBS-mediated increase in energy expenditure resulting in a reduction of body weight. In 2 vervet monkeys, bilateral DBS (monopolar, 185 Hz) of the VMH increased food consumption without serious side effects,201 while a study in rats with unilateral, bipolar (150 and 500 Hz) DBS stimulation of the VMH did not show changes in body weight after 32 days of stimulation.202 Whether these different results are due to species differences or differences in the strength and mode of stimulation remains to be further investigated. In order to possibly target the VMH to treat obesity further analyses are necessary, especially observations of psychological and behavioral side effects. Until then, other areas appear to be more promising targets.
Another interesting approach is to target the NAc as part of the reward circuitry. The NAc is divided into core and shell and was first targeted to treat neuropsychiatric disorders, like Tourette’s syndrome203 or alcoholism.204 Based on these studies, it is known that electrical stimulation of the NAc is safe and feasible in humans.196 Direct stimulation of the NAc shell results in a modulation (either stimulation or inhibition) of food intake,205,206 an effect likely involving GLP-1 signaling.207,208 Treatment of the NAc shell and core with exendin-4 reduced food intake, especially of highly palatable food.207 However, only injection of exendin-4 into the NAc core reduced intake of 15% sucrose, whereas no effects on sucrose intake were observed after injection into the NAc shell.207 On the other hand, antagonism of GLP-1 signaling using exendin-9 injected into the NAc core and shell increased food intake.207 These data point towards a role of the endogenous GLP-1 signaling in the NAc to regulate food intake. Also, CCK is involved in the regulation of palatable food intake by affecting the NAc as shown in rats.209 Moreover, ghrelin injected into the NAc also stimulates food intake210 and increases extracellular dopamine levels following administration into the NAc shell.211 This indicates that the NAc shell might be an interesting target to increase food intake, as shown by a Dutch group that reported an increase of food intake in rats after DBS stimulation of the NAc medial shell, whereas DBS stimulation of the NAc core did not alter food intake.205 Interestingly, subsequent research in DIO rats showed that DBS stimulation of the NAc shell reduced food intake and body weight gain despite the fact that dopamine levels were increased in the NAc shell.206 Whether these discrepancies are due to different settings of stimulation, species or nutritional status needs to be further elucidated. The main effects of DBS on body weight and food intake are summarized in the table.
Although the basic mechanisms regulating hunger and satiety were extensively investigated, the complex and redundant system is still difficult to modulate. Besides (so far not very successful) conservative treatment options, surgical techniques can be applied. While bariatric surgery has become an effective treatment option for obesity associated with a long-term alteration of gastrointestinal peptidergic signaling, deep brain stimulation might be a promising and less invasive tool for the treatment of obesity.
Overview of Current Studies on the Effects of Deep Brain Stimulation on Body Weight and Food Intake
|Target area||Mode||Species (n)||Results||References|
|Lateral hypothalamic area||Bilateral, monopolar, 185 Hz||Humans (3)||2 out of 3: body weight ↓||197|
|Bilateral, bipolar, 130 Hz||Obese Zucker rats (10)||Body weight ↓, food intake ↓||198|
|Ventromedial hypothalamus||Bilateral, monopolar, 50 Hz||Human (1)||Body weight ↓||199|
|Bilateral, monopolar, 50 Hz||Göttingen minipigs (8)||Body weight gain ↓||200|
|Bilateral, monopolar, 185 Hz||Vervet monkeys (2)||Food intake ↑||201|
|Unilateral, bipolar, 150 Hz||Sprague Dawley rats (4)||No effect on body weight||202|
|Unilateral, bipolar, 500 Hz||Sprague Dawley rats (5)||No effect on body weight||202|
|Nucleus accumbens shell||Bilateral, bipolar, 130 Hz||Wistar rats (8)||Food intake ↑||205|
|Unilateral, stimulation mode not specified, 130 Hz||Diet-induced obese rats (8)||Body weight ↓, food intake ↓||206|
|Unilateral, stimulation mode not specified, 130 Hz||Sprague Dawley rats (8)||No effects on body weight and food intake||206|
|Nucleus accumbens core||Bilateral, bipolar, 130 Hz||Wistar rats (8)||No effect on food intake||205|
↓, decrease; ↑, increase.