Satiety and the role of m-opioid receptors in the portal veinFilipe De Vadder1,2,3, Amandine Gautier-Stein1,2,3 and Gilles Mithieux1,2,3

Available online at www.sciencedirect.com

ScienceDirect

Mu-opioid receptors (MORs) are known to influence food

intake at the brain level, through their involvement in the food

reward system. MOR agonists stimulate food intake. On the

other hand, MOR antagonists suppress food intake. MORs are

also active in peripheral organs, especially in the small intestine

where they control the gut motility. Recently, an indirect role in

the control of food intake was ascribed to MORs in the extrinsic

gastrointestinal neural system. MORs present in the neurons of

the portal vein walls sense blood peptides released from the

digestion of dietary protein. These peptides behave as MOR

antagonists. Their MOR antagonist action initiates a gut-brain

circuitry resulting in the induction of intestinal gluconeogenesis,

a function controlling food intake. Thus, periportal MORs are a

key mechanistic link in the satiety effect of protein-enriched

diets.

Addresses1 Inserm U855, Lyon, France2 Universite Lyon 1, Villeurbanne, France3 Universite de Lyon, Lyon, France

Corresponding author: Mithieux, Gilles (gilles.mithieux@inserm.fr,

gilles.mithieux@gmail.com)

Current Opinion in Pharmacology 2013, 13:959–963

This review comes from a themed issue on Endocrine and metabolic

diseases

Edited by Frank Reimann and Fiona M Gribble

For a complete overview see the Issue and the Editorial

Available online 3rd October 2013

1471-4892/$ – see front matter, # 2013 Elsevier Ltd. All rights

reserved.

http://dx.doi.org/10.1016/j.coph.2013.09.003

Hedonic and motivational roles of brain m-opioid receptors in food rewardThe huge worldwide increase in cases of obesity and its

associated diseases such as type 2 diabetes or cardiovas-

cular failure makes a better understanding of the mech-

anisms of body weight control, namely food intake and/or

energy expenditure, more and more crucial. Among these

mechanisms, the sensations of hunger and satiety play

important roles. It has been known for a long time that the

switch between the hunger preceding the meal and the

sensation of fullness following the ingestion of food is

altered in obese subjects, notably relating to lipid-

enriched food [1�,2�]. There are various causes for this.

A key component of these defects could arise from

alterations in the so-called ‘reward system’ [3,4]. Indeed,

food is one of the intense and necessary rewards in life.

We eat what we like, and we want the food we like. Thus,

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food reward can be separated into hedonic ‘liking’ and

motivational ‘wanting’. The brain mechanisms of plea-

sure and incentive motivation for food influence nearly all

varieties of eating. Any dysfunction in either of these

mechanisms can lead to food-related disorders, including

obesity and binge eating, which are characterized by

excessive ‘liking’ or ‘wanting’ [3,4].

Mu-opioid receptors (MORs) are well known to interfere

with the mechanisms of regulation of pain. In particular,

they are the targets of opioids, which act as agonists on

MORs to promote analgesia. Additionally, they are

involved in the food reward system by attributing a value

of enjoyment to the taste of food and play also a key

role in modulating food intake. Opioid receptor agonists

increase food intake, whereas opioid receptor antagonists

decrease it [5–7]. For example, a central administration of

the m-opioid agonist DAMGO elicits feeding in satiated

animals [8]. Moreover, administering m-opioid agonists or

antagonists modulates pleasure ratings of foods [5,6,9].

Systemic exposure to opioid-stimulating molecules

increases ‘liking’ reactions to a sweet tasting food [10].

Activation of mu-opioid receptor ‘hotspots’, which have

been identified in the ventral pallidum and nucleus

accumbens of the brain, increase hedonic reactions to

sweet tastes [11] and the intake of palatable foods such as

high fat/high sucrose diets [12]. On the contrary, central

antagonism of MORs reduces positive taste reactions [13]

and prevents food seeking and binge eating [14�]. Accord-

ingly, the potent mu-opioid antagonist naloxone sup-

presses the intake of a sucrose solution [15], and blocks

the preference for saccharin [16]. In addition to MORs,

other types of opioid receptors exist, such as the kappa-

opioid or delta-opioid receptors. Their roles in the control

of hunger are less clearly established.

The role of peripheral m-opioid receptors infood intake controlIt is noteworthy that, after the brain, the body site in

which MORs are most widely expressed is the gastro-

intestinal area, especially the small intestine, where they

have been shown to control gut motility [17–19]. That

intestinal MORs may influence food intake has been

suggested from the following observations. (i) The

well-known MOR agonist morphine is often used in

cancer patients to combat pain. A frequent adverse effect

is constipation caused by the arrest of gut motility. When

naloxone, a chemical MOR antagonist, is given orally to

prevent constipation in patients treated by morphine,

naloxone restores gut motility while the central analgesic

effect of morphine is preserved [20,21]. This suggests that

the drug might be active as an MOR antagonist at a

Current Opinion in Pharmacology 2013, 13:959–963

960 Endocrine and metabolic diseases

gastrointestinal site, without reaching the brain. (ii) In

agreement with the aforementioned observation, nalox-

one and its relatives suppress food intake when given

orally in humans [5]. However, the drug is actively

metabolized in the liver [22,23]. This suggests that the

drug might modulate hunger sensations from a gastroin-

testinal site.

A connection between the protein digestion process and

MORs?

It is a well established fact, both in animals and humans,

that diets enriched in protein decrease hunger sensations

and food intake [24,25]. The mechanisms by which this

takes place have long been unclear. A long-known and

intriguing property of proteins in relation to MORs is that

a number of them, especially those involved in human

nutrition such as caseins from milk or gluten, release

oligopeptides exhibiting m-opioid activity in vitro upon

partial proteolytic digestion [26]. Depending on the

protein source, the resulting effect is that of an agonist

or an antagonist [26]. Moreover, there is a vast literature

reporting the m-opioid activity of various oligopeptides, of

which the minimal structure required is a dipeptide [27–30]. Like protein digests, some peptides behave as MOR

agonists [28–30], others as MOR antagonists [27,29]. It is

also well known that dietary proteins are absorbed from

the intestinal lumen after incomplete proteolysis. Hence,

it has been hypothesized that alimentary proteins (e.g.

caseins) might exert a systemic signaling role via their

proteolytic digests with m-opioid activity [31,26]. How-

ever, it seems doubtful that these oligopeptides might

reach the brain following oral ingestion. For instance, b-

casomorphin 1–7 (b1–7), an MOR agonist released by the

digestion of b-casein, is actively degraded by the liver

[32] and is not detected in systemic blood after the

ingestion of milk or dairy products [33]. Alternatively,

it has been proposed that MOR modulators from an

alimentary origin might act at a gastrointestinal or

mesenteric portal site [34,31]. The possibility that dietary

MOR modulators might interfere in the control of food

intake was not specifically evoked. However, this cannot

be ruled out, since peripheral MOR signaling could be

transmitted to central targets via the afferents of the

gastrointestinal system.

Intestinal gluconeogenesis links the protein digestion

process and satiety

Compelling evidence has been provided that the con-

nection between dietary proteins and their hunger

decreasing effects is dependent on an unexpected inter-

mediate process, namely intestinal gluconeogenesis

(IGN). Like the liver and kidney, the small intestine is

a gluconeogenic organ, capable of synthesizing glucose

and releasing it in the portal blood when the body needs

it, for example, during prolonged fasting [35–38]; for a

review, see [39]. A strong induction of the expression of

the genes of intestinal gluconeogenesis (glutaminase,

Current Opinion in Pharmacology 2013, 13:959–963

glucose-6 phosphatase, phosphoenolpyruvate carboxyki-

nase-cytosolic form (PEPCK-c)) takes place in rats or

mice after a protein-enriched diet [40]. This leads to

glucose production in the portal vein lasting during the

post-absorptive period. This activates a neural glucose

sensing mechanism in the walls of the portal vein (the so-

called ‘portal glucose signal’), which has been known for

decades to curb hunger by acting at an hypothalamic level

after transmission of the signal via the afferents of the

extrinsic gastro-intestinal neural system (for a review,

see [41]). Genetic manipulation of the glucose-6 phos-

phatase catalytic subunit (G6PC) in mice has shown that

IGN is a mandatory link between protein dieting and

satiety. Mice depleted in G6PC specifically in the small

intestine are insensitive to the satiety effect of protein-

enriched diets [42]. Finally, protein-induced satiety is still

present in mice whose major hypothalamic components

in the control of food intake (receptors and neuromedia-

tors of the hypothalamic melanocortin system) are

deleted [43�].

It is worth noting that IGN is a process that takes time to

establish, since it depends on gene induction. Thus, it

may endure after food assimilation as it depends on the

robust induction of enzyme activities. This may explain

why protein feeding decreases hunger at a period after the

preceding meal, which is the definition of the phenom-

enon called ‘satiety’ [24,25].

MORs connect the protein digestion process to the

induction of intestinal gluconeogenesis

The mechanisms by which dietary protein could induce

IGN have not been identified. Given the aforementioned

connections between MORs and intestinal dietary

protein metabolism, we first tested the hypothesis that

MORs could be present in the periportal neural system

and regulate expression of IGN genes via a gut-brain

reflex arc. To this aim, we infused MOR modulators in

the portal vein of conscious rats through a catheter

implanted in a mesenteric vein. Casomorphin b 1–7, from

human b-casein, and another MOR agonist (DAMGO)

reduced the activity of the key enzymes of IGN (glucose-

6-phosphatase and PEPCK-c) after infusion for 8 hours.

By contrast, MOR antagonists (naloxone, casoxine C)

increased these activities. In agreement with the gene

expression pattern, intestinal glucose production

represented 25–30% of the total endogenous glucose

production after infusion of naloxone, whereas no appear-

ance of glucose was observed in rats infused with

DAMGO. This led rats infused with an MOR antagonist

to decrease their food intake, whereas those infused with

an agonist increased it [44��]. An immunofluorescence

approach allowed us to demonstrate co-localization of the

neuronal marker PGP9.5 and MORs in the walls of the

portal vein of rats and mice and in the portal vein branches

irrigating the portal spaces in human liver. We also

identified brain regions activated by MOR signals by

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m-Opioid receptors in the portal vein for satiety De Vadder, Gautier-Stein and Mithieux 961

Fig. 1

1/ Dietary proteins

2/ peptides

3/ MOR

4/ GluconeogenesisGlucose

Protein-induced Satiety

(a) (b)

Glucose sensing

Current Opinion in Pharmacology

Role of peripheral MORs in the satiety induced by food protein. (a) Peptides resulting from the hydrolysis of proteins from the meal are released in the

portal vein and exert an antagonist effect on the MORs expressed in the neural system of the walls of the portal vein. The signal conveyed by the

ascending nerves controlled by MORs to its central targets, travelling via both the vagus nerve and the spinal cord, drives the induction of intestinal

gluconeogenesis gene expression. (b) Lasting after nutrient assimilation has ended, glucose released into the portal blood is sensed by the portal

glucose sensor and exerts its hunger-curbing effect.

immunostaining of the gene product C-FOS. This

suggests that both the vagal pathway (connected to the

dorsal vagal complex), and the spinal pathway (connected

to the parabrachial nucleus), are involved in MOR signal

transmission from the portal vein to the central nervous

system [44��]. Finally, the regulation of IGN, as well as

the activation of brain targets, did not take place after

prior denervation of the rat portal vein by capsaicin, a drug

inactivating neural afferents. This demonstrates the

importance of the periportal nervous system in the trans-

mission of the MOR signal (Fig. 1). In a second phase, we

tested the hypothesis that food protein digests (oligopep-

tides) could interfere with periportal MORs during meal

protein assimilation. Since oligopeptides can pass into the

portal blood [45], we infused protein hydrolysates or

selected oligopeptides (di-or tri-peptides) in the mesen-

teric vein of rats. In all cases, a marked induction of IGN

genes was observed. On the other hand, these effects

were absent in animals with denervated portal vein, as

previously observed with MOR modulators. In addition,

protein hydrolysates and oligopeptides behaved as MOR

antagonists in neuroblastoma cells constitutively expres-

sing these receptors [44��]. To establish definitive causal

links between peptides and MORs and between MORs

and IGN, we investigated these mechanisms in mice

deficient in the gene encoding the MORs and in mice

deficient for IGN. In wild-type mice, oligopeptides

induced IGN and cancelled the suppressive effect of

DAMGO. However, none of these effectors induced

any effect in the MOR-KO mice [44��]. Thus, the

MOR-KO mice did not reduce their food intake in

response to diets enriched in protein, unlike wild-type

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mice, which decreased their food intake by 20%. Finally,

we studied food intake in IGN-deficient mice during

portal infusions with a MOR antagonist or a dipeptide.

Although wild-type mice reduced their food intake by

15%, no effect was observed in the absence of intestinal

gluconeogenesis.

In summary, we have shown that the global modulating

activity of peptides vis-a-vis the MORs under physiologi-

cal conditions of protein digestion is that of an antagonist.

This could appear surprising, given the literature report-

ing that peptides or dietary protein digests could behave

as either MOR agonists or MOR antagonists [26–30].

However, various MOR-initiated intracellular processes

occur after ligand–receptor interaction (such as receptor

internalization and degradation or intracellular sorting

and recycling). This results in complex adaptations in-

cluding receptor down-regulation, desensitization and re-

sensitization, which may depend on the nature or the

concentration of the ligand and/or on the time of

exposure. These cumulative processes make the final

effects of MOR modulators (i.e. agonist-like or antagon-

ist-like) crucially dependent on the conditions of the

experiment (for a detailed review, see [46]). Altogether,

this probably explains at least some of the diverging

results previously published in the field.

A fascinating question remains whether assimilated pep-

tides counterbalance a constitutive activity of MOR or

endogenous agonist of yet-to-be-defined origin. Arguing

for the latter possibility, endogenous peptides, the so-

called ‘endorphins’, have been identified in the brain and

Current Opinion in Pharmacology 2013, 13:959–963

962 Endocrine and metabolic diseases

gastrointestinal system, and exhibit m-opioid activity invitro. However, the MOR also exhibits constitutive

activity in vitro in the absence of agonist [44��,47]. Since

experimental evidence for a physiological role of endor-

phins in vivo is lacking, particularly in the intestine, this

question remains open.

Concluding remarksUntil now, the regulatory role of MORs in the control of

food intake had been documented in the central nervous

system, especially those regions known to be involved in

the so-called ‘reward’ system (see introductory para-

graph). We have now found that MORs expressed in

the mesenteric-portal area control a neural gut-brain

circuit regulating intestinal gluconeogenesis, and food

intake [40,42,48]. Moreover, the role of peripheral MORs

in the neural circuitry by which alimentary proteins

initiate their satiety effects (via the m-opioid antagonist

activity of their proteolytic digests and then IGN) has

been established. Remarkably, various m-opioid

antagonists given orally decrease hunger in humans [5].

Moreover, the satiety effect of food protein concerns

animal species and humans as well [24,25,40].

It is interesting to make a connection with the field of

gastric bypass surgery. Gastric bypass is an increasingly

popular surgical operation to treat morbid obesity, and

promotes a dramatic reduction of hunger sensation within

a few days after the operation. This is true in obese mice

[48] and in obese humans (for a review see [49]). In a

mouse model of gastric bypass, it has been strongly

suggested that the hunger-curbing effect is the con-

sequence of inducing IGN [48]. IGN is a feature of

the human small intestine [35,50] and has been suggested

to occur after bypass surgery in obese patients [51��,52�].Since MORs are widely expressed along the human gut,

the possibility that they might be involved in the induc-

tion of IGN in relation to the protein content of the diet is

attractive and deserves further consideration.

AcknowledgementsThe author thanks all members of the team who contributed in various waysto this work. The contribution of Christophe Magnan and FabrizzioAndreelli and their respective teams is greatly acknowledged.

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Current Opinion in Pharmacology 2013, 13:959–963