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The metabolic actions of neurotensin secreted from the gut

Ratner, Cecilia; Hundahl, Cecilie; Holst, Birgitte

Cardiovascular Endocrinology & Metabolism: September 2016 - Volume 5 - Issue 3 - p 102–111
doi: 10.1097/XCE.0000000000000085
Review Articles

Neurotensin (NT) is a 13 amino acid peptide hormone primarily expressed in the brain and in the gastrointestinal (GI) tract. NT in the brain is generally considered an anorexigenic neuropeptide, but the potential metabolic actions of GI tract NT have not been investigated extensively. In the GI tract, NT is mainly found in so-called N cells, but is also coexpressed with a number of functionally related hormones including glucagon-like peptide-1 (GLP-1) and peptide YY. NT, GLP-1, and peptide YY can further be released together in response to a number of different physiological stimuli and can coact on some but not all target organs. In line with the recent focus on developing antiobesity agents targeting more than one signaling pathway, NT may be a candidate for such polytherapy drugs in combination with other gut hormones such as GLP-1.

aLaboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology

bSection for Metabolic Receptology, The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

Correspondence to Cecilia Ratner, PhD, Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, University of Copenhagen, Panum Institute Building 18.5, Blegdamsvej 3B, 2200 Copenhagen N, Denmark Tel: +45 2299 9320; e-mail:

Received June 7, 2016

Accepted June 23, 2016

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Neurotensin (NT) is a 13 amino acid peptide hormone initially isolated from bovine hypothalamus by Carraway and Leeman 1 and shortly thereafter from bovine small intestine 2. NT is primarily expressed in the brain and in the gastrointestinal (GI) tract but also in a variety of other peripheral organs such as in chromaffin cells of the adrenal medulla and in the pancreas 3,4. The majority of studies investigating NT physiology have focused on brain functions, whereas NT released from enteroendocrine cells has largely been neglected in the last decades. In the brain, NT regulates appetite, opioid-independent analgesia 5, hypothermia 6, and pituitary hormone secretion 7 and modulates several neurotransmitter systems, particularly the dopaminergic system 8. This review will, however, focus on gut-derived NT and, in particular, on NT coacting with the functionally related hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY).

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Neurotensin processing and degradation

NT (pyroGlu–Leu–Tyr–Glu–Asn–Lys–Pro–Arg–Arg–Pro–Tyr–Ile–Leu–OH) is synthesized as a large 169–170 amino acid long precursor and is highly conserved among species. In addition to NT, the precursor also contains neuromedin N (NN), a six amino acid peptide with strong homology to the C-terminal of NT. NT and NN are located in the C-terminal of the precursor and are separated and flanked by Lys–Arg cleavage sites, which are post-translationally processed by prohormone convertases (PCs) 1, 2, or 5A into active NT and NN dependent on the tissue. Further, a fourth Lys–Arg cleavage site is present in the middle of the precursor, but it is poorly processed likely because of its conformational environment 9. The processing occurs in a tissue-specific manner dependent on the availability of the PCs and their specificity toward the cleavage sites. For example, the major forms found in the brain are NT and NN, a processing pattern generated by PC2, whereas GI tract processing mainly gives rise to NT and the large form of NN, a processing pattern generated by PC1 (Fig. 1) 10–12. Little is known about the large forms of the peptides, but they are speculated to have biological functions, albeit with lower potency, but better plasma stability compared with NT and NN 9,13.

Fig. 1

Fig. 1

NT is rapidly degraded into inactive metabolites once released into the extracellular space. The major cleavage products in brain and gut tissue have been identified as NT1–8, NT1–10, and NT1–11. Three Zn-metallopeptidases are responsible for cleaving NT: endopeptidase 24.15 generates the NT1–8 fragment, and endopeptidase 24.11 generates the NT1–11 fragment, whereas both endopeptidase 24.11 and 24.16 can give rise to the NT1–10 fragment 14.

NT has a very short half-life in vivo when administered intravenously, in the order of 0.5–1.5 min in rodents and humans 15–18. When NT is incubated in human or rodent plasma or whole blood in vitro, however, the half-life of NT is markedly increased 15,19,20, suggesting that NT degradation occurs in the organs rather than in the circulation. Studies performed in rodents, dogs, sheep and humans suggest that NT clearance occurs in the kidney and intestine, some occurs in the brain, whereas the liver does not seem to contribute considerably to NT degradation 17,19,21–24. Interestingly, the active part of NT, which is recognized by the NT receptors, is the 8–13 C-terminal segment, and thus not one of the degradation products.

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Neurotensin receptors

NT binds three known receptors, of which the neurotensin receptor 1 (NTS1) and neurotensin receptor 2 (NTS2) are G-protein coupled, whereas the neurotensin receptor 3 (NTS3) is a type 1 single-membrane spanning channel 25.

NTS1 is found both in the brain and in the GI tract 26,27. In the brain, it is widely distributed, and in-situ hybridization, quantitative RT-PCR, receptor autoradiography, and immunohistochemical studies showed high expression in the substantia nigra, ventral tegmental area, islands of Calleja, hypothalamus, diagonal band of Broca, amygdala, septal regions, and thalamic regions 28–32. Similarly, NTS1 is present throughout the GI tract, with the highest expression in the colon measured by quantitative RT-PCR 32. NTS1 binds NT with high affinity in the nanomolar range 26. It increases inositol phosphate, inhibits cyclic AMP formation, activates phospholipase C, and mobilizes intracellular calcium, indicating a preferential coupling to Gq/11, but has also been shown to couple to Gs and Gi/o in some cellular systems 25.

NTS2, which binds NT with lower affinity than NTS1 33, is found primarily in the brain, but NTS2 immunoreactivity has also been reported in the human GI tract 34. In-situ hybridization, immunohistochemistry, and receptor autoradiography showed widespread brain localization with high expression in the olfactory system, bed nucleus of the stria terminalis, cortex, hypothalamus, hippocampus, amygdala, and brainstem regions modulating descending control of nociceptive inputs 35–37. In the GI tract, high expression was observed in parietal cells of the gastric mucosa, which could indicate a role in the inhibition by NT of gastric acid secretion 34.

Although NTS1 is believed to mediate most of the effects of NT, there is evidence that NTS2 is responsible for the analgesic effect of NT 5 and for NT effects on the pancreas 38. NTS2 can couple to diverse signaling pathways and can also signal with constitutive activity in some cell systems 25. Coupling to Gq/11, Gi/o, and G12/13 has been shown to be dependent on the cell system studied and receptor species expressed, but in contrast to NTS1, no clear preference for a G-protein has been shown 25. However, contradictory data have been reported on the ability of NT to activate NTS2. Both agonisms, neutral antagonism and inverse agonism, have been observed depending on the cellular environment by this presumably endogenous ligand for the NTS2 33,39,40.

NTS3, the third well-known NT receptor, is identical to sortilin – a protein involved in receptor sorting and interactions with receptor-associated proteins. NT has a high binding affinity for NTS3 41; however, its exact function in relation to NT remains hypothetical. It has been suggested to be responsible for NT-induced migration of microglial cells 42. Because of its general role in receptor sorting and interaction, and the observation that it can form heterodimers with the other NT receptors 43,44, it has also been speculated to regulate the internalization and recycling process of NTS1 45 as well as modulating second messenger signaling caused by NT acting on NTS1 and NTS2 43. Furthermore, NTS3 may be important for NT effects on the pancreas 44.

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Neurotensin in glucose homeostasis

NTS1, NTS2, and NTS3 are expressed in rodent β cell lines as well as in insulin-secreting islets and pancreatic tissue 32,44,46 and, in contrast to other tissues, NTS2 and NTS3 seem to be important for the effects of NT in the pancreas 38. Further, NT immunoreactivity has been found in the endocrine pancreas 47 and thus NT could act on the pancreas both in a paracrine manner, as a locally produced hormone, or in an endocrine manner, through NT released from the GI tract.

Early in-vivo studies showed conflicting results on the role of NT in insulin release, with some studies performed in dogs and in calves suggesting a positive association between increased endogenous or exogenous NT and insulin and glucagon release 48–50, whereas others found that NT produced hypoinsulinemia and hyperglucagonemia and consequently hyperglycemia in rat studies 51,52. More detailed studies carried out in rat islets and insulin-secreting cell lines showed that NT played a dual role in insulin secretion depending on the glucose concentration. NT stimulated insulin release at low glucose concentrations, whereas NT inhibited the glucose-induced insulin release 53,54.

NT levels in the pancreas are increased in diabetic rodents 47,55,56, although plasma concentrations are similar between diabetic rodents and their littermate controls 55. Clinical studies show conflicting results on associations between plasma NT levels and the diabetic state. One study found no association between NT plasma levels and the diabetic state 57, whereas another study found increased pro-NT levels associated with an increased diabetic risk in women, but not in men 58. A third study found increased pro-NT levels in obese and insulin-resistant patients and a positive association between pro-NT levels and the risk of developing obesity and diabetes later in life 59.

In addition to regulating insulin and glucagon release, NT may affect the pancreas through other mechanisms. NT exerts a trophic effect on the pancreas, increasing pancreatic weight, DNA, and protein content 60,61. Furthermore, NT protects β cells from apoptosis in response to cytotoxic agents 44,46. An interesting idea proposed by Mazella et al. 38 is that NT may protect the endocrine pancreas from cell death. As NT is released after ingestion of a high-fat meal, it might serve as a protective agent from hyperlipidemia in a manner similar to GLP-1, protecting the endocrine pancreas from hyperglycemia 38.

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Neurotensin and metabolic regulation

It is well established that brain NT regulates appetite as NT can inhibit food intake in rodents when injected into several brain regions including intracerebroventricularly 62–65, hypothalamic areas 62,66, the nucleus of the solitary tract 67, and the dopaminergic nuclei 64,68.

Obese Zucker rats and obese ob/ob mice have lower hypothalamic NT levels compared with their lean littermates 69–71 and treatment with leptin or α-melanocyte-concentrating hormone increases NT expression in a hypothalamic cell line 72, all pointing to a role of NT as an anorexigenic neuropeptide.

Brain NT is also an important mediator of other satiety signals such as the hormone leptin. NT antiserum as well as antagonism or deletion of the NTS1 in mice blunt the anorexigenic action of leptin 73,74. This is at least partly mediated by leptin action on NT-expressing neurons projecting from the lateral hypothalamus to the ventral tegmental area 75. Furthermore, mice with a specific deletion of the leptin receptor in NT-expressing neurons in the lateral hypothalamus show increased appetite, decreased activity, and early-onset obesity probably caused by an impaired control of lateral hypothalamus orexin neurons and dopaminergic neurons 76.

NTS1 knockout (ko) mice have increased appetite and body weight and are nonresponsive to the anorexigenic effects of NT 73,77. In contrast, a more recent study found decreased feeding and increased activity levels in NTS1 ko mice placed on a chow diet, with no overall effect on body weight and body composition 75. However, when placed on a palatable high-fat/high-sucrose diet, NTS1 ko mice ate more and gained more weight than controls and had higher sucrose preference, suggesting that the NTS1 regulates hedonic feeding behavior 75. Interestingly, a recent study found that NT-deficient mice were protected from high-fat diet-induced obesity because of decreased absorption of fat from the intestine 59.

Two studies have tested brain-penetrating NT analogues with improved plasma stability in relation to food intake and body weight in a chronic setting. The NT analogue NT69L decreased food intake and body weight gain dose dependently in chow-fed Sprague–Dawley rats and obese hyperphagic Zucker rats during testing periods ranging from 15 to 38 days 78. Similarly, the NTS1 agonist PD149163 decreased food intake and body weight in Brown Norway rats and obese ob/ob mice during a 10-day test period 79. Thus, there is ample evidence for a role of brain NT and brain-penetrating stable NT analogues in regulating energy metabolism, but the role of peripherally derived NT is less well established. Some studies find that peripheral NT can inhibit food intake acutely both in lean 63,80,81 and in obese rodents 80, but others do not 66. Peripherally injected NT has only been tested chronically in one study in mice where tachyphylaxis was observed 63. This could be because of internalization and degradation of the NTS1 as described in in-vitro studies upon multiple agonist stimulations 45,82.

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Neurotensin in the gastrointestinal tract

NT is present throughout the GI tract with high levels in the ileum in pigs, rats, and humans and high levels in ileum and the proximal colon in mice 83–85. NT release is stimulated by endogenous fluids such as bile acids, gastric acid, and pancreatic juice 86,87 and by the ingestion of food, particularly fat 88,89, and to a lesser extent protein and carbohydrate 90. NT is released rapidly after food ingestion both through a direct contact of NT secreting cells to nutrients 86,91 as well as through feed-forward loops from the proximal GI tract including both neural and endocrine signals 88,91.

Once released, NT promotes absorptive processes through several mechanisms: NT increases ileal blood flow 89, pancreatic amylase secretion 60, and hepatic bile secretion 92. NT’s effect on bile acid secretion is mediated both directly by stimulating the contraction of the gall bladder and bile duct 93 and through reabsorption of bile in the ileum, thus upregulating enterohepatic bile recycling 94. In addition, NT stimulates electrolyte and fluid secretion 95,96 and regulates GI tract motility by slowing the transit time in the stomach and the small intestine and promoting movements that optimize absorption 97.

Because of the very short in-vivo half-life of NT, gut-derived NT was initially speculated to only work in a paracrine manner, but has been detected in plasma with increases in response to nutrient intake in humans 90 and been suggested to act as an endocrine hormone on for example, the pancreas in rats 94. Whether NT derived from the intestine can act as an endocrine hormone on the brain has similarly been questioned mainly because of the divergent effects observed after central and peripheral NT administration 98. We have recently observed that intraperitoneal administration of a high dose of NT increases the expression of c-Fos, a marker of neuronal activation, in brain areas with a leaky blood–brain barrier such as the arcuate nucleus and area postrema in mice (In press, Endocrinology). A recent study has directly examined the ability of NT to access the brain in mice and found NT capable of crossing the blood–brain barrier both from plasma to the brain and from the brain to plasma 19. Thus, the lack of centrally mediated effects upon peripheral administration of NT in some studies more likely reflects insufficiently high NT concentrations rather than incomplete penetration of the blood–brain barrier.

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Coexpression with other hormones

NT was originally described to be present in enteroendocrine N cells 99. However, the ‘one cell one hormone’ dogma has been challenged and it is now established that many enteroendocrine cells coexpress a variety of different peptides in addition to the well-described coexpression of GLP-1 and PYY in L cells 100–104. It is believed that cells expressing one or more hormones derive from a common precursor cell line, which specializes into expressing mainly one or a few hormones, dependent on a temporal-specific and spatial-specific expression pattern of different transcription factors 105. Coexpression of gut hormones has been observed even in mature villi cells and is fairly common – for example, one mouse study found that out of all cholecystokinin (CCK)-expressing cells analyzed, 44% expressed at least two distinct peptides and 11% expressed at least three different peptides 100. Thus, NT is mainly expressed in N cells, but has been shown to be coexpressed with several other hormones such as GLP-1, PYY, and CCK 85,100–102,104,105. These hormones are also functionally related in for example their inhibition of appetite and gastric emptying; however, in relation to their expression pattern throughout the intestine, NT is likely most related to PYY and GLP-1, with all three hormones being abundant in the distal small intestine 85.

Coexpression between NT and either GLP-1 or PYY has been estimated to be around 15% of the cells positive for any of the three hormones in the rat small intestine 85. Another study showed that NT colocalized with PYY in ∼50% of analyzed NT cells in the proximal mouse colon 106. We recently showed that cells mono-labeled for NT ranged from 20 to 40% along the crypt–villus axis in mouse ileal tissue 101. The degree of colocalization differed along the crypt–villus axis, with ∼20% of NT cells in the top villus costaining for PYY, 10% costaining with GLP-1, and 35% costaining for both PYY and GLP-1. A similar pattern was found in the lower villus, except a larger fraction of NT cells costained with GLP-1 compared with PYY. Finally, in the crypts, little colocalization of all three hormones was observed, whereas NT costained with GLP-1 to a large degree and only minor costaining with PYY was observed 101. NT was preferentially located in the upper villi, whereas PYY was mainly found in the middle villi and GLP-1 was predominantly found in the crypts (Fig. 2) 101. In the proximal mouse colon, NT has similarly predominantly been found in the surface epithelial cuff, whereas GLP-1 was most abundant in the lower crypt 106. This organization along the crypt–villus axis combined with the large degree of colocalization between NT, GLP-1, and PYY indicates that NT-expressing, PYY-expressing, and GLP-1-expressing cells derive from a common precursor cell line predominantly expressing GLP-1 in the crypts and increasingly starting to express NT and PYY as the cells move up the crypt–villus axis before being shed at the top villus. In support of this, transgenic mice with the diphtheria toxin receptor expressed under the proglucagon promoter have GLP-1-expressing, NT-expressing, and PYY-expressing cells ablated upon administration of the diphtheria toxin 101. This indicates that PYY and NT cells also express the proglucagon transcript. Furthermore, the first cells that reappeared were GLP-1 positive, whereas NT-positive and PYY-positive cells were only observed at later time points after ablation in concordance with the preferential expression of GLP-1 in the crypts and NT and PYY in the villi and thus in more mature cells 101. Despite this large degree of coexpression between NT and PYY and GLP-1, NT was found in separate secretory granules to PYY and GLP-1 101.

Fig. 2

Fig. 2

Finally, in addition to being colocalized, NT has also been shown to be co-released with PYY and GLP-1 in studies using perfused rat small intestine models and in mouse colonic crypt cultures in response to an array of neuropeptide, hormonal, and physiological metabolite stimuli 85,101. In isolated perfused rat small intestine, neuromedin C and glucose-dependent insulinotropic peptide (GIP) induced a fast and parallel release of NT, GLP-1, and PYY 101. Neuromedin C caused the largest release of NT on a molar basis compared with PYY and GLP-1, and GIP induced a larger release of NT and GLP-1 compared with PYY 101. In colonic crypt cultures, neuromedin C as well as agonists for the bile acid receptor TGR5, the 2-monoacylglycerol receptor GPR119, and the long-chain fatty acid receptor GPR40 stimulated NT, GLP-1, and PYY in a very similar pattern, with the TGR5 agonist being the most potent stimulator and the rank order of the different stimuli being identical for all three hormones 101. Although the secretion pattern in rats is very similar for NT, PYY, and GLP-1 in the distal small intestine, PYY release from the proximal small intestine is negligible, whereas both NT and GLP-1 are released from the proximal small intestine 85 and, in this respect, NT may be more related to GLP-1 than PYY. It is, however, not known whether this cosecretion occurs at a cellular level or whether it is purely physiological.

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Coactions with glucagon-like peptide-1 and peptide YY

Additive or synergistic effects have been described previously between PYY and GLP-1 in relation to inhibition of food intake both in rodents and in humans 107–109, but not in the regulation of energy expenditure and glucose homeostasis 107,110. It is evident, from the above-mentioned studies, that NT is also closely intertwined with GLP-1 and PYY in relation to expression and release and that these hormones are functionally related. We recently found that NT acted synergistically with GLP-1 in inhibiting the intake of a palatable liquid diet and in slowing gastric emptying, but not during an oral glucose tolerance test. Further, NT and PYY inhibited gastric emptying in an additive manner (Fig. 3) 101.

Fig. 3

Fig. 3

Whether the synergistic and additive effects observed are a result of the hormones acting on the same cell type or on different cell types in the same target organ or through divergent overall mechanisms is not known and is further discussed below.

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Effects on gastric emptying

Motility and emptying of the stomach are primarily controlled by the vagovagal reflex circuitry, which is integrated and controlled by the dorsal–vagal complex in the brainstem 111. Gut hormones modulating gastric emptying could either activate vagal afferents or act directly on targets in the brain controlling efferent vagal projections from the dorsal motor nucleus of the vagus (DMX) or by a direct paracrine action on the stomach. GLP-1, PYY, and NT receptors are present on vagal afferents in rats 112–114 and GLP-1 and PYY can modulate vagal afferent firing 114,115, suggesting that vagal afferents may be important for the inhibition of gastric emptying. There is, however, also evidence pointing to a direct role of these hormones in the dorsal–vagal complex. GLP-1, PYY, and NT receptors are expressed in the dorsal–vagal complex in rats 116–118. Further, GLP-1 and PYY directly regulate gastric motility when microinjected into the dorsal–vagal complex through a modulation of vagal efferent activity in rats 119,120. GLP-1 apparently acts by stimulating a nonadrenergic, noncholinergic vagal pathway inhibiting gastric tone rather than inhibiting cholinergic parasympathetic output 119, whereas PYY seems to target both pathways through Y2 receptor-dependent mechanisms 120,121.

To establish the relative contribution of the vagus nerve toward hormonal inhibition of gastric emptying, studies have been carried out using either full vagotomy or a selective afferent nerve vagotomy. Whereas the efferent vagal projections seem important for NT, PYY, and GLP-1 in their regulation of gastric emptying 120,122–124, discrepant results have been obtained on the contribution of the afferent nerve on the inhibition by GLP-1 of gastric emptying 125,126.

Finally, one study suggested that PYY can act directly on guinea pig stomach muscles to relax them 127, whereas a similar mechanism could not be found for GLP-1 in pigs 123 and has not been explored for NT. In conclusion, NT, PYY, and GLP-1 act synergistically or additively in their inhibition of gastric emptying, which is likely mediated through similar mechanisms involving the vagovagal reflex circuitry.

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Effects on food intake

Because of the short half-life of many gut hormones once released, the afferent vagus nerve has also been suggested to be important for hormone signaling to the brain in the regulation of food intake. In relation to GLP-1-mediated decreased food intake, the relative contribution of the vagus nerve has, however, given rise to discrepant results, with some studies finding it important in humans and rodents, whereas another study performed in rats did not find the vagus nerve necessary for GLP-1-mediated decreased food intake 124,128,129. In support of a direct humoral action of GLP-1 in the brain are studies showing that peripherally administered GLP-1 can bind receptors in the area postrema and subfornical area in the rat 130 and induce c-Fos expression, a marker of neuronal activation, in a number of brainstem nuclei including the area postrema 131. Although GLP-1 receptors are present in the arcuate nucleus of the hypothalamus, these receptors do not seem to contribute toward GLP-1-induced satiety 132, although this site may be important for the action of long-acting GLP-1 analogues such as liraglutide 133.

The brainstem may similarly be important for NT effects on food intake as NT can modulate neuronal firing in the canine area postrema 134. Results from our group suggest that the vagus nerve is not necessary, but may contribute toward peripherally administered NT-mediated anorexia in mice (In press Endocrinology). In support of this, we found that peripherally administered NT increased c-Fos expression in mouse brainstem regions including the area postrema, similar to GLP-1 131. We also observed increased c-Fos expression in the arcuate nucleus after NT administration and increased expression of the anorexigenic neuropeptide proopiomelanocortin following NT treatment. In contrast, NT has previously been shown not to increase α-melanocyte-stimulating hormone release from hypothalamic explants 63; thus, the exact contribution of these neurons needs to be determined.

In conclusion, NT and GLP-1 can act synergistically in relation to inhibition of palatable food intake, which may be through a direct action on central receptors in the brainstem, but likely also involve vagal afferents projecting to the brainstem.

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Effects on glucose homeostasis

Both NT and GLP-1 can directly act on pancreatic β cells to control insulin release 38,135. However, opposing actions between GLP-1 and NT on insulin levels have been observed during oral glucose tolerance tests in mice 101, and NT has been shown to delay the glucose excursion, likely through its inhibitory effects on gastric emptying 101. The hypoinsulinemic and thus opposite effect to GLP-1 of NT is not surprising considering previous studies showing that NT inhibits the glucose-induced insulin release 53,54. Therefore, NT and GLP-1 seem to, if anything, counteract each other in the control of glucose homeostasis. It is noteworthy, however, that GLP-1 almost completely abolished the hypoinsulinemic effect as well as effects on glucose excursions of NT when the hormones were coadministered 101.

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Additivity/synergism on a molecular level

As mentioned above, it is not known whether NT acts on the same cellular targets as GLP-1 and PYY in the inhibition of gastric emptying and food intake. The GLP-1 receptor is coupled to Gs and the NTS1 couple to Gq/11, signaling pathways that are known to act in synergy in some intracellular effector pathways 136,137. Peripheral PYY3–36 mainly exerts its effects through the Y2 receptor, which couples to Gi. Signaling through Gi can activate other signaling pathways such as through βγ signaling, which could act in synergy with Gq-mediated signaling 137. Thus, theoretically, it is plausible that the functional synergistic/additive effects observed between NT and GLP-1 and PYY 101 could occur at the cellular level; however, further studies are needed to determine whether this is the case or whether the hormones act through separate pathways on the same target organ.

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Therapeutic perspective

Past pharmacotherapy for the treatment of obesity has largely been withdrawn because of unacceptable side effects 138. Currently, a few anti-obesity agents are on the market including the GLP-1 analogue liraglutide but these only produce a modest weight loss of up to around 10% 139. The ineffectiveness of current pharmacotherapy, which generally targets only one physiological pathway, is not surprising considering the complexity and redundancy in energy balance regulation. The most effective obesity intervention today that produces a sustained and considerable weight loss is bariatric surgery, but it is associated with risks such as micronutrient deficiency, hypoglycemia, weight regain, and, in rare cases, mortality 140. Considerable effort has been expended to identify the physiological mechanisms of the metabolic improvements following bariatric surgery and altered gut hormone signaling through the gut–brain axis has received considerable attention as a number of anorexigenic hormones including GLP-1, PYY, and NT are increased in the circulation following surgery 141–143. The role of single hormones in mediating some of the beneficial effects of bariatric surgery – that is, weight loss and reduced appetite has, however, not yielded convincing results 141. It is more likely that the combined effects of enteroendocrine and other factors including the gut microbiome and bile acids are responsible for the weight loss and metabolic improvements 141. In line with this, recent focus in the development of antiobesity agents targets more than one signaling pathway often involving one or more gut hormones.

The success of already approved GLP-1-based treatments for diabetes and obesity has led to interest in developing combinatorial approaches with GLP-1 to enhance the rather modest weight loss observed with GLP-1 analogues alone. For example, the combination of GLP-1 analogues with either leptin, PYY, amylin, CCK, oxyntomodulin, GIP, or glucagon shows additive or synergistic body weight-lowering potential and improves a range of other metabolic parameters such as appetite, insulin sensitivity, glycemic control, energy expenditure, and adiposity in preclinical studies 144. In particular, the combination of GLP-1, GIP, and glucagon in a triagonist has been a very successful approach rivaling the weight loss observed after bariatric surgery in rodents 145, and currently, several combinatorial approaches based on GLP-1 receptor agonists and glucagon are in clinical development 144.

The recently demonstrated synergy between NT and GLP-1 in the inhibition of food intake 101 suggests that combining GLP-1 analogues with NT may also be a viable approach as an antiobesity intervention. In particular, the combination of stable NT analogues with GLP-1 analogues could be speculated to show enhanced effects on appetite and body weight. Stable NT analogues have previously been shown to inhibit appetite and lower body weight in chronic settings 78,79. Although GLP-1 and NT may have opposing physiological actions on glucoregulatory control during situations where the glucose concentration is high, the effect of GLP-1 on glucose metabolism would likely buffer the hyperglycemic effects exerted by NT, as has also been observed during GLP-1 and glucagon coadministration 146. Indeed, when NT and the GLP-1 receptor agonist liraglutide were coadministered during an oral glucose tolerance test, liraglutide, even at the low dose used, counteracted the hypoinsulinemic effect of NT as well as the delay in the glucose excursion caused by NT 101.

A crucial next step is the development of NT formulations with improved pharmacokinetic profiles that can be used in conjunction with GLP-1 analogues and potentially also other gut hormones. A better understanding of the mechanisms and molecular events responsible for the observed synergistic and additive effects between different gut hormones is also essential for the design of optimal combinatorial approaches.

In conclusion, NT is a metabolically active gut hormone with important effects related to energy balance regulation. The synergistic action between different hormones has been exploited recently in the development of novel antiobesity agents and shows promising results 144. The success of this approach, targeting several signaling pathways, is not surprising considering that obesity is a complex disease affecting multiple organs. The recently observed synergy between NT and GLP-1 and PYY 101 suggests that NT should also be considered and included among the anorexigenic hormones currently being studied for their combined effects on energy balance regulation.

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This study was funded by the Novo Nordisk Foundation Center for Basic Metabolic Research.

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Conflicts of interest

There are no conflicts of interest.

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coaction; glucagon-like peptide-1; metabolic regulation; neurotensin; peptide YY

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