Comparison of independent and combined effects of the neurotensin receptor agonist, JMV-449, and incretin mimetics on pancreatic islet function, glucose homeostasis and appetite control.

Authors: S L Craig, V A Gault, C E Shiels...

BACKGROUND

Neurotensin receptor activation augments the biosctivity of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). JMV-449, a C-terminal neurotensin-like fragment with a reduced peptide bond, represents a neurotensin receptor agonist.

METHODS

The present study assessed the actions of JMV-449 on pancreatic beta-cells alone, and in combination with GIP and GLP-1. Further studies examined the impact of JMV-449 and incretin mimetics on glucose homeostasis and appetite control in mice.

RESULTS

JMV-449 was resistant to plasma enzyme degradation and induced noticeable dose-dependent insulin-releasing actions in BRIN-BD11 beta-cells. In combination with either GIP or GLP-1, JMV-449 augmented (P < 0.05) the insulinotropic actions of both hormones, as well as enhancing (P < 0.001) insulin secretory activity of both incretin peptides. JMV-449 also increased beta-cell proliferation and induced significant benefits on beta-cell survival in response to cytokine-induced apoptosis. JMV-449 (25 nmol/kg) inhibited (P < 0.05-P < 0.001) food intake in overnight fasted lean mice, and enhanced (P < 0.01) the appetite supressing effects of an enzymatically stable GLP-1 mimetic. When injected co-jointly with glucose, JMV-449 evoked glucose lowering actions, but more interestingly significantly augmented (P < 0.05) the glucose lowering effects of established long-acting GIP and GLP-1 receptor mimetics. In terms of glucose-induced insulin secretion, only GIP receptor signalling was associated with increases in insulin concentrations, and this was not enhanced by JMV-449.

CONCLUSION

JMV-449 is a neurotensin receptor agonist that positively augments key aspects of the biological action profile of GIP and GLP-1.

GENERAL SIGNIFICANCE

These observations emphasise the, yet untapped, therapeutic potential of combined neurotensin and incretin receptor signalling for diabetes.

Topics: Animals; Appetite; Blood Glucose; Homeostasis; Incretins; Insulin Secretion; Insulin-Secreting Cells; Male; Mice; Mice, Inbred C57BL; Neurotensin; Oligopeptides; Receptors, Neurotensin

PubMed: 33964357
DOI: 10.1016/j.bbagen.2021.129917

Authors: Gizem Kurt, Nandan Kodur, Cristina Rivera Quiles...

The lateral hypothalamic area (LHA) is essential for ingestive behavior but has primarily been studied in modulating feeding, with comparatively scant attention on drinking. This is partly because most LHA neurons simultaneously promote feeding and drinking, suggesting that ingestive behaviors track together. A notable exception are LHA neurons expressing neurotensin (LHA neurons): activating these neurons promotes water intake but modestly restrains feeding. Here we investigated the connectivity of LHA neurons, their necessity and sufficiency for drinking and feeding, and how timing and resource availability influence their modulation of these behaviors. LHA neurons project broadly throughout the brain, including to the lateral preoptic area (LPO), a brain region implicated in modulating drinking behavior. LHA neurons also receive inputs from brain regions implicated in sensing hydration and energy status. While activation of LHA neurons is not required to maintain homeostatic water or food intake, it selectively promotes drinking during the light cycle, when ingestive drive is low. Activating LHA neurons during this period also increases willingness to work for water or palatable fluids, regardless of their caloric content. By contrast, LHA neuronal activation during the dark cycle does not promote drinking, but suppresses feeding during this time. Finally, we demonstrate that the activation of the LHA → LPO projection is sufficient to mediate drinking behavior, but does not suppress feeding as observed after generally activating all LHA neurons. Overall, our work suggests how and when LHA neurons oppositely modulate ingestive behaviors.

Topics: Food; Hypothalamic Area, Lateral; Neurons; Neurotensin; Water

PubMed: 35063424
DOI: 10.1016/j.physbeh.2022.113707

Review

Authors: Jariel Ramirez-Virella, Gina M Leinninger

The small peptide neurotensin (Nts) is implicated in myriad processes including analgesia, thermoregulation, reward, arousal, blood pressure, and modulation of feeding and body weight. Alterations in Nts have recently been described in individuals with obesity or eating disorders, suggesting that disrupted Nts signaling may contribute to body weight disturbance. Curiously, Nts mediates seemingly opposing regulation of body weight via different tissues. Peripherally acting Nts promotes fat absorption and weight gain, whereas central Nts signaling suppresses feeding and weight gain. Thus, because Nts is pleiotropic, a location-based approach must be used to understand its contributions to disordered body weight and whether the Nts system might be leveraged to improve metabolic health. Here we review the role of Nts signaling in the brain to understand the sites, receptors, and mechanisms by which Nts can promote behaviors that modify body weight. New techniques permitting site-specific modulation of Nts and Nts receptor-expressing cells suggest that, even in the brain, not all Nts circuitry exerts the same function. Intriguingly, there may be dedicated brain regions and circuits via which Nts specifically suppresses feeding behavior and weight gain vs other Nts-attributed physiology. Defining the central mechanisms by which Nts signaling modifies body weight may suggest strategies to correct disrupted energy balance, as needed to address overweight, obesity, and eating disorders.

Topics: Animals; Body Weight; Brain; Feeding Behavior; Humans; Neurotensin; Obesity; Receptors, Neurotensin

PubMed: 33599716
DOI: 10.1210/endocr/bqab038

Authors: Yuki Hiradate, Kenshiro Hara, Kentaro Tanemura...

Previously, we revealed that neurotensin (NTS) derived from the oviduct and uterus can function during fertilization. However, little is known about NTS actions on the pre-implantation embryo after fertilization. Here, we found that pro-Nts mRNA is expressed in the oviduct and uterus during when preimplantation embryos develop and an increase in mRNA level in the uterus is induced by human chorionic gonadotropin (hCG) treatment. Expression of mRNA for two NTS receptors, Ntr1 and Ntr3, was found throughout these stages, whereas Ntr2 mRNA was not detected, suggesting that NTS signaling occurred through NTR1 and NTR3. Supplementation of 1, 10, 100 or 1000 nM NTS to embryo culture medium after fertilization showed that 100 nM NTS significantly improved the blastocyst formation. In comparison, the total number of cells and inner cell mass ratio of blastocysts was not significant different between the 0 nM and 100 nM NTS treatment groups. These results indicate that NTS has a positive effect upon preimplantation embryo development in vitro.

Topics: Animals; Blastocyst; Chorionic Gonadotropin; Culture Media; Embryo, Mammalian; Embryonic Development; Female; Fertilization in Vitro; Gene Expression Profiling; Humans; In Vitro Techniques; Mice; Neurotensin; Oviducts; RNA, Messenger; Receptors, Neurotensin; Signal Transduction; Uterus

PubMed: 32493860
DOI: 10.1262/jrd.2020-002

Authors: Shengyang Qiu, Stella Nikolaou, Jie Zhu...

: Colorectal Cancer (CRC) accounts for 9% of cancer deaths globally. Hormonal pathways play important roles in some cancers. This study investigated the association of CRC expression of neurotensin (NTS), NTS receptors 1 and 3 (NTSR1 and NTSR3) and clinical outcomes. : A prospective cohort study which quantifies the protein expression of NTS, NTSR1 and NTSR3 in human CRCs using immunohistochemistry. Expression levels were then compared with clinico-pathological outcome including histological grade, overall survival (OS) and disease-free survival (DFS). : Sixty-four patients were enrolled with median follow-up of 44.0 months. There was significantly higher expression of NTS in cancer tissue in CRC with higher T stages ( < 0.01), N stages ( = 0.03), and AJCC clinical stages ( = 0.04). There was significantly higher expression of NTS, NTSR1 and NTSR3 in cancer tissue compared to surrounding normal epithelium (median H-score 163.5 vs 97.3, < 0.01). There was significantly shorter DFS in individuals with CRC with high levels of NTS compared to lower levels of NTS (35.8 months 95% CI 28.7-42.8 months vs 46.4 months 95% CI 42.2-50.5 months, respectively, = 0.02). Above median NTS expression in cancer tissue was a significant risk factor for disease recurrence (HR 4.10, 95% CI 1.14-14.7, = 0.03). : The expression of NTS and its receptors has the potential to be utilised as a predictive and prognostic marker in colorectal cancer for postoperative selection for adjuvant therapy and identify individuals for novel therapies targeting the neurotensinergic pathways. : High NTS expression appears to be associated with more advanced CRC and worse DFS.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Biomarkers, Tumor; Colorectal Neoplasms; Female; Humans; Male; Middle Aged; Neurotensin; Receptors, Neurotensin

PubMed: 32764278
DOI: 10.3390/biom10081145

Authors: Yuan-Yuan Wang, Rui-Yun Lu, Ji Shi...

In this study, we aimed to investigate the role of circORC2 in modulating miR-19a and its downstream signalling during the pathogenesis of STC. In this study, three groups of patients, that is healthy control (HC) group, normal transit constipation (NTC) group (N = 42) and slow transit constipation (STC) group, were, respectively, recruited. RT-PCR and Western blot analysis were exploited to investigate the changes in the expression levels of miR-19a and circORC2 in these patients, so as to establish a circORC2/miR-19a signalling pathway. The basic information of the patients showed no significant differences among different patient groups. Compared with the HC group, concentrations of neurotensin (NST) and motilin (MLN) were both significantly reduced in the NTC and STC groups, especially in the STC group. Also, miR-19a level was highest, whereas circORC2 level was lowest in the STC group. Furthermore, circORC2 was validated to sponge the expression of miR-19a, and the transfection of circORC2 reduced the expression of miR-19a. Meanwhile, MLN and NST mRNAs were both targeted by miR-19a, and the transfection of circORC2 dramatically up-regulated the expression of MLN and NST. On the contrary, the transfection of circORC2 siRNA into SMCs and VSMCs exhibited the opposite effect of circORC2. Collectively, the results of this study established a regulatory relationship among circORC2, miR-19a and neurotensin/motilin, which indicated that the overexpression of circORC2 could up-regulate the levels of neurotensin and motilin, thus exerting a beneficial effect during the treatment of STC.

Topics: Aged; Apoptosis; Biomarkers; Case-Control Studies; Cell Proliferation; Cells, Cultured; Constipation; Female; Gene Expression Regulation; Humans; Male; MicroRNAs; Motilin; Neurotensin; Origin Recognition Complex; Prognosis; RNA, Circular

PubMed: 33629528
DOI: 10.1111/jcmm.16211

Authors: Iustin V Tabarean

Neurotensin (NTS) is a neuropeptide acting as a neuromodulator in the brain and is a very potent hypothermic agent. However, the cellular mechanisms of actions are not fully understood. Here we report that NTS increases the firing rate of preoptic GABAergic neurons by activating both neurotensin receptor 1 (NTSR1) and neurotensin receptor 2 (NTSR2), expressed by neurons and astrocytes, respectively. Downstream of NTSR1 the neuropeptide activated an inward current, calcium release from intracellular stores and, postsynaptically, increased frequency and amplitude of inhibitory synaptic events. NTSR2 activation in astrocytes resulted in increased excitatory input in preoptic GABAergic neurons, an effect which was dependent upon the activation of P2X4 receptors. We also found that neuromedin N acted as a selective agonist at the NTSR1. Surprisingly, activation of both NTSR1 and NTSR2 in the median preoptic nucleus was required for activating a full hypothermic response.

Topics: Animals; Astrocytes; Excitatory Postsynaptic Potentials; Hypothermia; Male; Mice; Mice, Inbred C57BL; Neurons; Neurotensin; Patch-Clamp Techniques; Preoptic Area; Purinergic P2X Receptor Agonists; Receptors, Neurotensin; Receptors, Purinergic P2X4; gamma-Aminobutyric Acid

PubMed: 32275927
DOI: 10.1016/j.neuropharm.2020.108069

Review

Authors: Stella Nikolaou, Shengyang Qiu, Francesca Fiorentino...

BACKGROUND

Neurotensin, originally isolated in 1973 has both endocrine and neuromodulator activity and acts through its three main receptors. Their role in promoting tumour cell proliferation, migration, DNA synthesis has been studied in a wide range of cancers. Expression of Neurotensin and its receptors has also been correlated to prognosis and prediction to treatment.

MAIN BODY

The effects of NT are mediated through mitogen-activated protein kinases, epidermal growth factor receptors and phosphatidylinositol-3 kinases amongst others. This review is a comprehensive summary of the molecular pathways by which Neurotensin and its receptors act in cancer cells.

CONCLUSION

Identifying the role of Neurotensin in the underlying molecular mechanisms in various cancers can give way to developing new agnostic drugs and personalizing treatment according to the genomic structure of various cancers. Video abstract.

Topics: Cell Proliferation; Humans; Neoplasms; Neurotensin; Receptors, Neurotensin; Signal Transduction

PubMed: 32336282
DOI: 10.1186/s12964-020-00569-y

Authors: Charles D Nicoli, April P Carson, Timothy B Plante...

CONTEXT

The peptide neurotensin is implicated in insulin resistance, diabetes mellitus (DM), and cardiovascular disease.

OBJECTIVE

We studied the association of neurotensin's stable precursor, pro-neurotensin/neuromedin N (pro-NT/NMN) with incident metabolic syndrome (MetS) and DM.

METHODS

We included 3772 participants from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study who completed the baseline exam (2003-2007), the follow-up exam (2013-2016), and had pro-NT/NMN measured by immunoassay. Weighted logistic regression models were fitted to incident DM, incident MetS, and each MetS component, separately, incorporating demographics, metabolic risk factors, homeostasis model of insulin resistance (HOMA-IR), and diet scores. Incident MetS was defined by 3 or more harmonized criteria at follow-up in those with fewer than 3 at baseline. Incident DM was defined by use of hypoglycemic drugs/insulin, fasting glucose 126 mg/dL or greater, or random glucose 200 mg/dL or greater in those without these at baseline.

RESULTS

Median (IQR) plasma pro-NT/NMN was 160 pmol/L (118-218 pmol/L). A total of 564 (of 2770 without baseline MetS) participants developed MetS, and 407 (of 3030 without baseline DM) developed DM. Per SD higher log-pro-NT/NMN, the demographic-adjusted odds ratio (OR) and 95% CI of incident MetS was 1.22 (1.11-1.35), 1.16 (1.00-1.35) for incident low high-density lipoprotein (HDL), and 1.25 (1.11-1.40) for incident dysglycemia. The association of pro-NT/NMN with MetS was attenuated in the model adding HOMA-IR (OR per SD log-pro-NT/NMN 1.14; 95% CI, 1.00-1.30). There was no association with incident DM (OR per SD log-pro-NT/NMN 1.06; 95% CI, 0.94-1.19).

CONCLUSION

Pro-NT/NMN was associated with MetS and 2 components, dysglycemia and low HDL, likely explained by insulin resistance.

Topics: Blood Glucose; Case-Control Studies; Cohort Studies; Diabetes Mellitus; Diet; Female; Humans; Hypoglycemic Agents; Insulin Resistance; Lipoproteins, HDL; Male; Metabolic Syndrome; Middle Aged; Neurotensin; Peptide Fragments; Risk Factors; Stroke

PubMed: 34013344
DOI: 10.1210/clinem/dgab355

Authors: Kohei Umezu, Risa Yajima, Yuuki Hiradate...

Previously, we reported that neurotensin (NT), which is expressed in the uterus and oviduct, enhanced bovine sperm capacitation and acrosome reactions. As NT mRNA expression in bovine oviducts increases dramatically in the follicular phase, we hypothesized that NT modulates fertilization and subsequent conception in cattle. The objective of this study was to evaluate the effect of NT on embryo development and blastocyst quality. The rate of embryo cleavage was significantly increased by the addition of NT to the fertilization medium. Furthermore, the total number of cells and numbers of cells in the inner cell mass of blastocysts were significantly increased by NT during in vitro fertilization (IVF). These results suggested that NT enhanced the efficiency of early bovine embryo development and blastocyst quality. The expression of NT receptors (NTRs) in sperm, testes, oocytes, and cumulus cells was evaluated to determine whether NT acted via NTRs in sperm alone or in both male and female reproductive cells during IVF. Immunocytochemistry and reverse transcription polymerase chain reaction revealed that NTR1 and NTR2 were expressed in sperm and testes, but not in oocytes and cumulus cells. We propose that NT selectively acts upon sperm via NTR1 and NTR2 during IVF to improve the cleavage rate and quality of blastocysts, which are important determinants of sperm quality for successful conception. This research supports our hypothesis that NT acts as a key modulator of fertilization and conception in cattle. Further studies are necessary to apply our findings to the industrial framework of bovine reproduction.

Topics: Acrosome Reaction; Animals; Blastocyst; Cattle; Cells, Cultured; Embryo Culture Techniques; Embryo, Mammalian; Embryonic Development; Female; Fertilization; Fertilization in Vitro; Male; Neurotensin; Receptors, Neurotensin; Signal Transduction; Sperm Capacitation; Spermatozoa

PubMed: 30662011
DOI: 10.1262/jrd.2018-147