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Cell Metabolism Jul 2021The lymphatic vasculature plays important roles in the physiology of the organs in which it resides, though a clear mechanistic understanding of how this crosstalk is...
The lymphatic vasculature plays important roles in the physiology of the organs in which it resides, though a clear mechanistic understanding of how this crosstalk is mediated is lacking. Here, we performed single-cell transcriptional profiling of human and mouse adipose tissue and found that lymphatic endothelial cells highly express neurotensin (NTS/Nts). Nts expression is reduced by cold and norepinephrine in an α-adrenergic-dependent manner, suggesting a role in adipose thermogenesis. Indeed, NTS treatment of brown adipose tissue explants reduced expression of thermogenic genes. Furthermore, adenoviral-mediated overexpression and knockdown or knockout of NTS in vivo reduced and enhanced cold tolerance, respectively, an effect that is mediated by NTSR2 and ERK signaling. Inhibition of NTSR2 promoted energy expenditure and improved metabolic function in obese mice. These data establish a link between adipose tissue lymphatics and adipocytes with potential therapeutic implications.
Topics: Animals; Endothelial Cells; Energy Metabolism; Lymphatic Vessels; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Neurotensin; Signal Transduction; Thermogenesis
PubMed: 34038712
DOI: 10.1016/j.cmet.2021.04.019 -
Nature Neuroscience Nov 2022Obesity is a global pandemic that is causally linked to many life-threatening diseases. Apart from some rare genetic conditions, the biological drivers of overeating and...
Obesity is a global pandemic that is causally linked to many life-threatening diseases. Apart from some rare genetic conditions, the biological drivers of overeating and reduced activity are unclear. Here, we show that neurotensin-expressing neurons in the mouse interstitial nucleus of the posterior limb of the anterior commissure (IPAC), a nucleus of the central extended amygdala, encode dietary preference for unhealthy energy-dense foods. Optogenetic activation of IPAC neurons promotes obesogenic behaviors, such as hedonic eating, and modulates food preference. Conversely, acute inhibition of IPAC neurons reduces feeding and decreases hedonic eating. Chronic inactivation of IPAC neurons recapitulates these effects, reduces preference for sweet, non-caloric tastants and, furthermore, enhances locomotion and energy expenditure; as a result, mice display long-term weight loss and improved metabolic health and are protected from obesity. Thus, the activity of a single neuronal population bidirectionally regulates energy homeostasis. Our findings could lead to new therapeutic strategies to prevent and treat obesity.
Topics: Mice; Animals; Neurotensin; Neurons; Central Amygdaloid Nucleus; Energy Metabolism; Homeostasis; Obesity
PubMed: 36266470
DOI: 10.1038/s41593-022-01178-3 -
Nature Aug 2022The ability to associate temporally segregated information and assign positive or negative valence to environmental cues is paramount for survival. Studies have shown...
The ability to associate temporally segregated information and assign positive or negative valence to environmental cues is paramount for survival. Studies have shown that different projections from the basolateral amygdala (BLA) are potentiated following reward or punishment learning. However, we do not yet understand how valence-specific information is routed to the BLA neurons with the appropriate downstream projections, nor do we understand how to reconcile the sub-second timescales of synaptic plasticity with the longer timescales separating the predictive cues from their outcomes. Here we demonstrate that neurotensin (NT)-expressing neurons in the paraventricular nucleus of the thalamus (PVT) projecting to the BLA (PVT-BLA:NT) mediate valence assignment by exerting NT concentration-dependent modulation in BLA during associative learning. We found that optogenetic activation of the PVT-BLA:NT projection promotes reward learning, whereas PVT-BLA projection-specific knockout of the NT gene (Nts) augments punishment learning. Using genetically encoded calcium and NT sensors, we further revealed that both calcium dynamics within the PVT-BLA:NT projection and NT concentrations in the BLA are enhanced after reward learning and reduced after punishment learning. Finally, we showed that CRISPR-mediated knockout of the Nts gene in the PVT-BLA pathway blunts BLA neural dynamics and attenuates the preference for active behavioural strategies to reward and punishment predictive cues. In sum, we have identified NT as a neuropeptide that signals valence in the BLA, and showed that NT is a critical neuromodulator that orchestrates positive and negative valence assignment in amygdala neurons by extending valence-specific plasticity to behaviourally relevant timescales.
Topics: Basolateral Nuclear Complex; Calcium; Cues; Learning; Neural Pathways; Neuronal Plasticity; Neurotensin; Optogenetics; Punishment; Reward; Thalamic Nuclei
PubMed: 35859170
DOI: 10.1038/s41586-022-04964-y -
Neuropharmacology May 2020Neurotensin (NTS) is a neuropeptide neurotransmitter expressed in the central and peripheral nervous systems. Many studies over the years have revealed a number of roles... (Review)
Review
Neurotensin (NTS) is a neuropeptide neurotransmitter expressed in the central and peripheral nervous systems. Many studies over the years have revealed a number of roles for this neuropeptide in body temperature regulation, feeding, analgesia, ethanol sensitivity, psychosis, substance use, and pain. This review provides a general survey of the role of neurotensin with a focus on modalities that we believe to be particularly relevant to the study of reward. We focus on NTS signaling in the ventral tegmental area, nucleus accumbens, lateral hypothalamus, bed nucleus of the stria terminalis, and central amygdala. Studies on the role of NTS outside of the ventral tegmental area are still in their relative infancy, yet they reveal a complex role for neurotensinergic signaling in reward-related behaviors that merits further study. This article is part of the special issue on 'Neuropeptides'.
Topics: Animals; Humans; Nerve Net; Neurotensin; Reward; Ventral Tegmental Area
PubMed: 32057800
DOI: 10.1016/j.neuropharm.2020.108005 -
Cell Communication and Signaling : CCS Apr 2020Neurotensin, originally isolated in 1973 has both endocrine and neuromodulator activity and acts through its three main receptors. Their role in promoting tumour cell... (Review)
Review
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 -
Neuropeptides Aug 2019Neurotensin (Nts) is a neuropeptide implicated in the regulation of many facets of physiology, including cardiovascular tone, pain processing, ingestive behaviors,...
Neurotensin (Nts) is a neuropeptide implicated in the regulation of many facets of physiology, including cardiovascular tone, pain processing, ingestive behaviors, locomotor drive, sleep, addiction and social behaviors. Yet, there is incomplete understanding about how the various populations of Nts neurons distributed throughout the brain mediate such physiology. This knowledge gap largely stemmed from the inability to simultaneously identify Nts cell bodies and manipulate them . One means of overcoming this obstacle is to study mice crossed onto a Cre-inducible green fluorescent reporter line ( mice), as these mice permit both visualization and modulation of specific populations of Nts neurons (using Cre-inducible viral and genetic tools) to reveal their function. Here we provide a comprehensive characterization of the distribution and relative densities of the Nts-GFP populations observed throughout the male mouse brain, which will pave the way for future work to define their physiologic roles. We also compared the distribution of Nts-GFP neurons with - Hybridization (-ISH) data from the adult mouse brain. By comparing these data sets we can distinguish Nts-GFP populations that may only transiently express Nts during development but not in the mature brain, and hence which populations may not be amenable to Cre-mediated manipulation in adult mice. This atlas of Nts-GFP neurons will facilitate future studies using the line to describe the physiological functions of individual Nts populations and how modulating them may be useful to treat disease.
Topics: Animals; Atlases as Topic; Brain; Male; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Neurotensin
PubMed: 31079844
DOI: 10.1016/j.npep.2019.05.001 -
Proceedings of the National Academy of... Aug 2022Pain and itch are distinct sensations arousing evasion and compulsive desire for scratching, respectively. It's unclear whether they could invoke different neural...
Pain and itch are distinct sensations arousing evasion and compulsive desire for scratching, respectively. It's unclear whether they could invoke different neural networks in the brain. Here, we use the type 1 herpes simplex virus H129 strain to trace the neural networks derived from two types of dorsal root ganglia (DRG) neurons: one kind of polymodal nociceptors containing galanin () and one type of pruriceptors expressing neurotensin (). The DRG microinjection and immunosuppression were performed in transgenic mice to achieve a successful tracing from specific types of DRG neurons to the primary sensory cortex. About one-third of nuclei in the brain were labeled. More than half of them were differentially labeled in two networks. For the ascending pathways, the spinothalamic tract was absent in the network derived from -expressing pruriceptors, and the two networks shared the spinobulbar projections but occupied different subnuclei. As to the motor systems, more neurons in the primary motor cortex and red nucleus of the somatic motor system participated in the -containing nociceptor-derived network, while more neurons in the nucleus of the solitary tract (NST) and the dorsal motor nucleus of vagus nerve (DMX) of the emotional motor system was found in the -expressing pruriceptor-derived network. Functional validation of differentially labeled nuclei by c-Fos test and chemogenetic inhibition suggested the red nucleus in facilitating the response to noxious heat and the NST/DMX in regulating the histamine-induced scratching. Thus, we reveal the organization of neural networks in a DRG neuron type-dependent manner for processing pain and itch.
Topics: Animals; Galanin; Ganglia, Spinal; Herpesvirus 1, Human; Mice; Mice, Transgenic; Nerve Net; Neurotensin; Nociceptors; Pain; Pruritus; Solitary Nucleus
PubMed: 35943985
DOI: 10.1073/pnas.2118501119 -
International Journal of Molecular... Dec 2021Numerous regulatory peptides play a critical role in the pathogenesis of airway inflammation, airflow obstruction and hyperresponsiveness, which are hallmarks of asthma.... (Review)
Review
Numerous regulatory peptides play a critical role in the pathogenesis of airway inflammation, airflow obstruction and hyperresponsiveness, which are hallmarks of asthma. Some of them exacerbate asthma symptoms, such as neuropeptide Y and tachykinins, while others have ameliorating properties, such as nociception, neurotensin or β-defensin 2. Interacting with peptide receptors located in the lungs or on immune cells opens up new therapeutic possibilities for the treatment of asthma, especially when it is resistant to available therapies. This article provides a concise review of the most important and current findings regarding the involvement of regulatory peptides in asthma pathology.
Topics: Animals; Asthma; Gene Expression Regulation; Humans; Neuropeptide Y; Neurotensin; Peptides; Receptors, Peptide; Tachykinins; beta-Defensins
PubMed: 34948451
DOI: 10.3390/ijms222413656 -
Frontiers in Neuroendocrinology Apr 1997More than two decades of research indicate that the peptide neurotensin (NT) and its cognate receptors participate to a remarkable extent in the regulation of mammalian... (Review)
Review
More than two decades of research indicate that the peptide neurotensin (NT) and its cognate receptors participate to a remarkable extent in the regulation of mammalian neuroendocrine systems, potentially at multiple levels in a given system. NT-synthesizing neurons appear to exert a direct or indirect stimulatory influence on neurosecretory cells that synthesize gonadotropin-releasing hormone, dopamine (DA), somatostatin, and corticotropin-releasing hormone (CRH). In addition, context-specific synthesis of NT occurs in hypothalamic neurosecretory cells located in the arcuate nucleus and parvocellular paraventricular nucleus, including distinct subsets of cells which release DA, CRH, or growth hormone-releasing hormone into the hypophysial portal circulation. At the level of the anterior pituitary, NT stimulates secretion of prolactin and occurs in subsets of gonadotropes and thyrotropes. Moreover, circulating hormones influence NT synthesis in the hypothalamus and anterior pituitary, raising the possibility that NT mediates certain feedback effects of the hormones on neuroendocrine cells. Gonadal steroids alter NT levels in the preoptic area, arcuate nucleus, and anterior pituitary; adrenal steroids alter NT levels in the hypothalamic periventricular nucleus and arcuate nucleus; and thyroid hormones alter NT levels in the hypothalamus and anterior pituitary. Finally, clarification of the specific neuroendocrine roles subserved by NT should be greatly facilitated by the use of newly developed agonists and antagonists of the peptide.
Topics: Adjuvants, Immunologic; Animals; Central Nervous System; Humans; Hypothalamus; Nerve Growth Factors; Neurosecretory Systems; Neurotensin; Pituitary Gland, Anterior
PubMed: 9101258
DOI: 10.1006/frne.1996.0146 -
Progress in Neurobiology Aug 1997The serotonergic system, because of very diffuse projections throughout the central nervous system, has been implicated in numerous functions including nociception,... (Review)
Review
The serotonergic system, because of very diffuse projections throughout the central nervous system, has been implicated in numerous functions including nociception, analgesia, sleep-wakefulness and autonomic regulation. Despite an abundant literature indicating the presence of neurotensin-containing (neurotensinergic) neurons, fibres and terminals in most areas containing serotonergic neurons, little is known about the possible relationship between serotonergic and neurotensinergic systems. The purpose of this review is (i) to summarize current knowledge on the anatomical relation between neurotensinergic and serotonergic system, (ii) to summarize current knowledge on the action of neurotensin on serotonergic neurons and (iii) to discuss the possible physiological relevance of this action. Neurotensin-containing cell bodies can be found in the most rostral raphe nuclei. There are neurotensin-containing fibres and terminals in all raphe nuclei. Raphe nuclei have also been shown to contain neurotensin-receptor binding sites. In the dorsal raphe nucleus, neurotensin induces a concentration-dependent increase in the firing rate of a subpopulation of serotonergic neurons. The neurotensin-induced excitation, which is selectively blocked by the non-peptide neurotensin receptor antagonist SR 48692, is observed mainly in the ventral part of the nucleus. Most serotonergic neurons show marked desensitization to neurotensin, even at low concentrations. In intracellular experiments, neurotensin induces an inward current, associated in some cases with a decrease in apparent input conductance, which is occluded by supramaximal concentrations of the alpha 1-adrenoceptor agonist phenylephrine. In rare cases, neurotensin induces an excitation of GABAergic or glutamatergic neurons. Since the neurotensinergic system has also been implicated in nociception, analgesia, sleep-wakefulness, and autonomic regulation, the review discusses the possibility that part of this regulation could involve the activation of the serotonergic system.
Topics: Animals; Electrophysiology; Humans; Neurons; Neurotensin; Raphe Nuclei; Serotonin
PubMed: 9316156
DOI: 10.1016/s0301-0082(97)00025-7