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Peptides Oct 2020Amylin is a peptide hormone that is mainly known to be produced by pancreatic β-cells in response to a meal but amylin is also produced by brain cells in discrete brain... (Review)
Review
Amylin is a peptide hormone that is mainly known to be produced by pancreatic β-cells in response to a meal but amylin is also produced by brain cells in discrete brain areas albeit in a lesser amount. Amylin receptor (AMY) is composed of the calcitonin core-receptor (CTR) and one of the 3 receptor activity modifying protein (RAMP), thus forming AMY1-3; RAMP enhances amylin binding properties to the CTR. However, amylin receptor agonist such as salmon calcitonin is able to bind CTR alone. Peripheral amylin's main binding site is located in the area postrema (AP) which then propagate the signal to the nucleus of the solitary tract and lateral parabrachial nucleus (LPBN) and it is then transmitted to the forebrain areas such as central amygdala and bed nucleus of the stria terminalis. Amylin's activation of these different brain areas mediates eating and other metabolic pathways controlling energy expenditure and glucose homeostasis. Peripheral amylin can also bind in the arcuate nucleus of the hypothalamus where it acts independently of the AP to activate POMC and NPY neurons. Amylin activation of NPY neurons has been shown to be transmitted to LPBN neurons to act on eating while amylin POMC signaling affects energy expenditure and locomotor activity. While a large amount of experiments have already been conducted, future studies will have to further investigate how amylin is taken up by forebrain areas and deepen our understanding of amylin action on peripheral metabolism.
Topics: Animals; Appetite Depressants; Brain; Eating; Humans; Islet Amyloid Polypeptide; Pancreatic Hormones; Signal Transduction
PubMed: 32634450
DOI: 10.1016/j.peptides.2020.170366 -
Nature Feb 2024Many peptide hormones form an α-helix on binding their receptors, and sensitive methods for their detection could contribute to better clinical management of disease....
Many peptide hormones form an α-helix on binding their receptors, and sensitive methods for their detection could contribute to better clinical management of disease. De novo protein design can now generate binders with high affinity and specificity to structured proteins. However, the design of interactions between proteins and short peptides with helical propensity is an unmet challenge. Here we describe parametric generation and deep learning-based methods for designing proteins to address this challenge. We show that by extending RFdiffusion to enable binder design to flexible targets, and to refining input structure models by successive noising and denoising (partial diffusion), picomolar-affinity binders can be generated to helical peptide targets by either refining designs generated with other methods, or completely de novo starting from random noise distributions without any subsequent experimental optimization. The RFdiffusion designs enable the enrichment and subsequent detection of parathyroid hormone and glucagon by mass spectrometry, and the construction of bioluminescence-based protein biosensors. The ability to design binders to conformationally variable targets, and to optimize by partial diffusion both natural and designed proteins, should be broadly useful.
Topics: Biosensing Techniques; Computer-Aided Design; Deep Learning; Diffusion; Glucagon; Luminescent Measurements; Mass Spectrometry; Parathyroid Hormone; Peptides; Protein Structure, Secondary; Proteins; Substrate Specificity; Models, Molecular
PubMed: 38109936
DOI: 10.1038/s41586-023-06953-1 -
Vitamins and Hormones 2022Parathyroid hormone (PTH) and PTH-related peptide (PTHrP) regulate extracellular phosphate and calcium homeostasis as well as bone remodeling. PTH is a classic endocrine... (Review)
Review
Parathyroid hormone (PTH) and PTH-related peptide (PTHrP) regulate extracellular phosphate and calcium homeostasis as well as bone remodeling. PTH is a classic endocrine peptide hormone whose synthesis and negative feedback by multiple factors control release from the parathyroid glands. PTHrP is ubiquitously expressed (pre- and postnatally) and acts in an autocrine/paracrine manner. This review considers the structural pharmacology and actions of PTH and PTHrP, biological consequences of inherited mutations, engineered analogs that illuminate similarities and differences in physiologic actions, and targeted therapeutic opportunities.
Topics: Humans; Parathyroid Hormone; Parathyroid Hormone-Related Protein
PubMed: 35953106
DOI: 10.1016/bs.vh.2022.03.001 -
Current Opinion in Endocrinology,... Jun 2024Various gut hormones interact with the brain through delicate communication, thereby influencing appetite and subsequent changes in body weight. This review summarizes... (Review)
Review
PURPOSE OF REVIEW
Various gut hormones interact with the brain through delicate communication, thereby influencing appetite and subsequent changes in body weight. This review summarizes the effects of gut hormones on appetite, with a focus on recent research.
RECENT FINDINGS
Ghrelin is known as an orexigenic hormone, whereas glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), postprandial peptide YY (PYY), and oxyntomodulin (OXM) are known as anorexigenic hormones. Recent human studies have revealed that gut hormones act differently in various systems, including adipose tissue, beyond appetite and energy intake, and even involve in high-order thinking. Environmental factors including meal schedule, food contents and quality, type of exercise, and sleep deprivation also play a role in the influence of gut hormone on appetite, weight change, and obesity. Recently published studies have shown that retatrutide, a triple-agonist of GLP-1, GIP, and glucagon receptor, and orforglipron, a GLP-1 receptor partial agonist, are effective in weight loss and improving various metabolic parameters associated with obesity.
SUMMARY
Various gut hormones influence appetite, and several drugs targeting these receptors have been reported to exert positive effects on weight loss in humans. Given that diverse dietary and environmental factors affect the actions of gut hormones and appetite, there is a need for integrated and largescale long-term studies in this field.
Topics: Humans; Gastrointestinal Hormones; Appetite Regulation; Obesity; Cholecystokinin; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Peptide YY; Oxyntomodulin; Animals; Ghrelin; Appetite
PubMed: 38511400
DOI: 10.1097/MED.0000000000000859 -
Journal of Experimental Botany Aug 2019Sulfated peptides are plant hormones that are active at nanomolar concentrations. The sulfation at one or more tyrosine residues is catalysed by tyrosylprotein... (Review)
Review
Sulfated peptides are plant hormones that are active at nanomolar concentrations. The sulfation at one or more tyrosine residues is catalysed by tyrosylprotein sulfotransferase (TPST), which is encoded by a single-copy gene. The sulfate group is provided by the co-substrate 3´-phosphoadenosine 5´-phosphosulfate (PAPS), which links synthesis of sulfated signaling peptides to sulfur metabolism. The precursor proteins share a conserved DY-motif that is implicated in specifying tyrosine sulfation. Several sulfated peptides undergo additional modification such as hydroxylation of proline and glycosylation of hydroxyproline. The modifications render the secreted signaling molecules active and stable. Several sulfated signaling peptides have been shown to be perceived by leucine-rich repeat receptor-like kinases (LRR-RLKs) but have signaling pathways that, for the most part, are yet to be elucidated. Sulfated peptide hormones regulate growth and a wide variety of developmental processes, and intricately modulate immunity to pathogens. While basic research on sulfated peptides has made steady progress, their potential in agricultural and pharmaceutical applications has yet to be explored.
Topics: Peptide Hormones; Plant Development; Plant Growth Regulators; Plant Proteins; Plants; Sulfates
PubMed: 31231771
DOI: 10.1093/jxb/erz292 -
International Journal of Molecular... Apr 2023The apelinergic system is a highly conserved pleiotropic system. It comprises the apelin receptor apelin peptide jejunum (APJ) and its two peptide ligands,... (Review)
Review
The apelinergic system is a highly conserved pleiotropic system. It comprises the apelin receptor apelin peptide jejunum (APJ) and its two peptide ligands, Elabela/Toddler (ELA) and apelin, which have different spatiotemporal localizations. This system has been implicated in the regulation of the adipoinsular axis, in cardiovascular and central nervous systems, in carcinogenesis, and in pregnancy in humans. During pregnancy, the apelinergic system is essential for embryo cardiogenesis and vasculogenesis and for placental development and function. It may also play a role in the initiation of labor. The apelinergic system seems to be involved in the development of placenta-related pregnancy complications, such as preeclampsia (PE) and intrauterine growth restriction, but an improvement in PE-like symptoms and birth weight has been described in murine models after the exogenous administration of apelin or ELA. Although the expression of ELA, apelin, and APJ is altered in human PE placenta, data related to their circulating levels are inconsistent. This article reviews current knowledge about the roles of the apelinergic system in pregnancy and its pathophysiological roles in placenta-related complications in pregnancy. We also discuss the challenges in translating the actors of the apelinergic system into a marker or target for therapeutic interventions in obstetrics.
Topics: Pregnancy; Female; Humans; Mice; Animals; Apelin; Placenta; Peptide Hormones; Placentation; Pre-Eclampsia
PubMed: 37175743
DOI: 10.3390/ijms24098014 -
International Journal of Molecular... Jun 2020Somatostatin is a peptide hormone, which most commonly is produced by endocrine cells and the central nervous system. In mammals, somatostatin originates from... (Review)
Review
Somatostatin is a peptide hormone, which most commonly is produced by endocrine cells and the central nervous system. In mammals, somatostatin originates from pre-prosomatostatin and is processed to a shorter form, i.e., somatostatin-14, and a longer form, i.e., somatostatin-28. The two peptides repress growth hormone secretion and are involved in the regulation of glucagon and insulin synthesis in the pancreas. In recent years, the processing and secretion of somatostatin have been studied intensively. However, little attention has been paid to the regulatory mechanisms that control its expression. This review provides an up-to-date overview of these mechanisms. In particular, it focuses on the role of enhancers and silencers within the promoter region as well as on the binding of modulatory transcription factors to these elements. Moreover, it addresses extracellular factors, which trigger key signaling pathways, leading to an enhanced somatostatin expression in health and disease.
Topics: Animals; Autocrine Communication; Enhancer Elements, Genetic; Feedback, Physiological; Gene Expression Regulation; Humans; Promoter Regions, Genetic; Somatostatin; Transcription Factors
PubMed: 32545257
DOI: 10.3390/ijms21114170 -
Molecular Metabolism Apr 2021Non-alcoholic steatohepatitis (NASH) is a spectrum of histological liver pathologies ranging from hepatocyte fat accumulation, hepatocellular ballooning, lobular... (Review)
Review
BACKGROUND
Non-alcoholic steatohepatitis (NASH) is a spectrum of histological liver pathologies ranging from hepatocyte fat accumulation, hepatocellular ballooning, lobular inflammation, and pericellular fibrosis. Based on early investigations, it was discovered that visceral fat accumulation, hepatic insulin resistance, and atherogenic dyslipidemia are pathological triggers for NASH progression. As these pathogenic features are common with obesity, type 2 diabetes (T2D), and atherosclerosis, therapies that target dysregulated core metabolic pathways may hold promise for treating NASH, particularly as first-line treatments.
SCOPE OF REVIEW
In this review, the latest clinical data on nuclear hormone- and peptide hormone-based drug candidates for NASH are reviewed and contextualized, culminating with a discovery research perspective on emerging combinatorial therapeutic approaches that merge nuclear and peptide strategies.
MAJOR CONCLUSION
Several drug candidates targeting the metabolic complications of NASH have shown promise in early clinical trials, albeit with unique benefits and challenges, but questions remain regarding their translation to larger and longer clinical trials, as well as their utility in a more diseased patient population. Promising polypharmacological approaches can potentially overcome some of these perceived challenges, as has been suggested in preclinical models, but deeper characterizations are required to fully evaluate these opportunities.
Topics: Animals; Diabetes Mellitus, Type 2; Dyslipidemias; Fibroblast Growth Factors; Humans; Inflammation; Insulin Resistance; Liver; Nerve Tissue Proteins; Non-alcoholic Fatty Liver Disease; Obesity; Peptide Hormones; Receptors, Cytoplasmic and Nuclear; Receptors, Thyroid Hormone
PubMed: 33359400
DOI: 10.1016/j.molmet.2020.101153 -
Presse Medicale (Paris, France : 1983) Jun 2022Molecular imaging, which uses molecular targets due to the overexpression of specific peptide hormone receptors on the tumour surface, has become an indispensable... (Review)
Review
Molecular imaging, which uses molecular targets due to the overexpression of specific peptide hormone receptors on the tumour surface, has become an indispensable diagnostic technique. Neuroendocrine neoplasms (NENs) especially differentiated NENs or neuroendocrine tumours (NETs) are a rare group of heterogeneous tumours, characterized by the expression of hormone receptors on the tumour cell surface. This property makes them receptive to diagnostic and therapeutic approaches (theranostics) using radiolabelled peptides. Amongst the known hormone receptors, somatostatin receptors (SSTR) are expressed on the majority of NETs and are therefore the most relevant receptors for theranostic approaches. Current research aims to medically upregulate their expression, while other focuses are on the use of different radiopeptides (64Cu and 67Cu) or somatostatin-antagonists instead of the established somatostatin agonists. The GLP-1 receptor is another clinically relevant target, as GLP-1-R imaging has become the new standard for the localisation of insulinomas. For staging and prognostic evaluation in dedifferentiated NENs, 18F-FDG-imaging is useful, but lacks a therapeutic counterpart. Further options for patients with insufficient expression of SSTR involve metaiodobenzylguanidine (MIBG) and the molecular target C-X-C motif chemokine receptor-4 (CXCR4). New targets such as the glucose-dependant insulinotropic polypeptide receptor (GIPR) and the fibroblast activation protein (FAP) have been identified in NENs recently and await further evaluation. For medullary thyroid cancer 18-F-DOPA imaging is standard, however this technique is rather second line for other NENs. In this area, the discovery of minigastrin, which targets the cholecystokinin-2 (CCK2) receptors in medullary thyroid carcinoma and foregut NENs, may improve future management. This review aims to provide an overview of the most commonly used functional imaging modalities for theranostics in NENs today and in the possible future.
Topics: Humans; Copper Radioisotopes; Neuroendocrine Tumors; Molecular Imaging; Somatostatin
PubMed: 35131317
DOI: 10.1016/j.lpm.2022.104115 -
Peptides Jun 2023Spexin, also identified as neuropeptide Q (NPQ), is a 14 amino acid peptide discovered by bioinformatic methods. It has a conserved structure in many species and is... (Review)
Review
Spexin, also identified as neuropeptide Q (NPQ), is a 14 amino acid peptide discovered by bioinformatic methods. It has a conserved structure in many species and is widely expressed in the central nervous system and peripheral tissues. It has an associated receptor, galanin receptor 2/3 (GALR2/3). Mature spexin peptides can exert various functions by activating GALR2/3, such as inhibiting food intake, inhibiting lipid absorption, reducing body weight, and improving insulin resistance. Spexin is expressed in the adrenal gland, pancreas, visceral fat, and thyroid, with the highest expression in the adrenal gland, followed by the pancreas. Physiologically, spexin and insulin interact in pancreatic islets. Spexin may be one of the regulators of endocrine function in the pancreas. Spexin is a possible indicator of insulin resistance and it has a variety of functional properties, here we review its role in energy metabolism.
Topics: Humans; Energy Metabolism; Insulin; Insulin Resistance; Islets of Langerhans; Peptide Hormones; Peptides
PubMed: 36914115
DOI: 10.1016/j.peptides.2023.170991