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Neurotherapeutics : the Journal of the... Jan 2018The complex bidirectional communication between the gut and the brain is finely orchestrated by different systems, including the endocrine, immune, autonomic, and... (Review)
Review
The complex bidirectional communication between the gut and the brain is finely orchestrated by different systems, including the endocrine, immune, autonomic, and enteric nervous systems. Moreover, increasing evidence supports the role of the microbiome and microbiota-derived molecules in regulating such interactions; however, the mechanisms underpinning such effects are only beginning to be resolved. Microbiota-gut peptide interactions are poised to be of great significance in the regulation of gut-brain signaling. Given the emerging role of the gut-brain axis in a variety of brain disorders, such as anxiety and depression, it is important to understand the contribution of bidirectional interactions between peptide hormones released from the gut and intestinal bacteria in the context of this axis. Indeed, the gastrointestinal tract is the largest endocrine organ in mammals, secreting dozens of different signaling molecules, including peptides. Gut peptides in the systemic circulation can bind cognate receptors on immune cells and vagus nerve terminals thereby enabling indirect gut-brain communication. Gut peptide concentrations are not only modulated by enteric microbiota signals, but also vary according to the composition of the intestinal microbiota. In this review, we will discuss the gut microbiota as a regulator of anxiety and depression, and explore the role of gut-derived peptides as signaling molecules in microbiome-gut-brain communication. Here, we summarize the potential interactions of the microbiota with gut hormones and endocrine peptides, including neuropeptide Y, peptide YY, pancreatic polypeptide, cholecystokinin, glucagon-like peptide, corticotropin-releasing factor, oxytocin, and ghrelin in microbiome-to-brain signaling. Together, gut peptides are important regulators of microbiota-gut-brain signaling in health and stress-related psychiatric illnesses.
Topics: Anxiety; Brain; Cholecystokinin; Corticotropin-Releasing Hormone; Depression; Endocrine System; Gastrointestinal Microbiome; Ghrelin; Glucagon-Like Peptide 1; Humans; Neuropeptide Y; Oxytocin; Peptide Hormones
PubMed: 29134359
DOI: 10.1007/s13311-017-0585-0 -
Science (New York, N.Y.) Jan 2014Plant cells are immobile; thus, plant growth and development depend on cell expansion rather than cell migration. The molecular mechanism by which the plasma membrane...
Plant cells are immobile; thus, plant growth and development depend on cell expansion rather than cell migration. The molecular mechanism by which the plasma membrane initiates changes in the cell expansion rate remains elusive. We found that a secreted peptide, RALF (rapid alkalinization factor), suppresses cell elongation of the primary root by activating the cell surface receptor FERONIA in Arabidopsis thaliana. A direct peptide-receptor interaction is supported by specific binding of RALF to FERONIA and reduced binding and insensitivity to RALF-induced growth inhibition in feronia mutants. Phosphoproteome measurements demonstrate that the RALF-FERONIA interaction causes phosphorylation of plasma membrane H(+)-adenosine triphosphatase 2 at Ser(899), mediating the inhibition of proton transport. The results reveal a molecular mechanism for RALF-induced extracellular alkalinization and a signaling pathway that regulates cell expansion.
Topics: Arabidopsis; Arabidopsis Proteins; Cell Enlargement; Cell Membrane; Molecular Sequence Data; Peptide Hormones; Phosphorylation; Phosphotransferases; Plant Cells; Plant Roots; Protein Binding; Proteome; Proton-Translocating ATPases; Serine
PubMed: 24458638
DOI: 10.1126/science.1244454 -
Journal of Cellular Physiology Jul 2021Erythroferrone (ERFE) is the main erythroid regulator of hepcidin, the homeostatic hormone controlling plasma iron levels and total body iron. When the release of... (Review)
Review
Erythroferrone (ERFE) is the main erythroid regulator of hepcidin, the homeostatic hormone controlling plasma iron levels and total body iron. When the release of erythropoietin from the kidney stimulates the production of new red blood cells, it also increases the synthesis of ERFE in bone marrow erythroblasts. Increased ERFE then suppresses hepcidin synthesis, thereby mobilizing cellular iron stores for use in heme and hemoglobin synthesis. Recent mechanistic studies have shown that ERFE suppresses hepcidin transcription by inhibiting bone morphogenetic protein signaling in hepatocytes. In ineffective erythropoiesis, pathological overproduction of ERFE by an expanded population of erythroblasts suppresses hepcidin and causes iron overload, even in non-transfused patients. ERFE may be a useful biomarker of ineffective erythropoiesis and an attractive target for treating its systemic effects.
Topics: Bone Morphogenetic Proteins; Erythroblasts; Erythropoiesis; Hepcidins; Homeostasis; Humans; Iron; Iron Overload; Peptide Hormones; Protein Conformation; Signal Transduction
PubMed: 33372284
DOI: 10.1002/jcp.30247 -
Cell Apr 2016Hepatic glucose release into the circulation is vital for brain function and survival during periods of fasting and is modulated by an array of hormones that precisely...
Hepatic glucose release into the circulation is vital for brain function and survival during periods of fasting and is modulated by an array of hormones that precisely regulate plasma glucose levels. We have identified a fasting-induced protein hormone that modulates hepatic glucose release. It is the C-terminal cleavage product of profibrillin, and we name it Asprosin. Asprosin is secreted by white adipose, circulates at nanomolar levels, and is recruited to the liver, where it activates the G protein-cAMP-PKA pathway, resulting in rapid glucose release into the circulation. Humans and mice with insulin resistance show pathologically elevated plasma asprosin, and its loss of function via immunologic or genetic means has a profound glucose- and insulin-lowering effect secondary to reduced hepatic glucose release. Asprosin represents a glucogenic protein hormone, and therapeutically targeting it may be beneficial in type II diabetes and metabolic syndrome.
Topics: Adipose Tissue, White; Amino Acid Sequence; Animals; Antibodies; Circadian Rhythm; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Fasting; Female; Fetal Growth Retardation; Fibrillin-1; Glucose; Humans; Insulin; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Microfilament Proteins; Molecular Sequence Data; Peptide Fragments; Peptide Hormones; Progeria; Recombinant Proteins; Sequence Alignment
PubMed: 27087445
DOI: 10.1016/j.cell.2016.02.063 -
Nature Medicine Dec 2017Asprosin is a recently discovered fasting-induced hormone that promotes hepatic glucose production. Here we demonstrate that asprosin in the circulation crosses the...
Asprosin is a recently discovered fasting-induced hormone that promotes hepatic glucose production. Here we demonstrate that asprosin in the circulation crosses the blood-brain barrier and directly activates orexigenic AgRP neurons via a cAMP-dependent pathway. This signaling results in inhibition of downstream anorexigenic proopiomelanocortin (POMC)-positive neurons in a GABA-dependent manner, which then leads to appetite stimulation and a drive to accumulate adiposity and body weight. In humans, a genetic deficiency in asprosin causes a syndrome characterized by low appetite and extreme leanness; this is phenocopied by mice carrying similar mutations and can be fully rescued by asprosin. Furthermore, we found that obese humans and mice had pathologically elevated concentrations of circulating asprosin, and neutralization of asprosin in the blood with a monoclonal antibody reduced appetite and body weight in obese mice, in addition to improving their glycemic profile. Thus, in addition to performing a glucogenic function, asprosin is a centrally acting orexigenic hormone that is a potential therapeutic target in the treatment of both obesity and diabetes.
Topics: Adolescent; Adult; Animals; Appetite Depressants; Appetite Regulation; Female; Fibrillin-1; Humans; Hypothalamus; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microfilament Proteins; Neurons; Peptide Fragments; Peptide Hormones; Rats; Signal Transduction; Young Adult
PubMed: 29106398
DOI: 10.1038/nm.4432 -
Frontiers in Endocrinology 2022Adipose tissue malfunction leads to altered adipokine secretion which might consequently contribute to an array of metabolic diseases spectrum including obesity,... (Review)
Review
Adipose tissue malfunction leads to altered adipokine secretion which might consequently contribute to an array of metabolic diseases spectrum including obesity, diabetes mellitus, and cardiovascular disorders. Asprosin is a novel diabetogenic adipokine classified as a caudamin hormone protein. This adipokine is released from white adipose tissue during fasting and elicits glucogenic and orexigenic effects. Although white adipose tissue is the dominant source for this multitask adipokine, other tissues also may produce asprosin such as salivary glands, pancreatic B-cells, and cartilage. Significantly, plasma asprosin levels link to glucose metabolism, lipid profile, insulin resistance (IR), and β-cell function. Indeed, asprosin exhibits a potent role in the metabolic process, induces hepatic glucose production, and influences appetite behavior. Clinical and preclinical research showed dysregulated levels of circulating asprosin in several metabolic diseases including obesity, type 2 diabetes mellitus (T2DM), polycystic ovarian syndrome (PCOS), non-alcoholic fatty liver (NAFLD), and several types of cancer. This review provides a comprehensive overview of the asprosin role in the etiology and pathophysiological manifestations of these conditions. Asprosin could be a promising candidate for both novel pharmacological treatment strategies and diagnostic tools, although developing a better understanding of its function and signaling pathways is still needed.
Topics: Female; Humans; Diabetes Mellitus, Type 2; Peptide Hormones; Glucose; Obesity; Adipokines
PubMed: 36686442
DOI: 10.3389/fendo.2022.1101091 -
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 -
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 -
Molecules (Basel, Switzerland) Sep 2020Work from our laboratories over the last 35 years that has focused on Ste2p, a G protein-coupled receptor (GPCR), and its tridecapeptide ligand α-factor is reviewed.... (Review)
Review
Work from our laboratories over the last 35 years that has focused on Ste2p, a G protein-coupled receptor (GPCR), and its tridecapeptide ligand α-factor is reviewed. Our work utilized the yeast as a model system for understanding peptide-GPCR interactions. It explored the structure and function of synthetic α-factor analogs and biosynthetic receptor domains, as well as designed mutations of Ste2p. The results and conclusions are described using the nuclear magnetic resonance interrogation of synthetic Ste2p transmembrane domains (TMs), the fluorescence interrogation of agonist and antagonist binding, the biochemical crosslinking of peptide analogs to Ste2p, and the phenotypes of receptor mutants. We identified the ligand-binding domain in Ste2p, the functional assemblies of TMs, unexpected and interesting ligand analogs; gained insights into the bound α-factor structure; and unraveled the function and structures of various Ste2p domains, including the N-terminus, TMs, loops connecting the TMs, and the C-terminus. Our studies showed interactions between specific residues of Ste2p in an active state, but not resting state, and the effect of ligand activation on the dimerization of Ste2p. We show that, using a battery of different biochemical and genetic approaches, deep insight can be gained into the structure and conformational dynamics of GPCR-peptide interactions in the absence of a crystal structure.
Topics: Allosteric Regulation; Binding Sites; Ligands; Microscopy, Fluorescence; Peptide Hormones; Protein Binding; Protein Domains; Receptors, G-Protein-Coupled; Saccharomyces cerevisiae
PubMed: 32961885
DOI: 10.3390/molecules25184272 -
Endocrine Reviews Jul 2020DNA damage response (DDR) and DNA repair pathways determine neoplastic cell transformation and therapeutic responses, as well as the aging process. Altered DDR... (Review)
Review
DNA damage response (DDR) and DNA repair pathways determine neoplastic cell transformation and therapeutic responses, as well as the aging process. Altered DDR functioning results in accumulation of unrepaired DNA damage, increased frequency of tumorigenic mutations, and premature aging. Recent evidence suggests that polypeptide hormones play a role in modulating DDR and DNA damage repair, while DNA damage accumulation may also affect hormonal status. We review the available reports elucidating involvement of insulin-like growth factor 1 (IGF1), growth hormone (GH), α-melanocyte stimulating hormone (αMSH), and gonadotropin-releasing hormone (GnRH)/gonadotropins in DDR and DNA repair as well as the current understanding of pathways enabling these actions. We discuss effects of DNA damage pathway mutations, including Fanconi anemia, on endocrine function and consider mechanisms underlying these phenotypes. (Endocrine Reviews 41: 1 - 19, 2020).
Topics: Animals; DNA Damage; DNA Repair; Gonadotropin-Releasing Hormone; Gonadotropins; Growth Hormone; Humans; Insulin-Like Growth Factor I; Peptide Hormones; alpha-MSH
PubMed: 32270196
DOI: 10.1210/endrev/bnaa009