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1. Dietary protein defends lean mass and maintains the metabolic benefits of glucagon receptor agonism in mice

Author

Tatiana Lopes, David CD. Hope, Jose M. Ramos-Pittol, Anna Curtis, Jed V. Shrewsbury, Iona Davies, Zijing Zhou, Alessandro Sardini, James S. Minnion, Dirk Dormann, Gavin A. Bewick, Kevin G. Murphy, David Carling, Stephen R. Bloom, Tricia MM. Tan, and Bryn M. Owen

Subjects
Glucagon, Obesity, MAFLD, Drug, Side-effect, Lean mass, Internal medicine, RC31-1245
Abstract

Objective: Glucagon has long been proposed as a component of multi-agonist obesity therapeutics due to its ability to induce energy expenditure and cause weight loss. However, chronic glucagon-receptor agonism has been associated with a reduction in circulating amino acids and loss of lean mass. Importantly, it is currently not known whether the metabolic benefits of glucagon can be maintained under contexts that allow the defence of lean mass. Methods: We investigate the metabolic effects of the long-acting glucagon receptor agonist, G108, when administered to obese mice at low-doses, and with dietary protein supplementation. Results: Dietary protein supplementation can only fully defend lean mass at a low dose of G108 that is sub-anorectic and does not reduce fat mass. However, in this context, G108 is still highly effective at improving glucose tolerance and reducing liver fat in obese mice. Mechanistically, liver RNA-Seq analysis reveals that dietary protein supplementation defends anabolic processes in low-dose G108-treated mice, and its effects on treatment-relevant glucose and lipid pathways are preserved. Conclusion: Glucagon-mediated energy expenditure and weight loss may be mechanistically coupled to hypoaminocidemia and lean mass loss. However, our data suggest that glucagon can treat MAFLD at doses which allow full defence of lean mass given sufficient dietary protein intake. Therefore, proportionate glucagon therapy may be safe and effective in targeting hepatocytes and improving in glycaemia and liver fat.

Published
2024
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2. Chronic treatment with glucagon-like peptide-1 and glucagon receptor co-agonist causes weight loss-independent improvements in hepatic steatosis in mice with diet-induced obesity

Author

Emma Rose McGlone, David C.D. Hope, Iona Davies, Marian Dore, Rob Goldin, Ben Jones, Zhigang Liu, Jia V. Li, Panagiotis A. Vorkas, Bernard Khoo, David Carling, James Minnion, Stephen R. Bloom, and Tricia M-M. Tan

Subjects
Metabolic dysfunction-associated steatotic liver disease (MASLD), non-alcoholic Fatty Liver Disease (NAFLD), weight loss, type 2 diabetes mellitus, glucagon, glucagon-like peptide-1, Therapeutics. Pharmacology, RM1-950
Abstract

Objectives: Co-agonists at the glucagon-like peptide-1 and glucagon receptors (GLP1R/GCGR) show promise as treatments for metabolic dysfunction-associated steatotic liver disease (MASLD). Although most co-agonists to date have been heavily GLP1R-biased, glucagon directly acts on the liver to reduce fat content. The aims of this study were to investigate a GCGR-biased co-agonist as treatment for hepatic steatosis in mice. Methods: Mice with diet-induced obesity (DIO) were treated with Dicretin, a GLP1/GCGR co-agonist with high potency at the GCGR, Semaglutide (GLP1R monoagonist) or food restriction over 24 days, such that their weight loss was matched. Hepatic steatosis, glucose tolerance, hepatic transcriptomics, metabolomics and lipidomics at the end of the study were compared with Vehicle-treated mice. Results: Dicretin lead to superior reduction of hepatic lipid content when compared to Semaglutide or equivalent weight loss by calorie restriction. Markers of glucose tolerance and insulin resistance improved in all treatment groups. Hepatic transcriptomic and metabolomic profiling demonstrated many changes that were unique to Dicretin-treated mice. These include some known targets of glucagon signaling and others with as yet unclear physiological significance. Conclusions: Our study supports the development of GCGR-biased GLP1/GCGR co-agonists for treatment of MASLD and related conditions.

Published
2024
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3. The vagus nerve mediates the physiological but not pharmacological effects of PYY3-36 on food intake

Author

Aldara Martin Alonso, Simon C. Cork, Phyllis Phuah, Benjamin Hansen, Mariana Norton, Sijing Cheng, Xiang Xu, Kinga Suba, Yue Ma, Georgina KC. Dowsett, John A. Tadross, Brian YH. Lam, Giles SH. Yeo, Herbert Herzog, Stephen R. Bloom, Myrtha Arnold, Walter Distaso, Kevin G. Murphy, and Victoria Salem

Subjects
Vagus nerve, PYY, Appetite, Gut hormones, Internal medicine, RC31-1245
Abstract

Peptide YY (PYY3-36) is a post-prandially released gut hormone with potent appetite-reducing activity, the mechanism of action of which is not fully understood. Unravelling how this system physiologically regulates food intake may help unlock its therapeutic potential, whilst minimising unwanted effects. Here we demonstrate that germline and post-natal targeted knockdown of the PYY3-36 preferring receptor (neuropeptide Y (NPY) Y2 receptor (Y2R)) in the afferent vagus nerve is required for the appetite inhibitory effects of physiologically-released PYY3-36, but not peripherally administered pharmacological doses. Post-natal knockdown of the Y2R results in a transient body weight phenotype that is not evident in the germline model. Loss of vagal Y2R signalling also results in altered meal patterning associated with accelerated gastric emptying. These results are important for the design of PYY-based anti-obesity agents.

Published
2024
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4. Hepatocyte cholesterol content modulates glucagon receptor signalling

Author

Emma Rose McGlone, T. Bertie Ansell, Cecilia Dunsterville, Wanling Song, David Carling, Alejandra Tomas, Stephen R. Bloom, Mark S.P. Sansom, Tricia Tan, and Ben Jones

Subjects
Glucagon, Glucagon receptor, Cholesterol, Cell membrane, Non-alcoholic fatty liver disease, Type 2 diabetes mellitus, Internal medicine, RC31-1245
Abstract

Structured abstract: Objective: To determine whether glucagon receptor (GCGR) actions are modulated by cellular cholesterol levels. Methods: We determined the effects of experimental cholesterol depletion and loading on glucagon-mediated cAMP production, ligand internalisation and glucose production in human hepatoma cells, mouse and human hepatocytes. GCGR interactions with lipid bilayers were explored using coarse-grained molecular dynamic simulations. Glucagon responsiveness was measured in mice fed a high cholesterol diet with or without simvastatin to modulate hepatocyte cholesterol content. Results: GCGR cAMP signalling was reduced by higher cholesterol levels across different cellular models. Ex vivo glucagon-induced glucose output from mouse hepatocytes was enhanced by simvastatin treatment. Mice fed a high cholesterol diet had increased hepatic cholesterol and a blunted hyperglycaemic response to glucagon, both of which were partially reversed by simvastatin. Simulations identified likely membrane-exposed cholesterol binding sites on the GCGR, including a site where cholesterol is a putative negative allosteric modulator. Conclusions: Our results indicate that cellular cholesterol content influences glucagon sensitivity and indicate a potential molecular basis for this phenomenon. This could be relevant to the pathogenesis of non-alcoholic fatty liver disease, which is associated with both hepatic cholesterol accumulation and glucagon resistance.

Published
2022
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5. Receptor Activity-Modifying Protein 2 (RAMP2) alters glucagon receptor trafficking in hepatocytes with functional effects on receptor signalling

Author

Emma Rose McGlone, Yusman Manchanda, Ben Jones, Phil Pickford, Asuka Inoue, David Carling, Stephen R. Bloom, Tricia Tan, and Alejandra Tomas

Subjects
Glucagon receptor, Receptor activity-modifying protein 2, G protein-coupled receptors, Endocytic trafficking, Intracellular signalling, Carbohydrate metabolism, Internal medicine, RC31-1245
Abstract

Objectives: Receptor Activity-Modifying Protein 2 (RAMP2) is a chaperone protein which allosterically binds to and interacts with the glucagon receptor (GCGR). The aims of this study were to investigate the effects of RAMP2 on GCGR trafficking and signalling in the liver, where glucagon (GCG) is important for carbohydrate and lipid metabolism. Methods: Subcellular localisation of GCGR in the presence and absence of RAMP2 was investigated using confocal microscopy, trafficking and radioligand binding assays in human embryonic kidney (HEK293T) and human hepatoma (Huh7) cells. Mouse embryonic fibroblasts (MEFs) lacking the Wiskott-Aldrich Syndrome protein and scar homologue (WASH) complex and the trafficking inhibitor monensin were used to investigate the effect of halted recycling of internalised proteins on GCGR subcellular localisation and signalling in the absence of RAMP2. NanoBiT complementation and cyclic AMP assays were used to study the functional effect of RAMP2 on the recruitment and activation of GCGR signalling mediators. Response to hepatic RAMP2 upregulation in lean and obese adult mice using a bespoke adeno-associated viral vector was also studied. Results: GCGR is predominantly localised at the plasma membrane in the absence of RAMP2 and exhibits remarkably slow internalisation in response to agonist stimulation. Rapid intracellular accumulation of GCG-stimulated GCGR in cells lacking the WASH complex or in the presence of monensin indicates that activated GCGR undergoes continuous cycles of internalisation and recycling, despite apparent GCGR plasma membrane localisation up to 40 min post-stimulation. Co-expression of RAMP2 induces GCGR internalisation both basally and in response to agonist stimulation. The intracellular retention of GCGR in the presence of RAMP2 confers a bias away from β-arrestin-2 recruitment coupled with increased activation of Gαs proteins at endosomes. This is associated with increased short-term efficacy for glucagon-stimulated cAMP production, although long-term signalling is dampened by increased receptor lysosomal targeting for degradation. Despite these signalling effects, only a minor disturbance of carbohydrate metabolism was observed in mice with upregulated hepatic RAMP2. Conclusions: By retaining GCGR intracellularly, RAMP2 alters the spatiotemporal pattern of GCGR signalling. Further exploration of the effects of RAMP2 on GCGR in vivo is warranted.

Published
2021
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6. Partial agonism improves the anti-hyperglycaemic efficacy of an oxyntomodulin-derived GLP-1R/GCGR co-agonist

Author

Phil Pickford, Maria Lucey, Roxana-Maria Rujan, Emma Rose McGlone, Stavroula Bitsi, Fiona B. Ashford, Ivan R. Corrêa, David J. Hodson, Alejandra Tomas, Giuseppe Deganutti, Christopher A. Reynolds, Bryn M. Owen, Tricia M. Tan, James Minnion, Ben Jones, and Stephen R. Bloom

Subjects
GLP-1, Glucagon, Oxyntomodulin, Biased agonism, Partial agonism, β-arrestin, Internal medicine, RC31-1245
Abstract

Objective: Glucagon-like peptide-1 and glucagon receptor (GLP-1R/GCGR) co-agonism can maximise weight loss and improve glycaemic control in type 2 diabetes and obesity. In this study, we investigated the cellular and metabolic effects of modulating the balance between G protein and β-arrestin-2 recruitment at GLP-1R and GCGR using oxyntomodulin (OXM)-derived co-agonists. This strategy has been previously shown to improve the duration of action of GLP-1R mono-agonists by reducing target desensitisation and downregulation. Methods: Dipeptidyl dipeptidase-4 (DPP-4)-resistant OXM analogues were generated and assessed for a variety of cellular readouts. Molecular dynamic simulations were used to gain insights into the molecular interactions involved. In vivo studies were performed in mice to identify the effects on glucose homeostasis and weight loss. Results: Ligand-specific reductions in β-arrestin-2 recruitment were associated with slower GLP-1R internalisation and prolonged glucose-lowering action in vivo. The putative benefits of GCGR agonism were retained, with equivalent weight loss compared to the GLP-1R mono-agonist liraglutide despite a lesser degree of food intake suppression. The compounds tested showed only a minor degree of biased agonism between G protein and β-arrestin-2 recruitment at both receptors and were best classified as partial agonists for the two pathways measured. Conclusions: Diminishing β-arrestin-2 recruitment may be an effective way to increase the therapeutic efficacy of GLP-1R/GCGR co-agonists. These benefits can be achieved by partial rather than biased agonism.

Published
2021
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7. Disconnect between signalling potency and in vivo efficacy of pharmacokinetically optimised biased glucagon-like peptide-1 receptor agonists

Author

Maria Lucey, Philip Pickford, Stavroula Bitsi, James Minnion, Jan Ungewiss, Katja Schoeneberg, Guy A. Rutter, Stephen R. Bloom, Alejandra Tomas, and Ben Jones

Subjects
Type 2 diabetes, Biased signalling, Glucagon-like peptide-1 receptor, Exendin-4, Trafficking, Internal medicine, RC31-1245
Abstract

Objective: The objective of this study was to determine how pharmacokinetically advantageous acylation impacts on glucagon-like peptide-1 receptor (GLP-1R) signal bias, trafficking, anti-hyperglycaemic efficacy, and appetite suppression. Methods: In vitro signalling responses were measured using biochemical and biosensor assays. GLP-1R trafficking was determined by confocal microscopy and diffusion-enhanced resonance energy transfer. Pharmacokinetics, glucoregulatory effects, and appetite suppression were measured in acute, sub-chronic, and chronic settings in mice. Results: A C-terminally acylated ligand, [F1,G40,K41.C16 diacid]exendin-4, was identified that showed undetectable β-arrestin recruitment and GLP-1R internalisation. Depending on the cellular system used, this molecule was up to 1000-fold less potent than the comparator [D3,G40,K41.C16 diacid]exendin-4 for cyclic AMP signalling, yet was considerably more effective in vivo, particularly for glucose regulation. Conclusions: C-terminal acylation of biased GLP-1R agonists increases their degree of signal bias in favour of cAMP production and improves their therapeutic potential.

Published
2020
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8. Thyroid Hormone Receptor Beta in the Ventromedial Hypothalamus Is Essential for the Physiological Regulation of Food Intake and Body Weight

Author

Saira Hameed, Michael Patterson, Waljit S. Dhillo, Sofia A. Rahman, Yue Ma, Christopher Holton, Apostolos Gogakos, Giles S.H. Yeo, Brian Y.H. Lam, Joseph Polex-Wolf, Wiebke Fenske, Jimmy Bell, Jelena Anastasovska, Jacques Samarut, Stephen R. Bloom, J.H. Duncan Bassett, Graham R. Williams, and James V. Gardiner

Subjects
thyroid hormone, thyroid hormone receptor beta, hypothalamus, ventromedial hypothalamus, VMH, body weight, obesity, food intake, appetite, energy expenditure, Biology (General), QH301-705.5
Abstract

The obesity epidemic is a significant global health issue. Improved understanding of the mechanisms that regulate appetite and body weight will provide the rationale for the design of anti-obesity therapies. Thyroid hormones play a key role in metabolic homeostasis through their interaction with thyroid hormone receptors (TRs), which function as ligand-inducible transcription factors. The TR-beta isoform (TRβ) is expressed in the ventromedial hypothalamus (VMH), a brain area important for control of energy homeostasis. Here, we report that selective knockdown of TRβ in the VMH of adult mice results in severe obesity due to hyperphagia and reduced energy expenditure. The observed increase in body weight is of a similar magnitude to murine models of the most extreme forms of monogenic obesity. These data identify TRβ in the VMH as a major physiological regulator of food intake and energy homeostasis.

Published
2017
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9. Fermentable carbohydrate stimulates FFAR2-dependent colonic PYY cell expansion to increase satiety

Author

Lucy Brooks, Alexander Viardot, Anastasia Tsakmaki, Emilie Stolarczyk, Jane K. Howard, Patrice D. Cani, Amandine Everard, Michelle L. Sleeth, Arianna Psichas, Jelena Anastasovskaj, Jimmy D. Bell, Kim Bell-Anderson, Charles R. Mackay, Mohammad A. Ghatei, Stephen R. Bloom, Gary Frost, and Gavin A. Bewick

Subjects
Internal medicine, RC31-1245
Abstract

Objective: Dietary supplementation with fermentable carbohydrate protects against body weight gain. Fermentation by the resident gut microbiota produces short-chain fatty acids, which act at free fatty acid receptor 2 (FFAR2). Our aim was to test the hypothesis that FFAR2 is important in regulating the beneficial effects of fermentable carbohydrate on body weight and to understand the role of gut hormones PYY and GLP-1. Methods: Wild-type or Ffar2−/− mice were fed an inulin supplemented or control diet. Mice were metabolically characterized and gut hormone concentrations, enteroendocrine cell density measurements were carried out. Intestinal organoids and colonic cultures were utilized to substantiate the in vivo findings. Results: We provide new mechanistic insight into how fermentable carbohydrate regulates metabolism. Using mice that lack FFAR2, we demonstrate that the fermentable carbohydrate inulin acts via this receptor to drive an 87% increase in the density of cells that produce the appetite-suppressing hormone peptide YY (PYY), reduce food intake, and prevent diet-induced obesity. Conclusion: Our results demonstrate that FFAR2 is predominantly involved in regulating the effects of fermentable carbohydrate on metabolism and does so, in part, by enhancing PYY cell density and release. This highlights the potential for targeting enteroendocrine cell differentiation to treat obesity. Keywords: Obesity, Diet, Peptide YY, Microbiota, Colon

Published
2017
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10. Investigating the Glucagon Receptor and Glucagon-Like Peptide 1 Receptor Activity of Oxyntomodulin-Like Analogues in Male Wistar Rats

Author

Samantha L. Price, MRes, James S. Minnion, PhD, and Stephen R. Bloom, MD

Subjects
analogue, body weight, glucagons, oxyntomodulin, Therapeutics. Pharmacology, RM1-950
Abstract

Aims: To investigate the effect of Glu-3 OXM-like analogues on food intake and bodyweight in male rats. Background: Oxyntomodulin (OXM) is a natural agonist at both the glucagon receptor (GCGr) and the glucagon-like peptide 1 receptor (GLP-1r), and peripheral administration reduces food intake and increases energy expenditure in rodents and humans. Substituting the native glutamine (Gln) at amino acid position 3 of OXM for glutamate (Glu) has previously been shown to diminish GCGr activity without affecting GLP-1r activity. The effects of Glu-3 OXM analogues have not been investigated in rats. Methods: The effect of 2 Glu-3-substituted OXM-like analogues (eg, OXM14E3 and OXM15E3) on food intake and body weight was investigated in male Wistar rats during 6 days of daily subcutaneous (SC) administration. The effects of Glu-3 substitution on analogue binding and activity at the rat GCGr and rat GLP-1 receptor were investigated in vitro using Chinese hamster ovary or Chinese hamster lung cells. Results: We report the novel finding that 2 5-nmol/kg Glu-3 OXM-like analogues (OXM14E3 and OXM15E3) significantly increased rat body weight by up to 4% compared with the equivalent non-Glu-3 analogues (OXM14 and OXM15), without affecting food intake. The effect of OXM15E3 on body weight was dose–dependent. Glu-3 analogues, including Glu-3 OXM, decreased glucagon-mediated cyclic adenosine monophosphate accumulation in Chinese hamster ovary cells expressing the rat GCGr, suggesting they may be acting as antagonists. Conclusions: The results indicate Glu-3 OXM-like analogues might not be suitable tools to investigate the mechanism of OXM analogue action in a rat model because they significantly increase body weight independent of food intake. Glu-3 OXM analogues are partial agonists at the rat GCGr and may also act as antagonists, possibly resulting in the observed increase in body weight.

Published
2015
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11. Glucagon-like peptide 1 (GLP-1)

Author

Kerstin Stemmer, Stephen C. Woods, Harvey J. Grill, Jens J. Holst, Alessandro Pocai, Michael A. Nauck, Andreas Fritsche, Richard D. DiMarchi, David A. D'Alessio, Mads Tang-Christensen, Diego Perez-Tilve, Darleen A. Sandoval, Randy J. Seeley, Wolfgang Langhans, Daniel J. Drucker, Stephen R. Bloom, M.H. Tschöp, Brian Finan, Fiona M. Gribble, Timo D. Müller, Peter R. Flatt, Joel F. Habener, Juris J. Meier, Thue W. Schwartz, Frank Reimann, Gribble, Fiona [0000-0002-4232-2898], Reimann, Frank [0000-0001-9399-6377], and Apollo - University of Cambridge Repository

Subjects
Blood Glucose, 0301 basic medicine, endocrine system, lcsh:Internal medicine, medicine.medical_treatment, Incretin, 030209 endocrinology & metabolism, Review, Gastric Inhibitory Polypeptide, Pharmacology, Neuroprotection, Glucagon-Like Peptide-1 Receptor, 03 medical and health sciences, 0302 clinical medicine, GLP-1, Insulin, Glucagon, Diabetes, Obesity, Glucagon-Like Peptide 1, Insulin-Secreting Cells, Diabetes mellitus, Insulin Secretion, Receptors, Glucagon, medicine, Humans, Hypoglycemic Agents, ddc:610, Receptor, lcsh:RC31-1245, Molecular Biology, 2. Zero hunger, Gastric emptying, business.industry, digestive, oral, and skin physiology, Cell Biology, medicine.disease, Glucagon-like peptide-1, ddc, 3. Good health, Glucose, 030104 developmental biology, Diabetes Mellitus, Type 2, business, hormones, hormone substitutes, and hormone antagonists, Hormone
Abstract

Background: The glucagon-like peptide-1 (GLP-1) is a multifaceted hormone with broad pharmacological potential. Among the numerous metabolic effects of GLP-1 are the glucose-dependent stimulation of insulin secretion, decrease of gastric emptying, inhibition of food intake, increase of natriuresis and diuresis, and modulation of rodent beta-cell proliferation. GLP-1 also has cardio- and neuroprotective effects, decreases inflammation and apoptosis, and has implications for learning and memory, reward behavior, and palatability. Biochemically modified for enhanced potency and sustained action, GLP-1 receptor agonists are successfully in clinical use for the treatment of type-2 diabetes, and several GLP-1-based pharmacotherapies are in clinical evaluation for the treatment of obesity. Scope of review: In this review, we provide a detailed overview on the multifaceted nature of GLP-1 and its pharmacology and discuss its therapeutic implications on various diseases. Major conclusions: Since its discovery, GLP-1 has emerged as a pleiotropic hormone with a myriad of metabolic functions that go well beyond its classical identification as an incretin hormone. The numerous beneficial effects of GLP-1 render this hormone an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, and neurodegenerative disorders (C) 2019 The Authors. Published by Elsevier GmbH.

Published
2019

12. Control of insulin secretion by GLP-1

Author

Stephen R. Bloom, Ben Jones, Alejandra Tomas, Teresa Buenaventura, Guy A. Rutter, and Medical Research Council

Subjects
0301 basic medicine, endocrine system, MAP Kinase Signaling System, Physiology, Receptor signalling, Bariatric Surgery, Incretin, Endogeny, Stimulation, Type 2 diabetes, Pharmacology, GLP-1 receptor, Ligands, Incretins, Biochemistry, Glucagon-Like Peptide-1 Receptor, 03 medical and health sciences, Cellular and Molecular Neuroscience, Endocrinology & Metabolism, 0302 clinical medicine, Endocrinology, Glucagon-Like Peptide 1, Insulin-Secreting Cells, Extracellular, Humans, Insulin, Medicine, Obesity, Receptor, Glucagon-like peptide 1 receptor, business.industry, Kinase, Insulin secretion, digestive, oral, and skin physiology, Endocytic trafficking, Beta cells, medicine.disease, 0606 Physiology, 0304 Medicinal And Biomolecular Chemistry, 030104 developmental biology, Diabetes Mellitus, Type 2, 1115 Pharmacology And Pharmaceutical Sciences, Peptides, business, GLP-1, 030217 neurology & neurosurgery, hormones, hormone substitutes, and hormone antagonists
Abstract

Stimulation of insulin secretion by glucagon-like peptide-1 (GLP-1) and other gut-derived peptides is central to the incretin response to ingesting nutriments. Analogues of GLP-1, and inhibitors of its breakdown, have found widespread clinical use for the treatment of type 2 diabetes (T2D) and obesity. The release of these peptides underlies the improvements in glycaemic control and disease remission after bariatric surgery. Given therapeutically, GLP-1 analogues can lead to side effects including nausea, which limit dosage. Greater understanding of the interactions between the GLP-1 receptor (GLP-1R) and both the endogenous and artificial ligands therefore holds promise to provide more efficacious compounds. Here, we discuss recent findings concerning the signalling and trafficking of the GLP-1R in pancreatic beta cells. Leveraging "bias" at the receptor towards cAMP generation versus the recruitment of β-arrestins and extracellular signal-regulated kinases (ERK1/2) activation may allow the development of new analogues with significantly improved clinical efficacy. We describe how, unexpectedly, relatively low-affinity agonists, which prompt less receptor internalisation than the parent compound, provoke greater insulin secretion and consequent improvements in glycaemia.

Published
2017

13. Gut Hormones and Obesity

Author

Tricia Tan, Rebecca Scott, and Stephen R. Bloom

Subjects
medicine.medical_specialty, Gastric bypass surgery, digestive, oral, and skin physiology, Type 2 Diabetes Mellitus, Adipose tissue, Physiology, Biology, medicine.disease_cause, Energy homeostasis, Endocrinology, Hypothalamus, Weight loss, Internal medicine, medicine, medicine.symptom, Homeostasis, Hormone
Abstract

Over the past 30 years, it has been established that hormones produced by the gut, pancreas, and adipose tissue are key players in the control of body weight. These hormones act through a complex neuroendocrine system, including the hypothalamus, to regulate metabolism and energy homeostasis. In obesity, this homeostatic balance is disrupted, either through alterations in the levels of these hormones or through resistance to their actions. Alterations in gut hormone secretion following gastric bypass surgery are likely to underlie the dramatic and persistent loss of weight following this procedure, as well as the observed amelioration in type 2 diabetes mellitus. Medications based on the gut hormone GLP-1 are currently in clinical use to treat type 2 diabetes mellitus and have been shown to produce weight loss. Further therapies for obesity based on other gut hormones are currently in development.

Published
2013

14. Contributors

Author

Reidunn B. Aalen, Yasser H.A. Abdel-Wahab, Michael E. Adams, Roger A.H. Adan, Rexford S. Ahima, Naima Ahmed, Omar Al-Massadi, Miriam Altstein, Youssef Anouar, Laura Anselmi, Siegfried Ansorge, Nikolinka Antcheva, Yevgeniya Antonova-Koch, Jon R. Appel, Anam J. Arik, Alison L. Arter, Peter Arvan, Avraham Ashkenazi, P.W. Baas, André Bado, Andrew Baird, Monica Baiula, Lauren O. Bakaletz, Earl E. Bakken, Márta Balaskó, Graham S. Baldwin, William A. Banks, Donatella Barra, Jessica R. Barson, Magali Basille, Natalie N. Bauer, Andrea Bedini, Christine Beeton, David J. Begley, Margery C. Beinfeld, William G. Bendena, Stephen C. Benoit, Itay Bentov, Howard Bern, Gabriele Bierbaum, Charles J. Billington, Anna Blasiak, Norman L. Block, Stephen. R. Bloom, Iwona Bonney, John H. Bowie, Sunny K. Boyd, Susan D. Brain, Dag A. Brede, Jozef Vanden Broeck, Kelly L. Brown, Mark R. Brown, James M. Bugni, Jens R. Bundgaard, Delphine Burel, Melinka A. Butenko, Melissa J. Call, Girolamo Calò, Duncan John Campbell, Anna Carlsson, Daniel B. Carr, Robert E. Carraway, Marcos C. Carreira, Felipe F. Casanueva, Sarah N. Cassella, Stuart A. Casson, Justo P. Castaño, Marek Cebrat, Valerie Chappe, David Chatenet, Keqiang Chen, Chen Chen, Longchuan Chen, Duan Chen, Carrie Y.Y. Cheng, Sung Ki Cho, Billy K.C. Chow, Arthur Christopoulos, Shijian Chu, Iain J. Clarke, Geoffrey M. Coast, Vincent Compere, Gisela P. Concepcion, Roger D. Cone, J. Michael Conlon, Germaine Cornélissen, Maité Courel, Réjean Couture, W.A. Cramer, Nathan P. Croft, Ana B. Crujeiras, Frank Cuttitta, Holger Cynis, F. D’Acquisto, Jon F. Davis, Thomas P. Davis, Claire Barbier de La Serre, Guillaume de Lartigue, Luis de Lecea, Marcelo de Oliveira Santos, Michel De Waard, Carolyn F. Deacon Bolette Hartmann, Charlène Delestre, Mario Delgado, Hans-Ulrich Demuth, Xiaoming Deng, Palitha Dharmawardhana, Anna Di Cosmo, Simoni Campos Dias, Jonathan W. Dickerson, Dzung B. Diep, H. Dircksen, Jasmin Dischinger, Jean-Claude do Rego, Paul R. Dobner, Graham J. Dockray, Robert M. Dores, Robert Ducroc, Nadine L. Dudek, Yvan Dumont, Celine Duraffourd, Dominique Duterte-Boucher, Alex N. Eberlé, Richard D. Egleton, Betty A. Eipper, Jorg B. Engel, Ella W. Englander, Jacques Epelbaum, Charlotte Erlanson-Albertsson, S. Evangelista, Karen A. Fagan, Joshua M. Farber, Klára Farkasfalvi, Csaba Fekete, Peter R. Flatt, R.J. Flower, Wolf-Georg Forssmann, Alain Fournier, Kevin Chu Foy, Octávio Luiz Franco, Dan Frenkel, Lloyd D. Fricker, César de la Fuente-Núñez, Hiroo Fukuda, Gerd Gäde, Ludovic Galas, Patricia E. Gallagher, Pierrick Gandolfo, Maria A. Garcia-Espinosa, Josune García-Sanmartín, Nori Geary, Hua Geng, Patrizia M. Germano, Jens P. Goetze, Alexis A. Gonzalez, Ana Gonzalez, Blake A. Gosnell, Katsutoshi Goto, Guillaume Gourcerol, I. Gozes, Francisco Gracia-Navarro, Bernadette E. Grayson, George H. Greeley, Megan Greenwald-Yarnell, Pierre Gressens, John R. Grider, Jan Grünewald, Juliano R. Guerreiro, Remo Guerrini, Filomena Guida, Laure Guilhaudis, Sandra Guilmeau, Andrew L. Gundlach, Jolanta Gutkowska, Clifton Hackbarth, Y. Haim Ohana, Franz Halberg, Mathias Hallberg, Sayyed A. Hamidi, Song Han, Ji-Sheng Han, Robert E.W. Hancock, Samer-ul Haque, Ikuko Hara-Nishimura, Aliza Hariton, Wendy J. Hartsock, Alan L. Harvey, Itaru Hasunuma, Robert J. Henning, Kristy M. Heppner, Kate L. Hertweck, Herbert Herzog, Tetsuya Higashiyama, Shuji Hinuma, Stefan Hippenstiel, Yuki Hirakawa, Shuichi Hirose, Jochen R. Hirsch, Andreas C. Hocke, Robert S. Hodges, Werner Hoffmann, Tomas Hökfelt, Jens Juul Holst, Peter Holzer, Frank M. Horodyski, Hiroshi Hosoda, Xiaowen Hou, Alisa Huffaker, Norio Iijima, Momoko Ikeuchi, Julita S. Imperial, Giovanna Improta, Akio Inui, Nigel Irwin, Munehiro Ishii, Xavier Iturrioz, Ljubica Ivanisevic, Hiroshi Iwao, Takeo Iwata, Yasukatsu Izumi, Hajime Izumiyama, Marek Jankowski, Tom Janssen, Sylvie Jégou, Robert T. Jensen, Preeti H. Jethwa, Helene Johannessen, Conrad Johanson, Valeria Judkowski, Przemyslaw Kaczmarek, Haruaki Kageyama, Tatsuo Kakimoto, Ki Sung Kang, Kenji Kangawa, Abba J. Kastin, Johji Kato, Pravin T.P. Kaumaya, Richard F. Keep, William R. Kem, Tetyana Khomenko, Sakae Kikuyama, Young-Joon Kim, Sadao Kimura, Ross King, Paul Kiptoo, Ichiro Kishimoto, Kazuo Kitamura, Alicja Kluczyk, Hiroyuki Kobori, Yosuke Kodama, Masayasu Kojima, Yuki Kondo, Meike Körner, Piotr Kosson, Catherine M. Kotz, Bhavani Krishnan, Bård Kulseng, Robert Kumpf, Marc Laburthe, Hélène Lacaille, Ellen E. Ladenheim, Ali Ladram, Marlyn D. Laksitorini, David G. Lambert, Angela B. Lange, Wolfgang Langhans, Muriel Larauche, Dan Larhammar, Ignacio M. Larráyoz, Roberta Lattanzi, Ronald M. Lechan, Benjamin Lefranc, Sarah F. Leibowitz, Vincent Lelièvre, Jérôme Leprince, Allen S. Levine, Qun Li, Veronica Lifshitz, Isabelle Lihrmann, James Chi-Jen Lin, Iris Lindberg, Keith Lindsey, Andrzej W. Lipkowski, T. Liron, Junli Liu, Ying Liu, Min Liu, Catherine Llorens-Cortes, Marilena Loizidou, C. Lopez, David A. Lovejoy, Vincenzo Luca, Thomas A. Lutz, Sherie Ma, Richard E. Mains, Maria M. Malagon, Ludwik K. Malendowicz, Jennifer Man-Fan Wan, Maria Luisa Mangoni, Michaele B Manigrasso, Mohamed A. Marahiel, Heather G. Marco, Christine Maric-Bilkan, Nikki J. Marks, Roland Martin, Vicente Martinez, Alfredo Martínez, Antonio J. Martinez-Fuentes, Edward P. Masler, Yoshikatsu Matsubayashi, Harman S. Mattu, Aaron G. Maule, Patricia J. McLaughlin, Ivan F. McMurtry, Ellen Meelkop, Saher Mehdi, Pietro Melchiorri, R.P. Millar, Laurence J. Miller, Miles Miller, Mulugeta Million, Naoto Minamino, M. Mittelman, Takashi Miyauchi, Mikiya Miyazato, Hirokazu Mizoguchi, Malte Mohme, Maité Montero-Hadjadje, Terry W. Moody, Neeloffer Mookherjee, Timothy H. Moran, Irene Morganstern, Masatomo Mori, Fabrice Morin, John F. Morris, Daniel S. Moura, Anna J. Mudge, Joram D. Mul, Karnam S. Murthy, Martin G. Myers, Ronald J. Nachman, Jean-Louis Nahon, Sushma Naithani, Tomoaki Nakada, Tomoya Nakamachi, Yuki Nakamura, Natalia N. Nalivaeva, June B. Nasrallah, Dick R. Nässel, L. Gabriel Navar, Pratap Neelakantan, Lucia Negri, Ingolf F. Nes, D. Neumann, Cindy Neveu, Tzi Bun Ng, Stephanie Y.L. Ng, Graham M. Nicholson, Pierre Nicolas, Toshio Nishikimi, Mariko Nishiyama, Rubén Nogueiras, Raymond S. Norton, Laura A. Novotny, Krzysztof W. Nowak, Fred Nyberg, Laura Ochoa-Callejero, Sven Ove Ögren, Hideko Ohgusu, Shinsuke Oh-I, Opeolu O. Ojo, Baldomero M. Olivera, Francisco E. Olucha-Bordonau, Joost J. Oppenheim, Ian Orchard, André J. Ouellette, Gustavo Pacheco-López, Nigel M. Page, Mario Sergio Palma, Weihong Pan, Yoonseong Park, Marc Parmentier, Sandrine Passemard, Michael Patterson, Brankica Paunovic, Gregory Pearce, Jens Pedersen, Theo L. Peeters, A. Eugene Pekary, Georges Pelletier, Simona Perboni, Diego Pérez-Tilve, Ábel Perjés, M. Perretti, Erika Pétervári, Clemencia Pinilla, Jacek Pinskim, Joseph R. Pisegna, Kristof Plankensteiner, Sonia Podvin, Pierre Poitras, Gianluca Polese, David M. Pollock, William Farias Porto, Lourival D. Possani, Charalabos Pothoulakis, Françoise Presse, Minolfa C. Prieto, S. Prutchi-Sagiv, Anthony W. Purcell, Louise Purtell, Rémi Quirion, Catalina Abad Rabat, Miriam Rademaker, Gautam Rajpal, Harpal S. Randeva, Sylvie Rebuffat, Joseph R. Reeve, Jens F. Rehfeld, Dirk Reinhold, Rainer K. Reinscheid, Jean Claude Reubi, Katayoun Rezvani, Suzana Meira Ribeiro, D. Richard, Mark Richards, Michael A. Riehle, Andrea C. Rinaldi, Bernd M. Rode, Ricardo C. Rodríguez de la Vega, Susan Rotzinger, Marcin Rucinski, Heikki Ruskoaho, Philip J. Ryan, Jean-Marc Sabatier, Hans-Georg Sahl, Sami I. Said, Tsukasa Sakurada, Shinobu Sakurada, David S. Salomon, Willis K. Samson, Zsuzsanna Sandor, H. Uri Saragovi, Kazuki Sasaki, Takahiro Sato, Ryousuke Satou, Shinichiro Sawa, Ayman I. Sayegh, Andrew V. Schally, Stephan Schilling, Liliane Schoofs, David A. Schooley, Mitchell L. Schubert, Isabelle Segalas-Milazzo, Nabil G. Seidah, Michael E. Selsted, Kim B. Seroogy, Cinzia Severini, Patrick M. Sexton, Yechiel Shai, O. Sharma, Masayoshi Shichiri, Tomoo Shimada, Hiroyuki Shimizu, Seiji Shioda, Arthur Shulkes, Teruna J. Siahaan, Ignacy Z. Siemion, Osmar Nascimento Silva, Marcio C. Silva-Filho, Mariusz Skwarczynski, Caroline. J. Small, Craig M. Smith, David E. Smith, A. Ian Smith, Beka Solomon, Travis E. Solomon, Mireia Sospedra, M.C. Souroujon, Santi Spampinato, Eliot R. Spindel, A. Steiger, Andreas Stengel, Catia Sternini, Frederik J. Steyn, Edward Stopa, Mathias Z. Strowski, Shigeo S. Sugano, Görel Sundström, J. Gregor Sutcliffe, Norbert Suttorp, Jonathan V. Sweedler, Sandor Szabo, Miklós Székely, István Szokodi, Yvette Taché, Kazuhiro Takahashi, Yoshio Takei, Fumiko Takenoya, Sébastien Talbot, E. Ann Tallant, Tricia M. Tan, Liesbet Temmerman, Bettina Temmesfeld-Wollbrück, Manuel Tena-Sempere, Annika Thorsell, Nanda Tilakaratne, Stephen S. Tobe, Takeshi Tokudome, Ganna Tolstanova, Marie-Christine Tonon, Jennifer F. Topping, Alessandro Tossi, Hervé Tostivint, Istvan Toth, Kazuhito Totsune, Fumiyo Toyoda, Rachel Troke, Matthias H. Tschöp, Patrick Tso, Hirokazu Tsukaya, Kazuyoshi Tsutsui, Hong Tu, Anthony J. Turner, Takayoshi Ubuka, Elene R. Valdivia, Hans Peter Vandersmissen, David Vaudry, Hubert Vaudry, Rafael Vazquez-Martinez, Joseph G. Verbalis, Daniele Vicari, Nicolas Vidal, Marzia Vignoni, Cécile Viollet, K.S. Vishwanatha, Mirella Vivoli, Thierry Voisin, John P. Vu, John C. Walker, B.A. Wallace, Ji Ming Wang, Lixin Wang, Jonathan H. Wardman, Takuya Watanabe, Hazel Welch, Haim Werner, L. Whitmore, Imke Wiedemann, Raphaelle Winsky-Sommerer, Ken A. Witt, Tatiana Wojciechowicz, Jack Ho Wong, Stephen C. Woods, Denise Wootten, Vincent Wu, Olivier Wurtz, Ximing Xiong, Zhi-Qing David Xu, Yube Yamaguchi, Takahiro Yamaguchi, Kazutoshi Yamamoto, E. Yamashita, Hiroyuki Yamazaki, De Yang, Masaaki Yoshikawa, Pu-Qing Yuan, Sunny C. Yung, Ian S. Zagon, S.D. Zakharov, Mehfuz Zaman, M.V. Zhalnina, Ning Zhang, Lixin Zhang-Auberson, Chun-Mei Zhao, Agnieszka Ziolkowska, and Dusan Zitnan

Published
2013

15. Pancreatic Polypeptide

Author

Tricia Tan and Stephen R. Bloom

Subjects
Biochemistry, Chemistry, Pancreatic polypeptide
Published
2013

16. PYY

Author

Tricia Tan, Rachel C. Troke, and Stephen R. Bloom

Subjects
Chemistry
Published
2013

17. Contributors

Author

Lloyd Paul Aiello, Erik K. Alexander, Carolyn A. Allan, Bruno Allolio, Peter Angelos, Sree Appu, Richard J. Auchus, Joseph Avruch, Lloyd Axelrod, Rebecca S. Bahn, H.W.G. Baker, Randall B. Barnes, Murat Bastepe, John D. Baxter, Paolo Beck-Peccoz, Graeme I. Bell, John P. Bilezikian, Stephen R. Bloom, Manfred Blum, Steen J. Bonnema, Diego Botero, Roger Bouillon, Andrew J.M. Boulton, Glenn D. Braunstein, F. Richard Bringhurst, Frank J. Broekmans, Marcello D. Bronstein, Edward M. Brown, Chuong Bui, Col. Henry B. Burch, Henry G. Burger, Richard O. Burney, John B. Buse, Peter C. Butler, Paolo Cappabianca, Maria Luiza Avancini Caramori, Robert M. Carey, Esther Carlton, David Carmody, Jose F. Caro, Francesco Cavagnini, Jerry Cavallerano, Luigi M. Cavallo, Shu Jin Chan, R. Jeffrey Chang, Roland D. Chapurlat, V. Krishna Chatterjee, Luca Chiovato, Kyung J. Cho, Daniel Christophe, Teng-Teng Chung, John A. Cidlowski, Adrian J.L. Clark, Peter E. Clark, David R. Clemmons, Robert V. Considine, Georges Copinschi, Kyle D. Copps, C. Hamish Courtney, Leona Cuttler, Melita L. Daley, Mehul Dattani, Stephen N. Davis, Oreste de Divitiis, Mario De Felice, Ralph A. DeFronzo, Leslie J. De Groot, David de Kretser, Ahmed J. Delli, Pierre D. Delmas, Marie B. Demay, Paul Devroey, Roberto Di Lauro, Sean F. Dinneen, Jacques E. Dumont, Kathleen M. Dungan, Daniel J. Drucker, Michael J. Econs, David A. Ehrmann, Graeme Eisenhofer, Gregory F. Erickson, Barbro Eriksson, Eric Espiner, Felice Esposito, Victoria Esser, Erica A. Eugster, Sadaf Farooqi, Martin Fassnacht, Bart C.J.M. Fauser, Gianfranco Fenzi, Ele Ferrannini, David M. Findlay, Courtney Finlayson, Delbert A. Fisher, Maguelone G. Forest, Daniel W. Foster, Mason Wright Freeman, Mark Frydenberg, Peter Fuller, Robert F. Gagel, Jason L. Gaglia, Gianluigi Galizia, Chuanyun Gao, Thomas J. Gardella, Bruce D. Gaylinn, Harry K. Genant, Michael S. German, Mohammad A. Ghatei, Linda C. Giudice, Anna Glasier, Francis H. Glorieux, Javier González-Maeso, Louis J. Gooren, David F. Gordon, Karen A. Gregerson, Milton D. Gross, Ashley Grossman, Valéria C. Guimarães, Mark Gurnell, Nadine Haddad, Daniel J. Haisenleder, David J. Handelsman, John B. Hanks, Mark John Hannon, Simon W. Hayward, Matthias Hebrok, Laszlo Hegedüs, Georg Hennemann, Maria K. Herndon, Peter Hindmarsh, Ken K.Y. Ho, Nelson D. Horseman, Mara J. Horwitz, Mimi Hu, Ieuan A. Hughes, Christopher J. Hupfeld, Hero K. Hussain, Peter Illingworth, J. Larry Jameson, Nathalie Josso, Harald Jüppner, Jeffrey Kalish, Edwin L. Kaplan, Jeffrey B. Kerr, Ronald Klein, Meyer Knobel, Efstratios Kolibianakis, John J. Kopchick, Peter Kopp, Márta Korbonits, Melvyn Korobkin, Stephen M. Krane, Knut Krohn, Henry M. Kronenberg, John M. Kyriakis, Sue Lynn Lau, John H. Lazarus, Diana L. Learoyd, Harold E. Lebovitz, Paul Lee, Åke Lernmark, Laura J. Lewis-Tuffin, Zhi-Liang Lu, Paolo Emidio Macchia, Noel K. Maclaren, Carine Maenhaut, Christa Maes, Katharina M. Main, Carl D. Malchoff, Diana Mark Malchoff, Rayaz A. Malik, Susan J. Mandel, Christos Mantzoros, Eleftheria Maratos-Flier, Stefania Marchisotta, Michele Marinò, John C. Marshall, Thomas F.J. Martin, T. John Martin, Gabriel Á. Martos-Moreno, Christopher J. Mathias, Michael Mauer, Elizabeth A. McGee, Neil J. McKenna, Robert I. McLachlan, Geraldo Medeiros-Neto, Juris J. Meier, Shlomo Melmed, Boyd E. Metzger, Robert Millar, Walter L. Miller, Madhusmita Misra, Mark E. Molitch, David D. Moore, Damian G. Morris, Allan U. Munck, Jon Nakamoto, Anikó Náray-Fejes-Tóth, Ralf Nass, David M. Nathan, Maria I. New, Carolyn Nguyen, Lynnette K. Nieman, John H. Nilson, Jeffrey A. Norton, Robert H. Oakley, Kjell Öberg, Jerrold M. Olefsky, Stephen O’Rahilly, Umut Ozcan, Karel Pacak, Furio Pacini, Shetal H. Padia, Ralf Paschke, Adam Pawson, Alison C. Peck, Francesca Pecori Giraldi, Luca Persani, Richard L. Phelps, Louis H. Philipson, Kevin Phillips, Aldo Pinchera, Frank B. Pomposelli, John T. Potts, Charmian A. Quigley, Marcus Quinkler, Christine Campion Quirk, Miriam T. Rademaker, Ewa Rajpert-De Meyts, Eric Ravussin, David W. Ray, Nancy King Reame, Samuel Refetoff, Ravi Retnakaran, Rodolfo A. Rey, Christopher J. Rhodes, E. Chester Ridgway, Gail P. Risbridger, Robert A. Rizza, Bruce Robinson, Pierre P. Roger, Michael G. Rosenfeld, Robert L. Rosenfield, James H. Rosing, Peter Rossing, Robert T. Rubin, Neil Ruderman, Irma H. Russo, Jose Russo, Wael Antoine Salameh, Isidoro B. Salusky, Mary H. Samuels, Richard J. Santen, Nanette Santoro, Virginia D. Sarapura, Stuart C. Sealfon, Patrick M. Sexton, Gerald I. Shulman, Paolo S. Silva, Shonni J. Silverberg, Frederick R. Singer, Niels E. Skakkebaek, Dorota Skowronska-Krawczyk, Carolyn L. Smith, Philip W. Smith, Roger Smith, Steven R. Smith, Peter J. Snyder, Richard Stanhope, René St-Arnaud, Donald F. Steiner, Adam Stevens, Andrew F. Stewart, Paul M. Stewart, Donald L. St. Germain, Jim Stockigt, Jerome F. Strauss, Lillian Marie Swiersz, Lyndal J. Tacon, Shahrad Taheri, Rajesh V. Thakker, Chris Thompson, Michael O. Thorner, Henri J.L.M. Timmers, Jorma Toppari, Cristina Traggiai, Michael L. Traub, Yolanda Tseng, Fred W. Turek, Eve Van Cauter, Greet Van den Berghe, André C. Van Steirteghem, Gilbert Vassart, Eric Vilain, Theo J. Visser, Michael P. Wajnrajch, Gary Wand, Paul Webb, Anthony P. Weetman, Nancy L. Weigel, Gordon C. Weir, Roy E. Weiss, Katherine Wesseling-Perry, Anne White, Kenneth E. White, Morris F. White, Michael P. Whyte, Wilmar M. Wiersinga, Joseph I. Wolfsdorf, and Bernard Zinman

Published
2010

18. Neuromedin U (NMU): Brain Peptide

Author

Caroline J. Small, Preeti H. Jethwa, and Stephen R. Bloom

Subjects
medicine.medical_specialty, Central nervous system, Neuropeptide, Nucleus accumbens, Biology, medicine.anatomical_structure, Endocrinology, Arcuate nucleus, Hypothalamus, Internal medicine, medicine, Brainstem, Nucleus, Neuromedin U
Abstract

Neuromedin U (NMU) is one of the most abundant neuropeptides and has been found in significant concentrations in both the gastrointestinal (GI) tract and the central nervous system (CNS). Within the CNS NMU cell bodies are found in the rostrocaudal part of the arcuate nucleus (Arc) of the hypothalamus with more widespread distribution of NMU fibers in the nucleus accumbens, medial thalamus, and brainstem, and in the paraventricular nucleus (PVN), ventromedial nucleus, and dorsomedial nucleus, areas where the NMU2 receptor is expressed. Recently NMU has been shown to be a potent anorexigenic peptide and that alterations of NMU signaling can predispose to obesity.

Published
2006

19. Preface

Author

Lars Grundemar and Stephen R. Bloom

Published
1997

20. The Physiology of the Endocrine System

Author

John P.H. Wilding and Stephen R. Bloom

Subjects
medicine.medical_specialty, Growth-hormone-releasing hormone receptor, Physiology, Peptide hormone, Biology, Endocrinology, Somatostatin, Hormone receptor, Thyrotropin-releasing hormone receptor, Internal medicine, Second messenger system, medicine, Receptor, Hormone
Abstract

Publisher Summary This chapter discusses the physiology of the endocrine system. Once a hormone has been synthesized and secreted, it has to produce effects on the target cell. This is achieved by the binding of hormone to a receptor producing subsequent effects within the cell. In some cases, the hormone is internalized and may have direct actions within the cell or the effects are mediated by intracellular second messengers. Receptors can be measured using receptor binding assays or autoradiography with a radioactive ligand. This enables a study of factors influencing receptor regulation. The structure of receptors can be established, receptors can be cloned, and studies are being undertaken of the ways in which hormones produce their effects through second messengers and of changes in genetic expression. The production and release of growth hormone (GH) is primarily under the control of growth hormone-releasing hormone and somatostatin. Somatostatin was initially isolated during the search for a hypothalamic growth hormone-releasing factor, the identification of which took a further 10 years and was initially found in patients with pancreatic tumors causing acromegaly. These hormones are released from the hypothalamus in a pulsatile manner but out of phase with each other, and they act to control GH release from the somatotroph by acting on specific receptors that activate G proteins to stimulate or inhibit adenylate cyclase.

Published
1993

21. Binding Sites of Pituitary Adenylate Cyclase-Activating Polypeptide in Human Brain

Author

Stephen R. Bloom and David M. Smith

Subjects
endocrine system, medicine.medical_specialty, Vasoactive intestinal peptide, Adenylate kinase, Human brain, Biology, Glucagon, Cyclase, Secretin, Endocrinology, medicine.anatomical_structure, Hypothalamus, Internal medicine, medicine, Receptor, hormones, hormone substitutes, and hormone antagonists
Abstract

Publisher Summary Pituitary adenylate cyclase activating polypeptide (PACAP) derives its name from its ability to increase cyclic AMP production and hormone release in superfused rat pituitary cells. PACAP shows sequence homology with a number of members of the secretin/glucagon family of peptides, in particular the first 28 amino acids of PACAP and vasoactive intestinal polypeptide (VIP) show a 68% homology. Specific receptors for PACAP have been demonstrated in a number of tissues and species, including rat central nervous system, rat astrocytes, human neuroblastoma cells, rat pancreatic acinar AR4-2J cells, bovine hypothalamus, and human brain. These receptors show a much greater affinity for PACAP (in the nanomolar range) than VIP (micromolar range). PACAP is highly abundant in the brain (especially the hypothalamus) and the testes. PACAP-binding sites are most often detected using 125I-labeled PACAP 27, as complete 125I-PACAP 38 gives very high nonspecific binding. The PACAP-binding sites in human brain are specific for PACAP and have a low affinity for VIP.

Published
1993

22. Contributors

Author

M.C. Aldridge, Timothy R. Arnett, M.L. Barnard, Claire Barton, Irving S. Benjamin, A.E. Bishop, Stephen R. Bloom, Randell Brown, J.M. Burrin, A.D. Cheesman, J.R. Cockcroft, Christopher Davies, P. Dawson, Michael de Swiet, John B. Eastwood, D.L. Ewins, Peter Fells, A.E. Fournier, R.B. Galland, S.G. Gilbey, A.B. Grossman, P.J. Hammond, A.T. Hattersley, Christopher Heneghan, H. Holden, I.A. Hughes, Steven Hughes, Graham F. Joplin, Anne Kennedy, E. Kiely, Paul D. Lewis, J.P. Lavender, John Lynn, A. McGregor, A. MacRae, M.N. Maisey, P.H. Morinière, D.A. Nicholson, Ruth Owen, Michaelis Pazianas, Maria Victoria Perez, P.N. Plowman, J.M. Polak, Graeme J. Poston, Martin Press, J.M. Ritter, Mary E. Roddie, Zuhair Saidan, John C. Stevenson, Simon Stewart, John G.N. Studley, Jonathan W. Swan, R.V. Thakker, David Uttley, Simon Wallis, Jonathan Waxman, John P.H. Wilding, R.C.N. Williamson, and D. Wynick

Published
1993

23. Contributors to Volume 11

Author

Alain Beaudet, Ann M. Benz, Eric L. Bittman, Stephen R. Bloom, S. Marc Breedlove, A. Cadieux, Annick Cauvin, Joëlle Chabry, Frédéric Checler, Yi-Zhang Chen, Jean Christophe, Daniela Cirillo, C.S. Cockram, P. D'orléans-Juste, Errol B. De Souza, M.B. Emerit, Louise M. Freeman, Hong Fu, Paola Gallo, Steen Gammeltoft, J.A. Gingrich, Bruno Giometto, H. Gozlan, Zuo Guo, M. Hamon, Janice M. Hickok, Robert T. Jensen, Richard Kris, Ellen E. Ladenheim, Manfred P. Lutz, Paul G. Lysko, Jean Mazella, Laurence J. Miller, M.-C. Miquel, Terry W. Moody, Timothy H. Moran, Luigi Naldini, Ponnal Nambi, M.G. Nicholls, D. Regoli, Patrick Robberecht, Steven A. Rosenzweig, Enrique Rozengurt, James Sinnett-Smith, David M. Smith, Barbara C. Swarzenski, Toshihiro Takao, Jeffrey B. Tatro, Bruno Tavolato, Ian L. Taylor, Richard D. Todd, André Vandermeers, Marie-Claire Vandermeers-Piret, Steven R. Vigna, Jean-Pierre Vincent, Andrew A. Welcher, Patricia M. Whitaker-Azmitia, David C. Whitcomb, Zsuzsanna Wiesenfeld-Hallin, Xiao-Jun Xu, V.T.F. Yeung, and Ian Zachary

Subjects
Volume (thermodynamics), Petroleum engineering, Environmental science
Published
1993

26. Cytochemical Techniques in Work with Gastrointestinal Hormones

Author

Julia M. Polak, Anne E. Bishop, and Stephen R. Bloom

Subjects
chemistry.chemical_classification, Pathology, medicine.medical_specialty, Immunocytochemistry, Cell, Peptide, Enteroendocrine cell, Biology, Cell biology, medicine.anatomical_structure, Gastrointestinal hormone, chemistry, medicine, Cytochemistry, Function (biology), Hormone
Abstract

Publisher Summary Within the gut, various gastrointestinal hormones are present in the cells of mucosal epithelium that tend to have defined, limited distributions in the various regions. This is in direct contrast to the peptide-containing nerves, which can be found at each level of the gut and which show few differential distributions. A range of different cytochemical methods have been applied in the identification and characterization of these cells and nerves, and in recent years, immunocytochemistry has emerged as a particularly useful technique in this field. With the advent of new technology, immunocytochemistry has become a reliable analytical tool. The biochemical study of peptide structures and their variant or precursor forms and the synthesis of appropriate fragments of peptide molecules, at present enables immunocytochemistry to identify cells that contain little active peptide. Information can be derived beyond just the localization of active peptides to their cells of origin. At present, it is possible to obtain data on cell or tissue function and on synthetic processing of peptides. These scientific developments and the improved availability of immunocytochemical methods and reagents have opened a new era in the cytochemical study of gut hormones.

Published
1988

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