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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
This book provides a comprehensive review of the history of concepts of the endocrine, nervous and immune systems throughout the last century. Historically, these systems were long considered as compartments that performed separate and different functions. However, a breakthrough occurred when advances in genetics and cellular and molecular biology techniques revealed that these systems shared molecular entities (such as cytokines, hormones and neurotransmitters) with their cognate receptors. These molecular links between the three systems broaden our understanding of the regulation of physiological processes. This approach has generated a multiplicity of new concepts, including crosstalk between organs, axis, feedback, molecular sensors, protein multi-functionality, positive and negative signaling ratios and pathways (such as cell signaling, metabolism and stem cell differentiation, to name a few). The improvement of experimental approaches has often resulted in major discoveries. This, combined with clear reasoning, intuition and coherence gave rise to new and unexpected concepts, and sometimes evolving ones. These new concepts lead the reader to the incredible transformation of biology in recent years.
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Veröffentlichungsjahr: 2023
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Table of Contents
Cover
Table of Contents
Title Page
Copyright Page
Preface
1 Historical Overview of Endocrinology, Neurology and Immunology
1.1. The history of endocrinology
1.2. The history of neurology
1.3. The history of immunology
2 Regulatory Systems Integrating External and Internal Changes
2.1. Regulatory systems: endocrine, nervous and immune
2.2. Origin and diversity of signals and communication modes
2.3. Integration of extracellular signals: plasma membrane receptors
2.4. Nuclear receptors
3 Intracellular Events in Response to Signals
3.1. Signaling pathways
3.2. Sensing of extracellular and intracellular cues
3.3. Functional diversity of proteins
4 Integrative Aspects: From Cellular to Whole-Body Level
4.1. Homeostasis equilibrium: dynamic steady state
4.2. Homeostasis disruption
4.3. Crosstalk between organs, tissues and regulatory systems
5 Epigenetics and Circadian Rhythms: Role of Environmental Factors
5.1. Epigenetics: general overview
5.2. Circadian rhythms
5.3. Conclusion
Concluding Remarks
References
Index
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End User License Agreement
List of Illustrations
Chapter 2
Figure 2.1
Schematic illustration of systemic, tissue and cellular homeostas
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Figure 2.2
Schematic illustration of the different components involved in th
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Figure 2.3
Experimental approach to demonstrate the potential role of an end
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Figure 2.4
The Cori cycle. It shuttles lactate to the liver to fuel the gluc
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Figure 2.5
Endocrine organs: (A) kidney, (B) bone and (C) gastrointestinal t
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Figure 2.6
Concept of preprohormone, prohormone and hormone
Figure 2.7
Schematic illustration of the different communication modes, incl
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Figure 2.8
Subcellular localization of glutamate receptors (mGlu) at synapti
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Figure 2.9
Intracellular synthesis of sex steroids from DHEA of adrenal orig
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Figure 2.10
Receptor families: GPCR, receptors intrinsic kinase activity, li
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Figure 2.11
Integrin receptors and bidirectional signaling (A). Extracellula
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Figure 2.12
Mechanisms of transactivation of RTKs by GPCRs. Heterocomplex of
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Figure 2.13
Activation of receptors by (A) ligands, in association with co-r
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Figure 2.14
Modulation of the binding site of GPCR by allosteric proteins (R
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Figure 2.15
Schematic illustration of the mechanisms enabling the diversity
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Figure 2.16
Hormonal regulation of hyper- and hypocalcemia requires two extr
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Figure 2.17
Immune response relayed by Th1 and Th2 through the secretion of
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Figure 2.18
The balance between co-stimulatory and co-inhibitory molecules d
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Figure 2.19
Characteristics of nuclear receptors and their ligands
Figure 2.20
Glucocorticoid receptor, ligand (cortisol) and coactivators
Chapter 3
Figure 3.1
Signal attenuation of neurotransmitter signal through degradation
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Figure 3.2
Signal termination of activated GPCRs: uncoupling, internalizatio
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Figure 3.3
Attenuation of the GPCR signaling pathway
Figure 3.4
Attenuation of RTK signaling pathways. Ras/MAPK signaling (A) and
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Figure 3.5
Attenuation of signaling pathways. The JAK/STAT cytokine signalin
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Figure 3.6
Schematic illustration of cell signaling dynamics in time and spa
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Figure 3.7
Example of coordinated allosteric regulation in metabolism. To pr
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Figure 3.8
Concentration–response curves for a hypothetical hormone. A: Norm
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Figure 3.9
Under normal conditions, 11β-hydroxysteroid dehydrogenase type 2
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Figure 3.10
Translocation and sequestration of the transcription factor Foxo
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Figure 3.11
Sequestration of the β-catenin by the E-cadherin (A), and bioava
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Figure 3.12
Schematic illustration of different concepts discussed in sectio
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Figure 3.13
Crosstalk between PI3K/mTOR and Ras/ERK signaling pathways (A),
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Figure 3.14
Crosstalk between the β1 integrin and the IL-3 β receptor and th
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Figure 3.15
Crosstalk between PI3K–mTORC1, Ras–ERK and AMPK signaling pathwa
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Figure 3.16
Schematic illustration of four types of sensors. AMPK (energy),
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Figure 3.17
Decoy molecules, OPG and DcR3, regulating osteoclast differentia
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Chapter 4
Figure 4.1
Hypothalamo–pituitary–adrenal (HPA) axis
Figure 4.2
Hypothalamo–pituitary–somatotropic (HPS) axis
Figure 4.3
Hypothalamo–pituitary–gonadal (HPG) axis
Figure 4.4
Hypothalamo–prolactin axis
Figure 4.5
Schematic illustration of the key mechanisms regulating the neuro
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Figure 4.6
Crosstalk between HPG axis and the two other major axes, HPA and
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Figure 4.7
Crosstalks between organs and brain, and crosstalks between bone,
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Figure 4.8
Interorgan crosstalks between the bone, the liver, the kidney and
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Figure 4.9
Role of sympathetic nervous system and parasympathetic nervous sy
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Figure 4.10
Hormonal and neuronal signals regulating energy balance, in resp
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Figure 4.11
Experiments showing a bidirectional communication between the ne
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Figure 4.12
Regulation of the immune system in response to inflammation: act
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Figure 4.13
Cancer immunoediting. It describes how the immune system can fac
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Figure 4.14
Randle cycle also named the “glucose–fatty acid” cycle. It expla
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Figure 4.15
Tumor cells or proliferative cells shift from oxidative phosphor
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Figure 4.16
Role of Myc and HIF-1 in the control of glycolysis and mitochond
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Figure 4.17
Role of p53: it restrains the glycolytic flux and maintains oxid
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Figure 4.18
Oncometabolites arising from mutations of key enzymes of the Kre
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Chapter 5
Figure 5.1
Schematic illustration of the differences between genetics and ep
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Figure 5.2
Localization of DNA methylation: CpG islands are mainly located i
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Figure 5.3
Summary of epigenetic regulation: DNA methylation, histone modifi
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Figure 5.4
Maternal and paternal genomic contributions are not functionally
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Figure 5.5
Summary of genomic imprinting (A) and X inactivation (B)
Figure 5.6
Setting and maintenance of DNA methylation. Detailed description
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Figure 5.7
Germline establishment of imprints: during oogenesis or spermatog
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Figure 5.8
The
A
vy
allele displays a labile epigenetic state in relation to
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Figure 5.9
Epigenetic regulation of the
A
vy
allele. The “pseudoagouti” pheno
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Figure 5.10
Influence of maternal care on offspring neurobiology. Low matern
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Figure 5.11
Epigenetic action of endocrine disruptors. Bisphenol A prevents
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Figure 5.12
Therapies for aberrant DNA methylation and histone acetylation:
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Figure 5.13 In vitro
reprogramming systems: somatic nuclear transfer, genera
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Figure 5.14
Kinetics of an oscillator. The period is about 24 h, and the amp
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Figure 5.15
Canonical transcriptional feedback loops in the core clock. See
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Figure 5.16
Pathways of peripheral clock entrainment. The central clock (SCN
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Figure 5.17
Circadian control of glucose metabolism. The suprachiasmatic nuc
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Figure 5.18
The different hormone secretions listed above potentially feedba
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Guide
Cover Page
Title Page
Copyright Page
Foreword
Table of Contents
Begin Reading
Concluding Remarks
References
Index
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Wiley End User License Agreement
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Concepts in Biology
A Historical Perspective
Marc GilbertSergej Pirkmajer
First published 2023 in Great Britain and the United States by ISTE Ltd and John Wiley & Sons, Inc.
Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permitted under the Copyright, Designs and Patents Act 1988, this publication may only be reproduced, stored or transmitted, in any form or by any means, with the prior permission in writing of the publishers, or in the case of reprographic reproduction in accordance with the terms and licenses issued by the CLA. Enquiries concerning reproduction outside these terms should be sent to the publishers at the undermentioned address:
ISTE Ltd
John Wiley & Sons, Inc.
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London SW19 4EU
Hoboken, NJ 07030
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© ISTE Ltd 2023The rights of Marc Gilbert and Sergej Pirkmajer to be identified as the authors of this work have been asserted by them in accordance with the Copyright, Designs and Patents Act 1988.
Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s), contributor(s) or editor(s) and do not necessarily reflect the views of ISTE Group.
Library of Congress Control Number: 2023942286
British Library Cataloguing-in-Publication DataA CIP record for this book is available from the British LibraryISBN 978-1-78630-940-2
Preface
This book has the ambitious aim to provide a comprehensive view of the history of concepts in biological sciences that organized our scientific knowledge and shaped our understanding of the endocrine, nervous and immune systems throughout the last century. Biological concepts take a central place in science and their meanings should be clearly defined because they influence the direction of basic research. They are vectors of scientific knowledge communication among non-experts, and consequently enable them to understand the findings of scientific research. It should be kept in mind that some concepts have undergone continuous changes. One of the best examples is the gene concept, which was initially defined in Mendelian genetics as a factor that modifies the development of a trait (classical gene concept). Thereafter, in the 1950s, a new concept emerged that claimed the gene was made of DNA, which contains information about a specific molecular product (molecular gene concept) (Kampourakis and Stern 2018).
It is noteworthy that the three fields, mentioned above, contributed to the emergence of major concepts in the first decade of the 20th century. Leading biologists considered that there were no links between these disciplines. Consequently, they functioned independently, which therefore erected disciplinary barriers, for practical formulations. Over the last 60–70 years, advances in genetics and cellular and molecular biology techniques have led to major discoveries that have highlighted how these three systems shared several molecular entities such as cytokines, hormones and neurotransmitters with their cognate receptors, broadening the communication between the three systems. This network of signals coordinates mechanisms that aim to regulate diverse biological responses including cell growth, differentiation, inflammation, metabolism, etc. It gave rise to a multiplicity of concepts so that biologists realized that these systems are indeed related and should come together in a common discipline. It became evident that these networks add another level of complexity, which is amplified at the cellular level and often reveals the universality or singularity of most cellular responses from a molecular perspective.
In the first part of this book, we present a chronological panorama of the history of these three disciplines: endocrinology, neurology and immunology. It should be emphasized that it is quite common in the history of science that an important question arises long before the development of experimental strategies or techniques needed to resolve the issue. Thus, an important but often overlooked approach to discovery is the revisiting of old questions with new techniques. This principle is often illustrated in these pages. We will emphasize how new tools, techniques and instrumentation associated with conceptual changes have helped to elucidate the complexity of the different fields. All new discoveries have consolidated our understanding in the homeostatic control mechanisms that should now be viewed as a complex interacting system. It is noteworthy that most fundamental discoveries have been initiated by researchers over many years, building intuition, clear reasoning, observation, tenacity, coherence and creativity coupled with technical excellence. To keep this spirit of creativity alive, most eminent researchers have also been the scientific progenitors of numerous careers in biology, and one day these exceptional curiosity-driven traits may be recognized by the scientific community.
Writing this book has been an immense learning experience, namely on how the emergence of new concepts has led to major breakthroughs in physiology and cell biology. Emphasis is often put on technology, which is an important tool and can be a limiting factor or a driver in biological discoveries. This book will serve as a general reference for those interested in embracing the field, as well as for experts. Readers will likely be convinced that it is difficult to predict the future trends in biology, but it is obvious that unsolved problems can potentially generate new concepts. K. Popper, a philosopher of science, stated in the mid-1930s that knowledge should never be static and suggested that “humans had no ability to accept a theory as true for all time” (Popper 2014). One of the best examples is the discovery of iPS cells, which was a paradigm shift. Old ideas may also re-emerge in a new context of research. This is exemplified by the theory of evolution that continues to evolve. In 1802, J.B. Lamarck proposed the concept that the environment can directly alter phenotype in a heritable manner. His simplistic idea that acquired characteristics are transmitted from the parents to offspring was wrong, and Darwin’s theory advanced. However, we now believe that epigenetics also impacts phenotypic variation and therefore facilitates natural selection. Both theories can therefore be reconciled, as seen in a chapter of this book.
In every domain, theories and proposed mechanisms to support them continue to shift over time. A. Lwoff, winner of the Nobel Prize in Physiology or Medicine in 1965, liked to remind us that science is a “permanent revolution” and that changing ideas are a sign of good scientific health (Lwoff 1962).
June 2023
1Historical Overview of Endocrinology, Neurology and Immunology
1.1. The history of endocrinology
The study of endocrine function was born in the second half of the 19th century and the first decades of the 20th century. However, it should be emphasized that the humoral concept derived from the speculation of pre-Socratic philosophers. Later, the concept of internal secretions was put forward in the anatomical studies of the Renaissance, when organs without ducts were described. After that, the discovery of circulation by W. Harvey (1578–1657) fueled the development of the concept of internal secretions in 1775 by T. de Bordeu (1722–1776), physician of Louis XV: “Each organ in the body released emanations which were useful to the whole body” (Eknoyan 2004). In 1855, C. Bernard (1813–1878) used the term “internal secretion” when he determined that the liver secretes glucose into the hepatic veins and bile into the intestinal tract. Even though glucose is certainly not a hormone, his concept of internal secretion was the first step in defining the endocrine system. In 1902, W. Bayliss (1860–1924) and E. Starling (1866–1927) discovered secretin (Bayliss and Starling 1902) and introduced the concept of blood-borne chemical messages. In 1905, the word “hormone” (from the Greek hormao, meaning “I activate”) was coined by Starling. He defined it as “any substance normally produced in the cells of some part of the body and carried by the blood stream to distant parts, which it affects for the good of the organism as a whole”. It was originally suggested by the linguist Mr Hardy of Cambridge, UK, to distinguish glandular extracts from other internal secretions. The term “endocrinology” was proposed shortly thereafter by N. Pende (1880–1970) in 1909. According to H. Dale (1875–1968), clinical endocrinology achieved respectability only with the discovery of insulin (Banting et al. 1923). By 1922, the discipline was in the forefront of biomedical science, since it was possible – by using extracts of endocrine glands – to treat three human endocrine disorders successfully: hypothyroidism, diabetes insipidus and diabetes mellitus (Dale 1935). The importance of the anterior pituitary gland as “conductor of the endocrine orchestra” was not understood until the early 1930s, when P.E. Smith published his parapharyngeal approach for removing the gland (“hypophysectomy”) (Smith 1932). By the 1950s, the major hormones had been identified, and the history of their discovery started with the surgical ablation of endocrine glands (testes, ovaries, adrenal glands, thyroid, etc.), followed by studies of the physiological changes in the subject. Then, transplantation of the gland or gland extracts were given in replacement therapy to see whether they reversed the effect of the gland removal. Such an experiment was first carried out by A. Berthold (1803–1861) in 1849, which subsequently enabled the characterization of the pathophysiology of most hormone deficiencies. However, a straightforward interpretation of the outcomes was often misleading because it was originally thought that endocrine glands or cells released only a single hormone, but it is now known that endocrine glands or even cells may produce two or more hormones. For instance, ablation of the adrenal gland removes the corticosteroids (i.e. glucocorticoids and mineralocorticoids), as well as the catecholamines (primarily adrenaline (epinephrine), since noradrenaline is also secreted from the sympathetic nerve endings), and the outcome is a combination of deficiency of both hormone types. Although there was a growing number of newly identified hormones, investigators could not measure their blood levels. The lack of quantitative data describing hormonal changes led to the development of the radioimmunoassay technique in the laboratory of Yalow and Berson (1959), and in 1960 it enabled an accurate insulin measurement. Once this had been achieved, it was possible to prove that insulin action may be deficient despite hyperinsulinemia, meaning that diabetes is not always caused just by insufficient secretion of insulin. This technique was also used to measure numerous hormones or other substances in body fluids and to diagnose hormone-related diseases (Lepage and Albert 2006). This period was followed by the molecular biology revolution, and endocrinology became one of the most dynamic disciplines, which was mainly attributed to the applications of advances in other fields. Fundamental discoveries have been made over the last decades and shed light on the molecular processes that mediate the conversion of the hormonal signal from outside the cell to a functional change in the cell. It started in the 1960s when E.W. Sutherland discovered that epinephrine induces the formation of cAMP in liver cells and that the nucleotide converts the inactive glycogen phosphorylase to the active enzyme, which leads to the formation of glucose. It raised the question of how the hormone regulates the conversion of ATP to cAMP. He proposed a model in which the enzyme that catalyzes this breakdown was located in the plasma membrane and composed of a regulatory subunit (R) and a catalytic unit (C). This enzyme was called adenyl cyclase, and he hypothesized an interaction of the hormone with R, which in turn may influence C. It led to the description of a “possible model of adenyl cyclase as related to adrenergic receptors” (Robison et al. 1967). Later, Sutherland suggested that the effects of many other hormones could also be explained through their binding to plasma membrane receptors, causing the formation of cAMP, which then stimulates or inhibits different metabolic processes. This hypothesis was initially met with strong resistance by scientists because it seemed impossible that a single agent could lead to the diverse biological effects in response to different hormones. Subsequently, the concept was shown to be correct and Sutherland was awarded the 1971 Nobel Prize in Physiology or Medicine. The focus in the field shifted from the hormones themselves to the receptors, second messengers and signaling molecules acting within complex networks. It broadened our understanding of endocrine physiology, but it also challenged many long-held beliefs in endocrinology, for example, that endocrine cells released only a single hormone. Likewise, there is evidence that hormones can bind to different receptors and receptors can bind to a wide number of different hormones. If we consider the way that most hormones were discovered, it was tedious and time-consuming work. Thus, the discovery of the TSH-releasing factor (TRF) required 80,000 sheep hypothalamic fragments (Guillemin et al. 1965). Thanks to the reverse pharmacology strategy, this process has been markedly improved, thus leading to the discovery of many endogenous compounds, including hormones. It revealed the chemical diversity of cell-to-cell signaling molecules, and over the last few decades endocrinology has undergone major paradigm shifts with the discovery of endocrine functions by organs not hitherto considered as endocrine organs, such as adipose tissue, liver, muscles, lungs and heart. It also highlighted that these organs are important regulators of biological responses through organ “crosstalk”. These discoveries increase the complexity of the endocrine system, and recently, new methods and techniques of investigation have demonstrated that the endocrinology world is expanding as a multifaceted discipline. Thus, using a comprehensive bioinformatics approach, the concept of “molecular mimicry”, coined by R.T. Damian (1964) and which gained ground in type 1 diabetes (T1D) research (Atkinson 1997), was reinvestigated. Recently, it was discovered that the mechanism of molecular mimicry applies to viruses, as they create factors that mimic host features that may give rise to hormone ligands (Huang et al. 2019). These ligands do not have sequence similarity with the host proteins, but instead have structural or functional similarities. Thus, the viral insulin/IGF1-like peptides have been identified, which can bind the human IGF1 receptors and stimulate classic post-receptor signaling pathways. This system of viral hormones can be viewed as a paradigm shift for host–virus interactions. These observations also give new insights into the evolution of peptide hormones. However, today, there are only a few studies investigating this concept. Similarly, it took a long time to recognize the hypothalamic–pituitary regulation of peripheral endocrine organ function.
1.2. The history of neurology
The term “brain” was initially used by the ancient Egyptians in about 1700 BCE (Breasted 1905). The distinction between the “cerebrum” (enkephalon in Greek) and “cerebellum” (parenkephalis in Greek) was first made by Aristotle around 300 BCE. Next, R. Descartes proposed his view of the brain anatomy in “Traité de l’homme” (1648), which had a major influence on the conception of human physiology in the last half of the 17th century. The internal surface of the brain is its most important part, and is riddled with pores, which are simply the gaps between fine nervous threads that form a kind of mesh or network. Descartes also separated the notion of mind, which holds abstract thoughts, from that of the physical body.
The terms “neuron”, “synapse” and “neurotransmitter” all have an interesting history (López-Muñoz and Alamo 2009). The introduction of the “anatomo-clinical method” in the first half of the 19th century resulted in the extensive development of the histological disciplines, which led to the formulation of the neuron theory in the 1830s. A group of four researchers contributed to this theory: J.E. Purkinje (1787–1869), F.G.J. Henle (1809–1885), M.J. Schleiden (1804–1881) and A.V. Kölliker (1817–1905), and published their findings in 1852. It was also stated that cells “should be conceived as the essential formal units of the body”.
The concept of the synapse emerged in the late 19th century, and the assimilation of the neurotransmission phenomenon was difficult. In the 1870s, F. Kühne mentioned that nerve endings terminate in the formation of the muscular membrane (subsequently named the motor end-plate/the neuromuscular junction). R. y Cajal (1852–1934), in his anatomical drawings (1889), anticipated the concept of the synapse, but it was C.S. Sherrington (1858–1952) who provided a functional explanation of the structural postulates of Cajal (1894). He combined the anatomical and physiological concepts into a single unit, which was then called a “synapsis” (from the Greek, “junction, connection”). Likewise, he provided the first data on the existence of excitatory and inhibitory synapses. This duality of stimulating or inhibiting inputs regulating a cellular response is a major concept in biology.
The discovery of neurotransmitters was a great scientific advancement in the 20th century. In 1877, E.H. du Bois-Reymond (1818–1896) suggested that nerves could stimulate muscles by means of chemical substances, whereas the prevailing theory was that of electrical transmission. It took another three decades before the chemical hypothesis of neurotransmission was consolidated and firmly confirmed. In 1904, synaptic transmission was postulated by T.R. Elliot (1905) and J.N. Langley (1905), and their experiments on sympathetic stimulation strongly suggested that the action potential could cross the synapse through chemical substances, and they were named chemical mediators. However, the concept of chemical neurotransmission, as well as the existence of neurotransmitters, was only confirmed decades later. In 1905, Langley suggested the existence of the receptor. He called it the “receptive substance of target cells” (Langley 1905, 1906).
Throughout the following decades, the theory of neurotransmission was consolidated between 1921 and 1926 when O. Loewi carried out experiments on the vagal stimulation of the isolated heart of amphibians (Loewi 1921; Loewi and Navratil 1926). He postulated that the vagal nerve releases a substance (“Vagusstoff”), and in 1926 he successfully identified it as acetylcholine (Loewi and Navratil 1926). Then, in 1936, H. Dale confirmed the neurotransmitter role of acetylcholine in the peripheral nervous system of mammals (Dale et al. 1936). However, the idea of a direct communication via electrical synapses, especially in the central nervous system, was persistent, and it took a further decade for chemical transmission in the central nervous system to be accepted. It is marvelously recounted in E.S. Valenstein’s book “The War of the Soups and the Sparks” (Valenstein 2007).
In the mid-1950s, the electron microscopy technique allowed us to describe the individuality of the neurons and the discontinuity at the synaptic level. Another technical advancement in the early 1960s was the fluorescence histochemical method, which enabled the visualization of catecholamine neurons and their pathways in the brain. Using this technology, A. Carlsson provided evidence for the existence of dopamine as a neurotransmitter in the central nervous system (Carlsson et al. 1958), which was an essential step towards rational pharmacotherapy of disorders, such as Parkinson’s disease and schizophrenia
The history of interaction between drugs and their targets started with C. Bernard and O. Schmiedeberg (1838–1921), who put forward the idea of a specific receptor structure on which drugs would act. As mentioned above, in 1905, Langley suggested that curare and nicotine produced their effects through the stimulation of a “receptive substance” (Langley 1906). A year later he proposed the concept of the transmitter receptor (neuroreceptor), but it was not well accepted by the scientific community. The idea was developed further by P. Ehrlich, who postulated that microorganisms and cancer cells possess surface chemoreceptors for dyes, which led to the concept of chemotherapy of infectious diseases and cancer. Between 1970 and 1974, S. Langer and K. Starke suggested the presence of α-adrenergic autoreceptors at synaptic terminals of the sympathetic system, which would act as a regulator mechanism of neurotransmitter release (Langer and Lehmann 1988). This autoreceptor concept was then extended to other transmitter systems. Since the postulate of the “receptive substance” theory, proposed by Langley in the early 1900s, diverse disciplines such as electrophysiology, pharmacology and biochemistry joined together with a common goal of successfully identifying the first neurotransmitter receptor, the nicotinic acetylcholine receptor (Changeux 2020). This receptor has become “the founding father of the pentameric ligand – gated ion channel superfamily”, and the sequence of 20 amino acids comprising the N-terminal of the α-subunit of the Torpedo marmorata was obtained by J.P. Changeux’s group (Changeux 2012).
Over the last half of the 20th century, advances in the discipline of molecular biology have allowed us to identify, sequence and clone numerous types and subtypes of receptors. Likewise, it became possible to identify the chain of molecular events that is initiated by receptor activation, and which triggers the biological response. These sequential events, which are tightly regulated, are called signaling pathways.
Given the diversity of extracellular signals that may potentially regulate our sensations, emotions and creativity, it has been suggested that the transmission of information could be mediated by neurotransmitters (neuropeptides, amino acids or their derivatives and monoamines), neuromodulators (cytokines, neurotrophins, purines, adenosine) that would modify the neurotransmitter response, and neuroregulators (NO, prostaglandins) that would influence the excitability of neurons.
The history of neuroendocrinology is quite fascinating. It emerged in the mid-20th century after discovering that the brain produces neurohormones (hormone production by neurons) that control hormonal secretion, and in turn how hormones affect brain function. However, it should be kept in mind that the concept of “neurosecretion”, which was first proposed by C. Speidel in 1917, was vigorously rejected over the next two decades, as it was said that a neuron could not have a glandular function (Sarnat 1983). Then, the field of neuroendocrinology took a major step forward when H.B. Friedgood in 1936, and J.C. Hinsey in 1937, postulated that the anterior pituitary gland was controlled by substances liberated into the hypophysial portal vessels from nerve terminals in the median eminence (for review, see Fink (1976)). This hypothesis was not accepted until work from G.W. Harris in 1955 clearly demonstrated the flow of blood from the hypothalamus at the median eminence to the anterior pituitary gland (Harris 1955). This supported the concept that the hypothalamus controlled anterior pituitary gland function. Subsequently, Schally’s and Guillemin’s groups identified several peptide hormones released by the hypothalamus, which control the endocrine function of the gland (Guillemin 1975, 2005). This scientific breakthrough was then followed by general descriptions of neuroendocrine systems, hypothalamic–pituitary–end-organ axes and feedback mechanisms. One of them, which regulates the cortex of the adrenal gland, is a multisystem axis that used feed-forward and feedback loops to regulate glucocorticoid hormone levels. Likewise, the crosstalk between axes has emerged as potential regulators of key biological processes such as growth hormones and sexual hormones, which play a major role in the termination of linear growth. Similarly, gut and adipose hormones interact with the reproductive axis to regulate both energy homeostasis and reproductive function.
1.3. The history of immunology
Immunology is a relatively new discipline and its origin is attributed to E. Jenner (1749–1823), who reported in 1796 that cowpox induced protection against human smallpox, which is often a fatal disease (Jenner 1801). However, in ancient China and Persia, there were previous observations showing that inoculation of vesicle fluid from cases of smallpox into people protect them from this disease, which was referred to as variolation (variola – smallpox). Jenner called his procedure vaccination (from vacca – Latin for cow), and this term is still used to describe the inoculation of healthy individuals with attenuated disease-causing agents to protect them from an infectious disease. However, Jenner did not identify the nature of the infectious agent.
It was not until late in the 19th century that R. Koch (1843–1910) proved that infectious diseases are caused by microorganisms/pathogens, each one suspected of being responsible for a particular disease (for a historical review, see Kaufmann and Schaible (2005)). This discovery stimulated the strategy of vaccination, and in the 1880s, L. Pasteur successfully developed a vaccine for cholera and rabies, while E. von Behring (1854–1917) introduced serum (i.e. antibody) therapy of diphtheria, a breakthrough for which he received the first Nobel Prize in Physiology or Medicine in 1901. Since this time, this discipline has made major advances in deciphering the immune system. It is currently considered as a multilayered system comprising three major defense mechanisms: 1) physical and chemical barriers, 2) innate and 3) adaptive responses.
This scientific discipline was kicked-off by two seminal discoveries. E. Metchnikoff (1845–1916) discovered that many pathogens are immediately destroyed by phagocytic cells, which he called macrophages, and thereby introduced the concept of phagocytosis (Tauber 1992). They are rapidly recruited at the site of infection, thus providing the first line of defense that initiates the inflammatory response. It is noteworthy that this complex response is stereotyped in nature, since a subsequent infection will cause the same cascade of events with similar kinetics and intensity.
The second discovery was a neutralization of bacterial toxins by antibodies. These two discoveries led to the concept of antigen-unspecific innate immunity mediated by cells, and antigen-specific acquired immunity mediated by humoral factors. In parallel, immunobiology identified lymphocytes, which were segregated into antibody-producing B-cells (also known as plasma cells), as well as T-cells, which are central regulators of immunity.
To elicit an adequate immune response, a close cooperation between different immune cell types is required. One of the main issues which has been addressed and investigated was the identification of the cellular and molecular mechanisms triggering the activation of the system and regulating its intensity and duration. A key process in initiating an adaptive response is in the delivery of antigens to the lymphocytes (Moser and Leo 2010). It was suggested that macrophages could initiate this crucial step due to the fact that they are likely among the earliest immune cells to encounter antigens. It was logical to assume that they could present the antigen, or a fragment of the latter, to the lymphocyte. Numerous lines of evidence confirmed these hypotheses, which gave rise to the concept of “antigen-presenting cells (APC)” for any cells involved in this process (Burgdorf and Kurts 2008). Their role is therefore to capture and transfer information from the outside world to the cells of the adaptive immune system. Subsequently, it was noted that the antigen had to be associated with a special class of molecules to transfer the information to the lymphocytes. It gave rise to the concepts of “major histocompatibility complex (MHC)” and that of the “T-cell receptor” (Bonilla and Oettgen 2010). Regarding the mechanisms of T-cell activation and function, they have recently been clarified, and the concepts of co-stimulatory and co-inhibitory receptors have revealed that the immune system is a tightly regulated network that is able to maintain a balance of immune homeostasis (Chen and Flies 2013). However, there are circumstances in which the balance is not maintained and the immune system either overreacts against innocuous antigens (allergy), mistakenly attacks our own antigens (autoimmunity), or is inefficient (cancer, immunodeficiency).
The topic of autoimmunity began in 1901, first with Ehrlich’s doctrine of “horror autotoxicus”, then interpreted as “autoimmunity cannot happen”, after he noted that goats immunized with their own red blood cells do not develop antibodies (Ehrlich 1900). This implied that autoimmunity was “dysteleological” such that “contrivances” must exist to prevent immune reactions from harming the body. However, by 1904, the antibody nature of the autohemolysin responsible for hemoglobinuria was reported, but without generating a concept of autoimmunization as the cause of the disease. About 30 years (1915–1945) thereafter, was the era of “eclipse” for autoimmunity, followed by a series of studies that put “horror autotoxicus” into a realistic frame. The year 1965 was the beginning of the acceptance of autoimmunity, when a wide range of autoimmune diseases were reported. Since the original formulation, much has been learned and investigators focused mainly on the factors responsible for the initiation and progression of the autoimmune process. A large amount of data supports the notion that autoimmune diseases arise from a combination of genetics and environmental factors. The latter are probably the most intriguing players and the largest group consists of bacterial, viral and parasitic infections. The mechanisms by which an infectious agent results in autoimmune disease have not been fully elucidated. However, an attractive explanation has been introduced by G. Snell and gave rise to the concept of molecular mimicry (Oldstone 1987). Note that this concept was also introduced in endocrinology (see above). G. Snell suggested that there are structural antigen similarities between the infectious agent and the host cell, resulting in the generation of autoantibodies. Regardless of the mechanisms involved, genetics and environmental factors disrupt the fragile balance between self-recognition and protection from non-self that depends on a tight control of the activity of numerous immune cell populations. A detailed description of cell types and their respective roles highlighted the diversity of mechanisms required to establish and maintain immunological tolerance. These studies revealed some key mechanisms or events that have been conceptualized, and specific vocabulary was used, such as central (thymus) and peripheral (lymphoid tissue) tolerance, autoreactive T lymphocytes and immune tolerance checkpoint inhibitors.
Immune deficiency is exemplified in cancer patients. In the early 1990s, it was known that the immune system can identify and eliminate tumor cells, and this process was termed as cancer immune surveillance. Unfortunately, some tumor cells can evade immune surveillance, and this immune deficiency is related to a decreased function of components of the immune system (immunosuppression concept). In 2001, an important study provided evidence that the immune system both protects against tumor development and promotes their outgrowth. This dual role led to the formulation of the immunoediting concept, which is developed in detail in section 4.3.5.
For decades it was assumed that the CNS was ignored by the immune system due to the presence of the blood–brain barrier that was supposed to protect the brain, but it turned out that the view was overly simplistic. It is becoming increasingly evident that there is an intricate relationship between the immune and nervous systems (Ransohoff and Brown 2012). A range of mechanisms exist to limit the immune response in the CNS. This type of interaction is explicated through the production of molecules (cytokines, hormones and peptides) from the CNS and through the activation of afferent and efferent neurological pathways, with both immunosuppressive and immunostimulating effects. On the contrary, some peripheral signals also communicate with the CNS, and some of them, like leptin, are key players linking the immune system, metabolism and brain function. Finally, cytokines, the prototypical mediators of intercellular communication in the immune system, affect brain functions, modulate activity of the hypothalamo–pituitary axis and have hormone-like metabolic effects in various peripheral tissues, which again highlights the intricate links between the endocrine, immune and nervous systems. These interactions among these systems determine the maintenance of health or the susceptibility to diseases.
It should be emphasized that many scientific concepts arose from hypotheses, which often turned out to be incomplete, combined with false paths, erroneous suppositions, inconclusive experiments and mistakes. Nevertheless, they provided a rationale for predictions that generated innovative experimental approaches, which then gave rise to new conceptual development. Last, but not least, it should be kept in mind that all the issues that scientists address bring an additional layer of complexity. The picture that emerges is that there is a wide variety of regulatory networks involving multiple mechanisms with different temporal and spatial properties.
This book has been written with the aim of discussing some of the emerging and evolving concepts that have shaped these three disciplines over the last century.
2Regulatory Systems Integrating External and Internal Changes
2.1. Regulatory systems: endocrine, nervous and immune
The purpose of this section is to review how the experimental physiology introduced by C. Bernard has enabled us to progressively evaluate the respective roles of endocrinology, neurology and immunology over time, when investigators brought up the first fundamental issues to be addressed. At the beginning, each discipline used very simple experimental approaches, but they brought about tremendous changes in our knowledge of biology, some of which are reported here. Independently, they made discoveries that highlighted the importance of their respective systems in the regulation of homeostasis in physiology and physiopathology. As the general understanding of major regulatory mechanisms progresses, it has emerged that immune and nervous systems share several molecular entities. The challenge was then to integrate knowledge of the roles of key players into a coherent sequence of mechanisms, such as a network of communication pathways, which are recruited during physiological and pathophysiological processes. Similarities were extended to the endocrine system, and gave rise to a multiplicity of concepts which are presented in different chapters.
To avoid extensive citation, several review articles containing many of the original references are included.
First, a key observation should be mentioned as it was likely a starting point for scientific thinking. It was the notion of equilibrium among bodily humors that was already mentioned by the Hippocratic school and transmitted to several schools of medicine, and it was resumed in purely physical terms by J.B. Lamarck. Then, the experimental physiology from the 1850s, conducted by C. Bernard, introduced the concept of “milieu intérieur”, and in the 1920s, W. Cannon introduced the concept of “homeostasis” of the “milieu intérieur” (Cannon 1929; Cooper 2008). After the first hormone discoveries, researchers have been interested in their respective role in regulating the stability of internal environment. They sought to understand how multicellular organisms sense and respond to external environmental changes/variations to maintain the whole-body homeostasis. Investigators first noted that there was a basal stability of the homeostasis, and it was constantly oscillating around a set-point and always ready to reset itself when the organism faced changes in the environment.
Figure 2.1Schematic illustration of systemic, tissue and cellular homeostasis through the combination of regulated variables
As mentioned above, any living organism faces a great diversity of physical or chemical changes that can threaten this stability, and these systems have the role of safeguarding, i.e. to integrate these signals and elicit appropriate responses, qualitatively and quantitatively, so that they reestablish and maintain the homeostasis. It should be emphasized that homeostasis operates at three levels: entire organism, tissues and cells. In each of these compartments, regulated variables like blood levels of glucose, ions and osmolarity in the whole organism are maintained within an acceptable dynamic range by the endocrine and autonomic nervous systems. It therefore enables cells of different organs to function under optimal conditions despite widely fluctuating factors outside of the body. For instance, all humans can experience a microbial invasion, or a physical injury, and this initiates a protective response, called inflammation. It must be fine-tuned and tightly regulated because a deficiency or an excess of inflammatory responses result in immunodeficiency or morbidity such as systemic inflammatory response syndrome, respectively. Homeostasis is restored when inflammation is resolved, and it is achieved through a rapid, localized and coordinated communication between immune, nervous and endocrine systems.
To summarize, these three systems have developed an intricate network of cellular specializations and interactions, which allow them to sense specific changes and produce an appropriate response through regulated variables. When a perturbation occurs, the functional integration of organs, tissues, cells and molecules enables a dynamic stability of homeostasis (Figure 2.1).
Figure 2.2Schematic illustration of the different components involved in the regulation of cellular responses to maintain homeostasis. The three regulatory systems (endocrine, nervous and immune systems) release chemical signals to communicate with their targets (organs/tissues). At the cellular level, they bind to plasma membrane receptors or nuclear receptors which then activate signaling pathways and elicit an appropriate biological response
Over the few last decades, we have learned a great deal about the molecular mechanisms underlying diverse cellular processes in these three systems. It has also been revealed to scientists that the level of complexity in the regulation of these systems and interactions between them are growing. Although they steadily bring a brick to the puzzle of our basic knowledge in biology, it seems to be more and more difficult to construct an overall picture of the network of an endless, diverse list of signals that elicit cell type-specific responses. From a philosophical standpoint, there is a master word: “integration”, which is often used when we elucidate the mechanism(s) that govern different biological responses at the body, cellular and molecular levels. For instance, integrative physiology describes the major functions and then detailed studies address one of the basic, but complex questions: “how do cells integrate the diversity of signals?” In a broad sense, a cell should translate them in terms of a cascade of molecular events for eliciting an appropriate biological response. These aspects are summarized in Figure 2.2, and we put a special emphasis on the regulatory systems, communication modes and molecular processes that mediate the conversion of the extracellular signal to a functional change in the cell, through signaling pathways.
2.1.1. Endocrine system
2.1.1.1. Role of glands
To demonstrate the potential role of a gland in human physiology, investigators used two complementary experimental approaches that were carried out on rodents (rats and mice) as well as dogs and sheep. At first, an ablation of the gland was performed to create a deficiency of a potential signal(s) emanating from the gland. This was followed by studies of the impact of gland deprivation on a limited number of biological processes (growth, organ development, blood substrate levels, etc.) because of a lack of biochemical assays and proper measurement equipment. The second step was to administer a crude extract of the gland to correct the deficiency-induced responses. The readout of these first experiments was mostly descriptive, but shortly thereafter, sometimes simultaneously, the chemical identification of the active principle, of the crude extract of the gland was undertaken. In parallel, investigators set up chemical assays, radio-immunoassays which allowed a quantitative measurement of proteins, steroids, etc. (Figure 2.3).
Figure 2.3Experimental approach to demonstrate the potential role of an endocrine gland in the regulation of biological processes
This technique of gland ablation was performed on the thyroid, adrenal, gonads, pancreas and pituitary glands. A second experimental approach involves pharmacological inhibition of hormone synthesis and/or secretion, which mimics the gland ablation used to define the role of the thyroid gland. It consists of an administration of propylthiouracil (PTU), which specifically blocks the hormone synthesis (thyroxine).
To interpret the role of these glands, through the administration of a crude extract of the gland, caution should be taken. For instance, when a pituitary gland extract was administrated (Houssay 1943), it had a diabetogenic effect, but it was not possible to say whether the adenohypophysis contained one or more anti-insulin, diabetogenic principles. We now know that the growth hormone is the critical hormone involved, and the carbohydrate metabolism does not depend merely on the action of insulin. These experiments laid out the general outline of the endocrine system that regulates the major biological responses. Key metabolic hormones, secreted by different glands, have been successfully identified, but over the last two decades, it was discovered that metabolic organs also produce hormones and their identification increased exponentially in recent years. They have been named adipokines (Fasshauer and Blüher 2015), myokines (Giudice and Taylor 2017) and hepatokines (Meex and Watt 2017) to describe that they are produced by white adipose tissue and brown adipose tissue, skeletal muscle and liver, respectively. They are secreted in response to changes in the metabolic status of the body, such as exercise, cold exposure, feeding and fasting periods, which therefore participate in metabolic adaptation/flexibility. Dysregulation of their secretion is currently known to contribute to a wide spectrum of endocrine diseases.
In this chapter, we summarize well-established mechanisms of communication between the endocrine, nervous and immune systems, and focus on how they gave rise to concepts such as feedback, crosstalk between organs, ratio, spatio-temporal order, critical period, etc. They are part of our scientific vocabulary, and have brought a new angle to the reading of experimental data.
2.1.1.2. Communication between organs: crosstalk concept
Communication between organs was first identified when C. Cori and G. Cori demonstrated that lactate produced by anaerobic glycolysis in muscles can be recycled by the liver and converted to glucose through the gluconeogenesis pathway. Then, the glucose is returned, through the blood, to muscles where it is metabolized into lactate (Cori and Cori 1946). It was named the “Cori cycle”, and was one of the first examples of a communication system between organs, and its main role was to facilitate metabolic adaptation to energy availability and demand (Figure 2.4). Note that under anaerobic conditions, the Cori cycle is the most important process permitting a re-oxidation of NADH to NAD+ and it is controlled by the lactate dehydrogenase, which catalyzes the conversion of pyruvate to lactate, which is then released in the blood to fuel the hepatic gluconeogenesis.
It should be underscored that the Cori cycle also involves the renal cortex, particularly the proximal tubules, another site where gluconeogenesis occurs.
Figure 2.4The Cori cycle. It shuttles lactate to the liver to fuel the gluconeogenesis pathway and the glucose is transported back to the muscle, thus closing the cycle
As noted above, peripheral organs produce a plethora of bioactive molecules that carry a signal in an endocrine, paracrine or autocrine manner (see section 2.2.3.3). Likewise, immune cells can also produce chemical signals, namely cytokines. Recently, their respective role has been explored and there is evidence that all of them play a role in the inter-organ communication to maintain homeostasis in physiological situations. For instance, interest has been focused on the communication between the white adipose tissue and the brain to understand the mechanisms controlling the energy balance, both in physiological and pathological (obesity) conditions. In section 4.3.3, we summarize well-established mechanisms of inter-organ communication and focus on how recent research has highlighted the importance of the crosstalk.
2.1.1.3. Ratio concept
The concept was introduced by R. Unger when considering the control of hepatic glucose production (Unger 1971). Knowing that the net flux of glucose is regulated by insulin (I) and glucagon (G) that work in tandem with each other, but in opposite directions, it was thought that the relative concentrations of these hormones may determine the hepatic glucose balance. In a series of experiments, it was clearly shown that the glucose flux was dictated by the I/G ratio and not the absolute concentration of either hormone. It also applies to the lipolytic and lipogenic fluxes across the adipose tissue. These findings also established that an increased I/G ratio favors an “anabolic” response, and the inverse promotes a “catabolic” response.
Similarly, a two-site, bi-hormonal concept was proposed for the control of ketone body production (McGarry and Foster 1977). The metabolic process of ketosis, which occurs in the fasting state, is initiated by an increased release of fatty acids from the adipose tissue, associated with an increase of their uptake by the liver, accompanied by an enhanced capacity to convert fatty acids into ketone bodies. The former event is triggered by a fall in insulin levels and the ketogenesis is under control of the glucagon rise. Hence, the investigators postulate that the I/G ratio may constitute a bi-hormonal system for the control of the ketogenic process. Since then, the molecular mechanism underlying the ketogenesis regulation has been reinvestigated and other players are now involved, but it is beyond the scope of this section to discuss this issue.
2.1.1.4. Critical period concept
This concept is also known as a sensitive period or time window. In 1921, C. Stockard was the first to formulate this concept after noting that almost any chemical was capable of producing malformations in fish embryos if applied at the “proper” time during development (Stockard 1921). He also reported that the most rapidly growing tissues are also the most susceptible to any change in environmental conditions. In other words, the faster rates coincide with the critical periods. To support this concept, three studies are briefly presented. Two studies demonstrate that hormone alterations during development result in central nervous system abnormalities. A third one deals with the alterations of the immune system during development, when exposed to chemicals.
The first study deals with the sexual differentiation of the rodent brain. Steroid hormones have significant effects on the developing brain and are known to program adult functions required for sex-specific reproductive behaviors. Many behavioral sex differences observed in the adult are the consequences of sex-specific exposure to gonadal steroid hormones during critical windows of development. In rodents, the absence of testosterone during a critical perinatal period results in the expression of the default program of the brain, which is female-like (McCarthy and Arnold 2011), whereas perinatal treatment of females with testosterone will defeminize the brain and prevent the expression of female reproductive behaviors in adulthood.
A second study illustrates this concept when studying the cerebellar cortex maturation of the newborn rat (Clos et al. 1974). When the surge of the thyroxine plasma level, which occurs in the newborn throughout the first three weeks of postnatal life, is prevented with the administration of propylthiouracil, which blocks the thyroxine synthesis, the differentiation of the Purkinje cells is incomplete. This abnormality can be corrected only if the thyroxine is administered during the first two weeks of postnatal life.
A third study has clearly defined two critical windows of vulnerability in fetal development of the immune system of rodents (Landreth 2002). Gestational days 7–10 encompass a period of hematopoietic stem cells formation from mesenchymal cells. Exposure of the embryo to toxic chemicals during this period results in failures of stem cell formation, abnormalities in the production of all hematopoietic lineages and immune failure. Then, between day 10 and day 16, there is a tissue migration of hematopoietic cells and an expansion of progenitor cells. This developmental window is particularly sensitive to agents that interrupt cell migration and proliferation.
The concept of critical window also applies to genomic imprinting (see more details in Chapter 5). This term was first used in biology by K.Z. Lorenz in the late 1930s. Genomic imprinting refers to the differential expression of genetic material, at either a chromosomal or allelic level, depending on whether the genetic material has come from the male or female parent. It involves modifications of the nuclear DNA, which do not involve a change in nucleotide sequence, and the term imprinting implies that something happens during a critical or “sensitive” period in development. Hence, the stage during which germ-line cells are formed may represent one critical period during which genetic information is “tagged”, temporarily changing this information to permit differential expression.
Similarly, genetic studies of people conceived during the Dutch famine in 1944 revealed that transient prenatal malnutrition induced permanent epigenetic alterations. These findings highlight the critical role of the gestational timing during which environmental conditions result in lifelong phenotypic consequences (Heijmans et al. 2008).
The concept of critical periods has also been well documented for neuronal circuits across several systems and species. It was initiated in 1958 by Lorenz (1958) and the concept has profoundly influenced not only biologists, but also psychologists, such as philosophers, physicians, parents and educators. The reader is referred to the excellent review for more details of the field that delineates critical phases in brain development that carry a social impact far beyond basic neuroscience (Hensch 2004).
2.1.2. Nervous system
The nervous system receives a wealth of information from an individual’s surroundings and body, and its main task is to ensure that the organism adapts to the environment. For a long time, it held the “top rank” or first position of all the organ systems, but the early 19th century saw a revolution in scientific thinking about its anatomy and functions. On an anatomic basis, it can be subdivided into the central nervous system (CNS: brain and spinal cord) and peripheral nervous system (PNS: the cranial and spinal nerves). From a functional perspective, somatic (voluntary) and autonomic (involuntary or vegetative) nervous systems are recognized. The autonomic nervous system is subdivided into the sympathetic system and the parasympathetic system. With respect to its functions, it should be emphasized that it exerts a highly centralized control over other structures and physiological functions of the body, through an incredibly complex network. This latter aspect has been investigated, and numerous studies highlight the key role of the bidirectional communication between the brain and the endocrine and immune systems.
Interactions between peripheral organs and the brain are well documented, and recent advances describe how the inter-organ communication networks regulate energy homeostasis (Castillo-Armengol et al. 2019). For instance, to maintain homeostasis in fasting (Al Massadi et al. 2017) or feeding (Turton et al. 1996; Ronveaux et al. 2015) conditions, a great number of studies have described how the brain integrates chemical signals, released from the peripheral tissues, and responds through the release of neurohormones and/or an activation of the autonomic nervous system of the target tissues, in order to maintain energy homeostasis. Other studies focused on cold-induced thermogenesis highlighted the role of the brain in response to cold stress. Cold is sensed by the sensory neurons in the skin, and they convey this signal to the hypothalamic preoptic area (Zhang and Bi 2015). The transduction of the signal stimulates other hypothalamic areas, namely orexin-producing neurons located in the lateral hypothalamus area (LHA) that in turn stimulate the sympathetic firing in brown adipose tissue, which promotes thermogenesis.
Other examples of communication between peripheral organs and the brain are presented in detail in section 4.3.3.
2.1.3. Immune system
In all living organisms, the immune system provides a high level of protection from invading pathogens in a robust manner. The immune system consists of billions of cells dispersed in the body, and it has long been evident that this system must be subjected to internal regulatory mechanisms to maintain its homeostatic balance. It was also thought that the molecular signals they release when mounting an immune response seemed to be completely devoted to the control of the function of the immune system. For a long period of time, there was a kind of consensus among immunologists claiming that there was no reason to incorporate other more integrative host systems into immunological thinking.
