TERMOREGOLAZIONE

thermoregulation Normal core body temperature is around 37°C and controlled within a narrow range (33.2–38.2° C) circadian rhythm menstrual cycle aging

Temperatura corporea Attività fisica la T può aumentare di 1-2 gradi Nella febbre anche 3-4 gradi

Temperatura corporea

body temperature of 42°C Cytotoxicity protein denaturation impaired DNA synthesis resulting in end-organ failure and neuronal impairment

body temperature drops below 27°C (severe hypothermia) neuromuscular, cardiovascular, hematological, respiratory

Neutralità termica Un insieme di condizioni ambientali nelle quali la temperatura corporea ottimale è mantenuta per effetto dei soli scambi termici passivi con l’ambiente senza l’intervento di meccanismi attivi che comportano dispendio energetico. Ta = 29 ͦC ; velocità dell’aria 0,1m/s Ti =37 ͦC Tc = 33 ͦC

heat balance equation equazione del bilancio termico Heat storage = metabolism - work – evaporation ± radiation ± conduction ± convection

Metabolism refers to the chemical reactions occurring within the body that produce heat.

Diverso rapporto fra superficie e massa corporea Negli animali più grandi la massa corporea elevata trattiene meglio il calore e quindi sarà necessario produrne minore quantità

Work Work is the external work done

Dall’aria se è più calda al corpo

Evaporation is the heat loss to environment as water vaporized from the respiratory passages and skin surface (perspiration insensibilis) 1. The surface area exposed to the environment 2. The temperature and relative humidity of ambient air 3. Convective air currents around the body

Evaporazione Dispersione di calore metabolico dal corpo in un ambiente a temperatura più alta di quella corporea. Evaporazione di un litro di acqua sottrae alla superficie corporea una quantità di calore di 580 Kcal, pari al calore prodotto a riposo in circa 7 ore. Perspiratio insensibilis ( 8ml/h) acqua che diffonde passivamente attraverso la cute e acqua che evapora lungo le vie aeree, umidificando l’aria inspirata (20 ml/h) Cessione all’ambiente di circa 16Kcal/h

Scambi termici con l’ambiente Irraggiamento – scambio di calore fra superficie corporea e superfici solide circostanti, non in contatto, per effetto di emissione e assorbimento di onde elettromagnetiche nell’ambito dell’infrarosso. Il calore metabolico prodotto a riposo se non venisse disperso nell’ambiente produrrebbe un aumento della temperatura corporea > 1 Cͦ/ora

Conduction and Convection Conduction is the movement of heat to/from the body directly to objects in contact with the body. Convection is the transfer of heat to a moving gas or liquid. When a body is warm, the air molecules that make contact with the body will be warmed, reducing their density, which causes the molecules to rise and be replaced with cooler air. Convective heat exchange is increased by movement of the body in air or water or movement of air or water across the skin.

Temperature Regulation

Temperature Regulation The core temperature reflects the temperature within the “deep” body tissues, organs that have a high level of basal metabolism (such as the brain, heart, and liver). The shell temperature is influenced by blood flow to the skin, which is raised with a high core temperature, and environmental temperature

Temperature Regulation Peripheral thermoreceptors are located in the skin, where cold receptors are more abundant than warm receptors. Warm central thermoreceptors, located in the hypothalamus, spinal cord, viscera, and great veins, are more numerous than cold thermoreceptors.

Effector Organ Responses Increase in Body Temperature

Skin blood vessels. Heat is dissipated from the body when blood is brought in close proximity to the skin’s surface.

Skin blood vessels In response to increased or decreased ambient or internal temperatures, skin blood flow is modified accordingly through sympathetic vasodilation and vasoconstriction mechanisms, respectively . Johnson JM, Minson CT, Kellogg DL. Cutaneous vasodilator and vasoconstrictor mechanisms in temperature regulation. Compr Physiol 4: 33–89, 2014

Nonglabrous skin is innervated by both noradrenergic vasoconstrictor and cholinergic vasodilator nerves

glaborous skin palms, soles, and lips, is innervated solely by vasoconstrictor nerve fibers the principal response to heat is to increase cutaneous blood flow through passive vasodilation of blood vessels through sympathetic nervous activity withdrawal

Control of peripheral blood flow to glaborous skin Tansey EA, Roe SM, Johnson CJ. The sympathetic release test: Adv Physiol Educ 38: 87–92, 2014.

Glaborous skin Precapillary sphincters are only sparsely innervated by sympathetic nerves. At rest, there is a high degree of sympathetic tone to the skin.

Nonglabrous skin if the heat loss resulting from relaxation of vasoconstrictor tone is insufficient to cool the core active vasodilatation from sympathetic cholinergic nerves increase cutaneous blood flow from 300 ml/min up to or exceeding 8 l/min Johnson JM, Minson CT, Kellogg DL. Cutaneous vasodilator and vasoconstrictor mechanisms in temperature regulation. Compr Physiol 4: 33–89, 2014

cutaneous active vasodilation Acetylcholine vasoactive intestinal peptide, substance P, histamine, prostaglandins, and transient receptor potential (TRP)V1 receptor activation

cutaneous active vasodilation The cholinergic nerves that govern sweating may be the same as those that control active vasodilation nitric oxide (nitric oxidesynthase inhibition).

Sweat glands Sweat production and the subsequent evaporation are the principal modes of heat loss in humans when ambient temperature rises as well as during exercise. van Beaumont W, Bullard RW. Sweating: its rapid response to muscular work. Science 141: 643–646, 1963. Shibasaki M, Crandall CG. Mechanisms and controllers of eccrine sweating in humans. Front Biosci 2: 685–696, 2010.

1.6-4 milioni di ghiandole sudoripare eccrine. Fibre simpatiche colinergiche. Osmolarità 10-20mOsm. Velocità di flusso elevata, osmolarità oltre 100 mOsm Acclimatazione aumento della capacità secretoria massima da 2 a 3 l/h e enorme riassorbimento del sodio per azione dell’aldosterone Armstrong LE, Hubbard RW, Jones BH, Daniels JT. Preparing Alberto Salazar for the heat of the 1984 Olympic Marathon. Phys Sportsmed 14: 73–81, 1986. 3. Bates GP, Miller VS. Sweat rate and sodium loss during work in the heat. J Occup Med Toxicol 3: 4, 2008.

Acclimatazione Sato F, Owen M, Matthes R, Sato K, Gisolfi CV. Functional and morphological changes in the eccrine sweat gland with heat acclimation. J Appl Physiol 69: 232–236, 1990. Lee JB, Kim TW, Min YK, Yang HM. Long distance runners present upregulated sweating responses than sedentary counterparts. PLos One 9: e93976, 2014.

Behavioral adaptations Flouris AD. Functional architecture of behavioural thermoregulation. Eur J Appl Physiol 111: 1–8, 2011

Exercise in heat Vasocostrizione cutanea e di altri distretti(splancnico, renale ecc….) che si traduce in………

Exercise in heat Accumulo di calore determina vasodilatazione Aumento del flusso ematico cutaneo con variazione della PA Sudorazione, dispersione di calore per convezione, irraggiamento e per evaporazione del sudore Ipovolemia e aumento della viscosità Vasocostrizione splancnica Conflitto fra produzione di sudore e volemia

Physiological adaptations Aumento del flusso sanguigno periferico pur mantenendo la PA L’allenamento di resistenza e l’acclimatazione al caldo hanno dimostrato di migliorare la vasodilatazione. Best S, Thompson M, Caillaud C, Holvik L. Exercise-heat acclimation in young and older trained cyclists. J Sci Med Sport 17: 677–682, 2014.

Physiological adaptations FC ridotta a un carico di lavoro fisso Volume plasmatico espanso Temperatura interna inferiore ad un equivalente carico di lavoro (aumentando così il tempo di fatica) Maggiore riassorbimento di Na⁺dal sudore Kondo N, Taylor NA, Shibasaki M, Aoki K, Che Muhamed AM. Thermoregulatory adaptation in humans and its modifying factors. Global Environ Res 13: 35–41, 2009

Physiological adaptations La fatica si manifesta precocemente quando è associata a deplezione del glicogeno muscolare infatti l’integrazione con alcuni carboidrati migliora la risposta al caldo durante l’attività fisica. Carter J, Jeukendrup AE, Mundel T, Jones DA. Carbohydrate supplementation improves moderate and high-intensity exercise in the heat. Pflügers Arch 446: 211–219, 2003.

Quali carboidrati due differenti categorie di carboidrati: quelli che vengono ossidati a tassi elevati (fino a 1 g/min) quelli che vengono ossidati a bassa velocità (fino a 0,6 g/min).

Struttura chimica dell’isomaltulosio Struttura chimica dell’isomaltulosio. Il legame glucosidico di tipo alfa 1,6 (cerchiato) è il responsabile della particolare lentezza richiesta per l’assorbimento di questo zuchero

10 atleti maschi durante esercizio fisico moderato (2ore e mezza di bicicletta), mostrano come i tassi di ossidazione di isomaltulosio esogeno rappresentino solo il 59% rispetto al tasso di ossidazione del saccarosio ingerito, presumibilmente a causa della minor digestione del primo rispetto al secondo Achten J, Jentjens RL, Brouns F, et al. Exogenous oxidation of isomaltulose is lower than that of sucrose during exercise in men. J Nutr 2007;137:1143-8.

Effector Organ Responses to a Decrease in Body Temperature Skin blood vessels In response to cold, sympathetic vasoconstrictor nerves act primarily on -noradrenergic receptors to cause blood vessel smooth muscle contraction and vasoconstriction. released cotransmitters: ATP and neuropeptideY

Termogenesi chimica Aumento delle ossidazioni cellulari Incremento dell’utilizzazione di ATP in reazioni che non producono lavoro Stimolazione della catena respiratoria con contemporanea riduzione dell’efficienza della fosforilazione ossidativa

Ormoni tiroidei termogenesi chimica Incremento del numero, superficie delle membrane, e volume mitocondriale per cellula, Immediata attivazione di meccanismi metabolici mitocondriali,con conseguente aumento della produzione di calore. La 3,5-T2 è capace di stimolare il metabolismo e ha proprietà termogeniche.

Catecolamine termogenesi chimica Adrenalina e noradrenalina determinano incremento delle ossidazioni cellulari, conseguenti all’innalzamento dei livelli plasmatici di glucosio ed aumentata attività lipolitica con incremento degli FFA e glicerolo

Grasso bruno termogenesi chimica

Adipocita bruno

Origins of fat cells. Origins of fat cells. At least three types of precursors give rise to white, beige, and brown adipose cells separately. Precursors for brown adipocytes developmentally originate from dermomyotome and express Pax7 and Myf5. White and beige adipocytes come from two distinct populations of precursors of Pax7- and Myf5-negative lineages. While PPARγ is essential for adipogenesis of all fat cells, various transcriptional components play different roles in the development, commitment, and differentiation of white, beige, and brown fat, and PRDM16 has been shown to play an important role in regulating both brown and beige fat (for details, see the text). Jun Wu et al. Genes Dev. 2013;27:234-250 Copyright © 2013 by Cold Spring Harbor Laboratory Press

Dual functions of beige fat cells. Dual functions of beige fat cells. Beige fat cells have a very low basal level of UCP1 but can robustly respond to cAMP to activate a thermogenic program to levels similar to those seen in the brown cells. When energy intake exceeds energy expenditure, the surplus energy can be stored in beige fat cells in the form of lipid, and beige fat cells take on a more “white” morphology. Many stimuli—including cold, sympathetic stimulation, TZDs, and hormones (including recently identified exercised induced polypeptide irisin)—can activate beige fat cells and result in increased energy dissipation Dual functions of beige fat cells. Beige fat cells have a very low basal level of UCP1 but can robustly respond to cAMP to activate a thermogenic program to levels similar to those seen in the brown cells. When energy intake exceeds energy expenditure, the surplus energy can be stored in beige fat cells in the form of lipid, and beige fat cells take on a more “white” morphology. Many stimuli—including cold, sympathetic stimulation, TZDs, and hormones (including recently identified exercised induced polypeptide irisin)—can activate beige fat cells and result in increased energy dissipation. Jun Wu et al. Genes Dev. 2013;27:234-250 Copyright © 2013 by Cold Spring Harbor Laboratory Press

Irisin, an exercise-induced myokine as a metabolic PGC-1α, peroxisome proliferator-activated receptor gamma coactivator-1-alpha FNDC5, fibronectin domain-containing protein Irisin, an exercise-induced myokine as a metabolic regulator: an updated narrative review DIABETES/METABOLISM RESEARCH AND REVIEWS Diabetes Metab Res Rev 2016;

Role of Exercise in the Activation of Brown Adipose Tissue Ann Nutr Metab 2015;67:21–32 DOI: 10.1159/000437173

Convertible visceral fat as a therapeutic target to curb obesity NATURE REVIEWS | DRUG DISCOVERY 11 Mar 2016 Saverio Cinti1,3

Piloerection The arrector pili muscle is innervated by the autonomic nervous system α₁-adrenergic receptors piloerection may become more important in conjunction with shivering, potentially enhancing the effectiveness of the shivering response

Shivering. It is initiated by the hypothalamic preoptic area but mediated by the somatic motor cortex in response to signals from cold receptors in the skin, the normal stimulus for shivering is the skin temperature rather than the core temperature is involuntary, rapid, oscillating contractions of skeletal muscle. ATP is hydrolyzed, but no work is done through the contraction In adults, shivering, at its peak, can elicit heat production equivalent to five times the basal metabolic rate in neonates, there is a notable absence of shivering due to the immaturity of their skeletal muscles

Behavioral adaptions to cold behavioral control is influenced by: medulla oblongata, pons, midbrain, somatosensory cortex, amygdala, and thermoregulatory centers in the hypothalamus as well as the prefrontal cortex Flouris AD. Functional architecture of behavioural thermoregulation. Eur J Appl Physiol 111: 1–8, 2011.

Transduction of Temperature TRP channels (transient receptor potential) are a superfamily of proteins that can be expressed in cell membranes and in membranes of internal structures Many are polymodal (thermic, mechanic, chemical) in their activation, all resulting in cation influx Wu LJ, Sweet TB, Clapham DE. International Union of Basic and Clinical Pharmacology. LXXVI. Current progress in the mammalian TRP ion channel family. Pharmacol Rev 62: 381–404, 2010.

Ciascuno ha una banda relativamente ristretta di attivazione di temperatura tuttavia la sovrapposizione di queste sensibilità consente una vasta gamma di discriminazione temperatura

Chemical agonist TRP channels cooling sensation of menthol (a TRPM8 agonist) warming/burning sensation food spiced with chili (capcaisin, a TRPV1 agonist). They may contribute by direct activation of sensory fibers; for example, TRPM8 channels are expressed in primary somatosensory neurons They may also indirectly stimulate primary sensory fibers; TRPV3 and TRPV4 channels are expressed in abundance in skin keratinocytes, which may secrete diffusible factors that stimulate sensory fibers

Transduction of Temperature in the brain The molecular mechanisms responsible for temperature transduction in the brain, particularly the hypothalamus, are largely unknown The neurons in the preoptic hypothalamus (POA), it has been proposed that spontaneous activity in their membranes represents pacemaker activity capable of generating spontaneous action potentials, and their temperature sensitivity reflects the temperature sensitivity of these membrane currents Wechselberger M, Wright CL, Bishop GL, Boulant JA. Ionic currents and conductance-based models for hypothalamic neuronal sensitivity. AmJ Physiol Regul Integr Comp Physiol 291: R518–R529, 2006.

Transduction of Temperature in the brain Su questi neuroni sono stati trovati recettori di membrana in grado di rispondere a determinati livelli termici canali TRP

thermal sensation in the spinal cord thermal sensation in the spinal cord may reflect the activation of TRP channels in the central end of sensory neurons located in the spinal dorsal horn Morrisson SF, Nakamura K. Central neural pathways for thermoregulation. Front Biosci 16: 74–104, 2011.

Transduction of Temperature in the viscera abdominal blood vessels, esophagus, and stomach, among other organ animal studies have revealed that several TRP channels, similar to the skin afferent nerves, are expressed in abdominal vagal afferent nerves Zhang L, Jones S, Brody K, Costa M, Brookes SJ. Thermo-sensitive transient receptor potential channels in vagal afferent neurons of the mouse. Am J Physiol Gastrointest Liver Physiol 286: G983–G991, 2004

Afferent Pathways

Cool and warm temperature information stimulates separate populations of primary somatosensory afferents in the skin. These enter the spinal (or trigeminal) dorsal horn to synapse with second-order ascending neurons in the lamina 1.

external

Central circuitry mediating the responses to warm

Afferent Pathways viscera Afferents arising in the viscera travel to the central nervous system mainly in vagus and splanchnic nerves. The majority of this sensory information, including temperature, converges at the level of the nucleus tractus solitarius before passing to the LPB (parabrachial nucleus), so the LPB may integrate both skin and visceral thermal information

I nuclei ipotalamici sono situati bilateralmente e sono disposti simmetricamente intorno alla cavità del terzo ventricolo Ipotalamo periventricolare Nuclei ipotalamici anteriori n. ipotalamico anteriore, area preottica (termodispersione) Nuclei ipotalamici laterali Nuclei ipotalamici posteriori n.ipotalamico posteriore (termogenesi)

TERMOREGOLAZIONE

Ipotesi del set point variabile integrazione dei segnali termici periferici e centrali coordinati nell’area preottica ipotalamica

Meccanismi termoregolatori

Central Control of Thermoregulatory Responses Evidence is accumulating that central and peripheral temperatures influence individual effector circuits independently Thermoreceptive neurons are activated when the appropriate temperature threshold for that neuron is reached, and action potentials ascend, via synaptic relays, to the POA. These signals, along with thermoreceptive signals arising within the POA, act on several effector outputs, and the influence of central and peripheral signals varies between different effectors Morrisson SF, Nakamura K. Central neural pathways for thermoregulation.Front Biosci 16: 74–104, 2011.

Per esempio la risposta al brivido e l’attivazione del BAT…………. Riduce le inibizioni Per esempio la risposta al brivido e l’attivazione del BAT………….

Central circuitry mediating the responses to warm

“balance point” the contribution of all the relatively independent individual effector pathways collectively contributes to a steady core temperature of 37°C Romanovsky AA. Thermoregulation: some concepts have changed. Functional architecture of the thermoregulatory system. Am J Physiol Regul Integr Comp Physiol 292: R37–R46, 2007.

Conclusions 1. On the sensory side, several membrane channel proteins (TRPs) have been identified that may transduce specific temperature ranges 2. Elucidation of discrete neuroanatomical circuitry for several of the thermoregulatory effectors within the hypothalamic region that updates the concept of the set point 3. Recognition of a potential role for BAT in thermoregulation and metabolism

Termoregolazione e ciclo veglia sonno Durante il sonno a onde lente sia nell’uomo che negli animali, la funzione termoregolatoria è presente Al contrario nel sonno REM Variazioni o ritmi ultradiani

Ipotalamo, regolazione veglia sonno e temperatura Competizione a livello ipotalamico nella gestione della regolazione della temperatura corporea e la fase REM del sonno

T telencefalo (sistema limbico neocorticale); D diencefalo (regione ipotalamo preottica); R romboencefalo(regione bulbo pontina)

neuropeptidi ADH e ossitocina ottenuti a partire da precursori di maggiori dimensioni (neurofisine) contenute in vescicole all’interno dei neuroni

Meccanismi di base della secrezione di ADH Attivazione dei neuroni spontanea e fasica che generano potenziali d’azione molto vicini fra loro alternati a periodi silenti. Quindi concentrazione basale di ADH in condizioni basali e in assenza di stimoli

Regolazione della sete Tensotermocettori orali, esofagei e gastrici

Azioni neurovegetative La stimolazione di diverse aree ipotalamiche è in grado di modificare il diametro pupillare, di indurre tachipnea, tachi o bradicardia, aritmie cardiache, variazioni imponenti della pressione arteriosa. La sezione delle efferenze orto e parasimpatiche abolisce questi effetti

Ipotalamo Filogeneticamente antica Integra messaggi per generare risposte complesse, neurovegetative e comportamentali Motivazione Controllo integrato sui sistemi ormonali Attività simpatica e parasimpatica Risposte stereotipate e istintive