Bazele hormonale ale comportamentului uman

Conf. Dr.Daniel Grigorie Catedra de Endocrinologie,

UMF “Carol Davila”,Institutul “C.I.Parhon”, Bucureşti

În încercarea de a defini comportamentul...

„Ansamblul reacţiilor unui obiect complex aparţinând unui nivel de organizare oarecare (speciilor biologice, grupurilor sociale) la factorii de mediu pentru menţinerea în condiţii optime a formei şi funcţiilor organelor acestuia”

Dicţionarul Explicativ al Limbii RomâneDicţionarul Explicativ al Limbii Române

Sisteme integrative

• - sistemul endocrin: operează cu hormoni, care în acceptiunea clasică, sunt substanţe chimice produse de glandele endocrine, secretate în sânge, vehiculate la distanţă unde acţioneaza asupra ţesuturilor prin legare de receptori specifici;

• - sistemul nervos: informaţia este purtată de impulsurile nervoase sau de mediatori chimici la nivelul sinapsei - aceşti mediatori se numesc neurotransmiţători;

• - sistemul imun: operează cu informaţia antigenică, al cărei substrat este de obicei proteic.

Hipotalamus: supravieţuire şi reproducere!

TA şi echilibrul electrolitic (tonus vasomotor, sete, apetit pentru sare)

Temperatura corpului (termogeneza metabolică - frison)

Metabolismul energetic (hrănire, digestie, rată metabolică)

Reproducere (controlul hormonal al procreerii, sarcina, lactaţia)

Răspunsul acut la stress (fluxul sanghin către muşchi, modificările hormonale şi imunologice)

Controlul axelor hipotalamus-hipofiză-organ ţintă

COMPORTAMENTUL ALIMENTAR

INTRODUCERE

• Eating behavior is a complex interplay of physiologic, psychological, social, and genetic factors that influence meal timing, quantity of food intake, and food preference.

• Functional magnetic resonance imaging (FMRI), has emerged as a modality to effectively study eating behavior and genetics in fascinating ways

Tipuri de comportament alimentar

Restraint -is characterized by intentional avoidance of certain foods in order to control body weight, and is measured by response to questions on the TFQ such as “I avoid certain foods because they make me fat.”

Disinhibition -is the tendency to overeat when surrounded by others who are overeating.

Hunger -measures the subjective sense of an individual’s need to eat.

1. Recognition for weight and constitution (e.g., ‘Do you think it is easier for you to gain weight than others?’),

2. External eating behavior (e.g., ‘If food smells and looks good, do you eat more than usual?’),

3. Emotional eating behavior (e.g., ‘Do you have the desire to eat when you are irritated?’),

4. Sense of hunger (e.g. ‘Do you get irritated when you feel hungry?’),

5. Eating style (e.g., ‘Do you eat fast?’),6. Food preference (e.g., ‘Do you like meat?’), 7. Regularity of eating habits (e.g., ‘Is your dinner time too late at

night?’).

Componente ale comportamentului alimentar

CIRCUITELE FOAMEI SI SATIETATII

• Pe baza conexiunilor sale anatomice ( input si out put) Hipotalamusul controleaza homeostazia energetica prin abilitatea de a orchestra raspunsuri hormonale, autonome si comportamentale.

• Nc arcuat este nodul central al controlului Ht al balantei energetice, ingestiei de alimente si homeostaziei glucozei.

NUCLEUL PARAVENTRICULAR

NUCLEUL DORSOMEDIAL

NUCLEUL VENTROMEDIAL

NUCLEUL ARCUAT

ARIA HIPOTALAMICĂ

LATERALĂ

HIPOFIZA

NUCLEUL SUPRACHIASMATIC

Conexiunile nucleilor hipotalamici implicaţi în comportamentul alimentar

Semnale orexigene si anorexigene

• A balanced interaction between two sets of neurons occurs within the arcuate nucleus of the hypothalamus.

• Activation of neurons secreting neuropeptide Y (NPY) and agouti-related protein (AgRP) promotes food intake, whereas

• that of neurons secreting pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) has an anorexigenic effect. The NPY/AgRP neurons also inhibit POMC/CART neurons through γ-aminobutyric acid (GABA).

• The orexigenic and anorexigenic signals from the NPY/AgRP and POMC/CART neurons are sent to other brain nuclei, ultimately resulting in alterations in food intake and energy expenditure. The system is very complex and involves interactions among various areas of the brain

POMC SI DERIVATE

• POMC – pro-peptid multifunctional prelucrat diferit; in creier un produs cheie este alfa-MSH care regleaza ingestia de alimente si homeost energetica actionind pe receptorii MC4, cu rol central in aceste procese

• Neuronii orexigeni NPY/AgRP si anorexigeni POMC din nc arcuat sunt coordonati si reglati de o varietate de hormoni, medicamente si nutriente

• Leptina – deficitul ei si postul produc scaderea POMC si cresterea prot aguty si NPY in nc arcuat.

• RAPORTUL NPY/POMC = DETERMINANTUL FUNDAMENTAL AL HOMEOSTAZIEI ENERGETICE GLOBALE

Sistemul canabinoid

• The endocannabinoid system is also involved in the regulation of food intake, particularly the cannabinoid 1 (CB1) receptors and their endogenous ligands.

• Administration of cannabinoids increases food intake and promotes body-weight gain, and treatment with selective CB1 receptor antagonists decreases food intake and body weight in obese mice.

•  Randomized, controlled trials in obese human patients have shown that treatment with rimonabant, a CB1 receptor antagonist, decreases body weight.These studies demonstrated that the cannabinoid system has an important role in the regulation of ingestive behavior in animals and humans.

• In 2008, the clinical development program of rimonabant was discontinued because of the risk of serious psychiatric disorders.

FACTORI DE SATIETATE SI FOAME- Rolul trunchiului cerebral

Centrul detectiei si raspunsurilor la semnalele de foame si satietate Pe linga efectele g-i peptidele gi au si efecte centrale directe asupra

centrilor de control hipot care se traduc si in raspunsuri asupra comportamentului alimentar.

nc. dorsal al vagului si nc.tract solitar primesc aferente senzoriale din tract digestiv, inclusiv pt gust, distensie gastrica, conc glucozei si lipidelor in ficat si vena porta. Aceste informatii sunt transmise si direct in ariile Ht mediala si laterala.

Semnalele primite de tr. cerebral, prin conexiunile neurale cu hipot, interactioneaza cu centrii care regleaza greutatea pe termen lung pentru a regla aportul zilnic prin ajustarea marimii si frecventei meselor.

Rolul organelor periferice

• The major peripheral organs participating in the regulation of food intake are the stomach, gut, pancreas, and adipose tissue. 

• The stomach and the duodenum secrete the orexigenic peptide ghrelin, which increases before eating and decreases after feeding. Many so-called satiety signals are transmitted to the brain via vagal afferent fibers from the gut that synapse in the nucleus tractus solitarius (NTS) , which participates in gustatory, satiety, and visceral sensation.

• Oral taste receptor cells generate information that is transmitted to the NTS by afferent sensory fibers.

• Insulin, secreted by the pancreas, has an anorexigenic effect through the arcuate nucleus.

• Peptide YY is secreted by the gastrointestinal tract after food ingestion and might have an anorexigenic signal.

Semnale anorexigene periferice

• Glucagon-like peptide 1 (GLP1) is derived from pre-proglucagon and secreted in response to food ingestion by the proximal gastrointestinal tract. It exerts pleiotropic effects, including slight anorexic effects.

• Satiety is also mediated by other gut proteins, such as cholecystokinin (CCK).

• Leptin, secreted by the adipose tissue, also serves as an anorexigenic signal.

AXA CREIER-INTESTIN-TESUT ADIPOS

• Leptina este un hormon care regleaza homeostazia energetica:

• -este produsa in tesutul adipos. Leptina circulanta este un hormon care semnalizeaza creierului ca depozitele energetice sunt suficiente.

-rol: comportamentul alimentar, termogeneza, functia reproductiva • Absenta totala a leptinei produce obezitate morbida la om• Deficitul de leptina produce rezistenta la insulina; actiunile leptinei in

nc. arcuat au efecte antidiabetice.• Infometarea, stare cu depozite energetice scazute, duce la

scaderea nivelelor leptinei, activarea axei Ht-Hf-adrenale, inhibitia axelor tiroidiana si de crestere si inhibitia functiei reproductive.

GLUCOCORTICOIZII SI HORMONII GONADICI

• Actioneaza central pe circuite implicate in homeostazia energetica• Deletia ERalfa din Ht ventromedial produce obezitate si sindrom

metabolic, implicind estrogenii in cheltuiala de energie.• Glucocorticoizii stimuleaza apetitul si cresterea in greutate prin

efecte complexe asupra multor tesuturi.• In exces, produc redistributia tes adipos pe linia mediana.

1.01.2006 5.09.2007 21.11.20071.01.2006 5.09.2007 21.11.2007

Metabolismul energetic

– Necesita o balanta intre aportul de energie si cheltuiala de energie– Cheltuiala de energie: energia necesara pt metabolismul bazal energia necesara pt activitatea fizica efectul termic al alimentelor (termogeneza indusa de alimente) –

cresterea cheltuielii de energie ca raspuns la aportul de energie.

Acest proces este controlat de SNS (tesutul adipos brun) si axa tiroidiana.Activarea SNS produce rezistenta la obezitatea prin hiperalimentare. Activarea din centrii Ht a SNS periferic regleaza cheltuiala de energie,

sistemul cardiovascular, secretia de catecolamine si pancreasul endocrin

Rolul MC4-R – agonistii lui stimuleaza activitatea simpatica in tesutul adipos brun

Balanta energetica

• Obesity is caused by an excessive intake of calories in relation to energy expenditure over a long period of time.

• Large increases in body fat can result from even minor, but chronic, differences between energy intake and energy expenditure. In 1 year, the ingestion of only 5% more calories than expended can promote the gain of approximately 5 kg in adipose tissue.

• Over 30 years, the daily ingestion of only 8 kcal more than expended can increase body weight by 10 kg.

Exista anomalii ale metabolismului energetic in obezitate?

• Obese persons usually have greater rates of REE than lean persons of the same height because obese persons have greater lean and adipose tissue cell mass.

• Diet-induced weight loss decreases REE, which promotes weight regain. This observation underlies the set-point theory, which posits that body weight is predetermined such that weight loss (or gain) promotes a decrease (or increase) in metabolic rate that acts to restore body weight to a preset level.

• When energy intake exceeds energy expenditure, weight gain usually occurs. However, genetic factors may influence the amount of weight gained with overfeeding.

OBEZITATEA SI DZ TIP 2

• The World Health Organization (WHO) estimates that 2.3 billion adults will be overweight and >700 million will be obese by 2015 . Effective therapeutic strategy for obese type 2 diabetes should be developed without delay, but it is often difficult to control appetite and to maintain body weight in obese type 2 diabetes patients.

• Intensive insulin therapy may result in fine glycemic control and prevent microvascular complications, but such treatment usually increases body weight. In addition, the oral glucose-lowering agents sulfonylurea (SU) and thiazolidinedione also increase body weight by enhancing glucose uptake into adipocytes.

OBEZITATEA SI DZ TIP 2

Tratamentul obezitatii prin modificari comportamentale

• Behavior modification for the treatment of obesity usually involves multiple strategies to modify eating and activity habits.

• These strategies include stimulus control (avoiding the cues that prompt eating), self-monitoring (keeping daily records of food intake and physical activity), problem-solving skills (developing a systematic manner of analyzing a problem and identifying possible solutions), cognitive restructuring (thinking in a positive manner), social support (cooperation from family members and friends in altering lifestyle behavior), and relapse prevention (methods to promote recovery from bouts of overeating or weight regain).

Liraglutide, a glucagon-like peptide (GLP-1) analogue, is a member of new classes of anti-diabetic agents and is characterized by induction of insulin secretion only during hyperglycemia as an incretin effect. GLP-1 promotes satiety and reduces food intake .

Componente ale comportamentului alimentar inainte si dupa liraglutid

Intersection of Energy Balance and Reward Circuits

• If rational strategies to combat obesity are to be developed, an increased understanding of the molecular mechanisms of the rewarding aspects of feeding behavior is required.

• A relatively recent and novel concept is that food and drug rewards share some common neural substrates.

• Motivation and reward have been studied in the context of drug addiction.The nucleus accumbens and its dopamine inputs have been strongly implicated in mediating several rewarding stimuli

Relationship between stress and eating behavior

• Stress appears to alter overall food intake in two ways, resulting in under- or overeating, which may be influenced by stressor severity. Chronic life stress seems to be associated with a greater preference for energy- and nutrient-dense foods, namely those that are high in sugar and fat. Evidence from longitudinal studies suggests that chronic life stress may be causally linked to weight gain, with a greater effect seen in men.

• Stress-induced eating may be one factor contributing to the development of obesity.

Reward Based Stress Eating

Repeated stimulation of the reward pathways through either stress induced HPA stimulation, intake of highly palatable food or both, may lead to neurobiological adaptations that promote the compulsive nature of overeating. Cortisol may influence the reward value of food via neuroendocrine/peptide mediators such as leptin, insulin and neuropeptide Y (NPY). Whereas glucocorticoids are antagonized by insulin and leptin acutely, under chronic stress, that finely balanced system is dysregulated, possibly contributing to increased food intake and visceral fat accumulation. Obesity epidemic may be exacerbated by :-the preponderance of chronic stress,-unsuccessful attempts at food restriction, and their -independent and possibly synergistic effects on increasing the reward value of highly palatable food.

Hormonii si selectia/cantitatea mesei

Genes identified with common variants influencing eating behavior with potential impact on obesity

Tulburările de comportament alimentar

• Anorexia nervoasă

• Bulimia

• Comportamentul de tip “binge

eating”

Comportamentul de tip” binge eating”

• se referă la o subsecvenţă din cadrul tulburărilor de alimentaţie, clasificată în DSM IV drept „tulburare de comportament alimentar fără altă specificaţie”, mai precis episoade recurente de „binge eating” (mâncat compulsiv), fără metode compensatorii inadecvate ca în bulimia nervosa

• alimentarea compulsivă înseamnă cantităţi mai mari decât la alte persoane, în aceleaşi circumstanţe, îngurgitate fără simţul controlului, mai repede decât e cazul, nelegat de senzaţia de foame, până ce pacientul se simte inconfortabil de sătul, episoade care apar cel puţin de 2 ori pe săptămână, minim 6 luni

HORMONUL ANTIDIURETIC

• Vasopresina sau hormonul antidiuretic este determinantul major al excretiei renale a apei libere si joaca un rol central in mentinerea balantei apei si osmolalitatii lichidelor organismului

• AVP este sintetizata in neuronii nc. SO si PV si depozitata in hipofiza posterioara de unde este secretata in circulatie

• Reglarea fiziologica a sintezei si secretiei AVP implica 2 sisteme: osmotic si de presiune/volum

• Reglarea osmotica:- este mediata de osmoreceptori localizati in structurile circumventriculare anterioare (OLVT); aprecierea setei, desi o functie corticala , depinde de osmoreceptori distincti-cresterea osm plasmei (normal 285-295 mOsm) determina cresterea lineara a secretiei AVP; pe masura ce AVP creste volumul urinar scade (antidiureza) si osm/densit urinara creste- daca osm plasmei este mai mare de 295 mOsm organismul este in pericol de deshidratare severa pt ca secretia de AVP este deja maxima- deci antidiureza e deja maxima; la subiectii sanatosi acest fapt este evitat prin stimularea mecanismului setei care determina ingestia de lichide; aceasta scade osm plasmei la nivele la care excretia renala a apei e reglata din nou de AVP. Acest aranjament are avantajul de a-i scuti pe oameni de episoade frecvente de sete care ar necesita o diversitate de activitati comportamentale pt cautarea apei cind deficitul de apa este usor si poate fi compensat de conservarea renala a apei si lasind mecanismul setei pt situatii de urgenta.- Daca se ingera volume mai mari de lichide decit cele cerute de sete, atunci secretia de AVP este supresata si rinichii pot excreta si 15-20 litri/24 ore.

HORMONUL ANTIDIURETIC

• Reglarea de presiune/volum:- modificarile volumului sanguin sunt mediate de receptorii de joasa presiune din atriul sting si venele mari ale toracelui, in timp ce reglarea prin TA este mediata de baro-receptorii din arcul aortic si arterele carotide- Relatia TA-AVP este exponentiala cind volumul sanguin scade mai mult de 10%.

Reglarea comparativa a AVP (osmolalitate vs volum/TA)

SETEA

• Pentru a mentine homeostazia apei este necesara ingestia de apa pt a inlocui pierderile urinare obligatorii si pe cele insensibile.

• Setea reprezinta un mecanism de protectie si consumul de apa creste ca raspuns la perceptia deficitului de lichide.

• Ca si AVP, setea este stimulata de cresterea osmolalitatii LEC (cu 2-3%) si de scaderea volumului intravascular.

• Desi setea este reglata osmotic, este putin probabil ca modificarile osm plasmatice sunt complet responsabile de ingestia zilnica de lichide; majoritatea oamenilor ingera cantitati mari de lichide odata cu ingestia de alimente, din motive de gust sau pt efecte secundare dorite (cofeina), sau din motive sociale sau obiceiuri (bauturi alcoolice sau nealcoolice). De aceea, in general atit oamenii cit si animalele ingera volume in exces fata de ceea ce se considera necesarul actual de lichide.

• Prin urmare desi setea are o importanta vitala in situatii de hiperosm si hipovolemie, in situatii fiziologice de balanta apei este responsabila in special AVP.

Diabetul insipid hipotalamic - neurogen, central, cranian

• Diabetul insipid hipotalamic (DIH) este o boală caracterizată prin incapacitatea de a concentra urina ca urmare a alterării secreţiei osmoreglate de AVP. Majoritatea pacienţilor au nivele detectabile ale AVP, dar care sunt inadecvat scăzute în comparaţie cu valorile concomitente ale osmolarităţii plasmatice. În consecinţă, se produce o poliurie persistentă care determină deshidratare hipertonă, iar pacienţii îşi menţin balanţa apei prin mecanismul setei (presupus intact).

POLIDIPSIA PRIMARA

• Polidipsia primara si poliuria ulterioara trebuie diferentiate de diabetul insipid si poate contribui la SIADH.

• PP poate fi produsa de leziunile organice ale hipotalamusului care produc DI, dar mai ales de sarcoidoza hipotalamica.

• PP poate fi produsa de medicamente care produc uscaciunea gurii (anticolinergice, antidepresive) sau de orice boala care stimuleaza secretia de renina.

• PP este adesea asociata cu sindroame psihiatrice

SINDROMUL HIPERNATREMIEI ADIPSICE

• Se caracterizeaza prin absenta osmostatului cu baro-receptori intacti: pacientii nu au senzatia de sete si nu beau apa

• Spre deosebire de subiectii normali, pe masura ce Na seric creste nu se secreta AVP si poliuria hipotona continua.

• Aportul scazut de apa si excretia excesiva de apa produc deshidratare cu hiperNa.