Neuroendocrinology Flashcards

Question

Luteinizing hormone (LH)

Answer 1

• stimulates testosterone synthesis in Leydig cells (together with FSH) (♂) • triggers ovulation and development of corpus luteum (♀)

Answer 2

• initiates follicular growth (♀) • sensitizes Leydig-cells for LH (♂) • stimulates spermatogenesis together with LH (♂)

Answer 3

• 44 or 45 AA, is processed into shorter forms • crucial for activity: AA 1-29 • pulsatile secretion • stimulates GH-secretion (but also LH and FSH) • belongs to the VIP-family of peptides • mainly in ventromedial hypothalamus (VMN) and ARC • outside CNS: in placenta and duodenum (amongst others) • stimulation through GABA, Opioids • inhibition through somatostatin and GH

Answer 4

• inhibitsGH-secretion • 14 AA, processed from a prohormone (92 AA) • synthetized also outside the brain (bowels) • inhibits TRH-stimulation of TSH

Answer 5

• episodic secretion, circadian rhythm • 191 AA secretion stimuli: • youth • starvation • stress • activity • all energy-expending processes direct actions: • hyperglycemic - promotion of gluconeogenesis - inhibition of glycogen synthesis in the liver • lipolytic • protein-anabolic - stimulation of aminoacid uptake and protein synthesis in muscle, liver, bone -> GH facilitates the use of products from intermediary metabolism for growth and sustainment indirect actions: Indirect actions through increased production of IGF-I in the liver • stimulates the growth of bones • activates mitosis of chondrocytes and proliferation of cartilage • bones lose sensitivity for IGF-1 during puberty

Answer 6

- short stature, normal proportions - growth hormone deficiency during childhood - gigantism - hypersecretion in children - acromegaly- hypersecretion in adults; growth of tissue and bones of the face, hands, feet

Answer 7

• tripeptide, N- und C-terminal modified • multiple copies in one pro-hormone sequence • identified in all parts of brain and spinal cord • stimulates thyrotropin (thyreocyte stimulating hormone (TSH)) secretion • stimulates also prolactin- and growth hormone secretion

Answer 8

• control of thyroid hormone synthesis

Answer 9

regulation of basal cell metabolism via control of ATP-production and utilisation • hyperglycemic: • stimulates gluconeogenesis in the liver • stimulates glycogenolysis in the liver • inhibits lipogenesis • essential for normal growth and development, in particular for the nervous system

Answer 10

• 41 AA • stimulates ACTH secretion • widely spread in central nervous system (CNS) • in CNS, existence of CRF-related peptides, e.g. urocortin

Answer 11

• 39 AAs • is processed (together with other peptides) from precursor protein proopiomelanocortin (POMC) • stimulates synthesis of steroids from the adrenal cortex

Answer 12

- increased in stress - hyperglycemic - inhibit synthesis of proteins and fat - inhibit immune system

Answer 13

Cushing syndrom • primary cause: excessive CRF secretion -> ACTH upregulation + cortisol upregulation • primary cause: excessive ACTH secretion -> cortisol upregulation, CRF down regulation • primary cause: excessive cortisol secretion -> CRF down regulation + ACTH down regulation primary adrenal cortex insufficiency (Morbus Addison) • primary cause: reduced cortisol secretion -> CRF upregulation + ACTH upregulation secondary adrenal cortex insufficiency • primary cause: reduced ACTH secretion -> cortisol down regulation, CRF upregulation

Answer 14

• CRF–release in hypothalamus • transport to anterior pituitary via portal system • inanterior pituitary, release of ACTH • ACTH stimulates cortisol-release in adrenal cortex • cortisol inhibits ACTH-release in pituitary (short loop feedback) • cortisolinhibitsCRF-releasein hypothalamus (long loop)

Answer 15

• HPA-axis • cardiovascular system • respiration • cognitive and locomotor behavior • food intake • gastrointestinal system • reproduction and growth • immune system

Answer 16

• pituitary (anterior and intermediate lobe) • adrenal cortex • lung • gastrointestinal organs • skin • Leydig cells, spermatocytes, ovaries • endometrium, placenta, amniotic fluid

Answer 17

• hypothalamus - hypophysiotropic structures, mainly parvocellular part of the PVN - but also neurons projecting to brain stem and spinal cord • cortex • subcortical structures associated with the regulation of autonomic functions

Answer 18

• diencephalon - med. preopt. area (MPOA), DMN, N. ARCTUS (ARC), post. hypothalamus, mamill. nuclei, med. nuclei of the thalamus • telencephalon - CeN and other n. of the AMYGDALA, striaterminalis, substantia innominata, some hippocampal areas... • brainstem and medulla - E.g. LOCUS COERULEUS, Kölliker-Fuse nucleus, N. TRACTUS SOLITARIUS, oculomotorius neurons, catecholaminergic cell group A7, n. parabrachialis, raphe nuclei, n. vestibularis medialis, n. paragigantocellularis, periaqueductal grey, dors. vagal complex • spinal cord

Answer 19

• afferences and efferences (examples) - efferences from amygdala to hypothalamus - reciprocal connections between Locus coeruleus (LC) and hypothalamus -reciprocal connections between amygdala and autonomic centers and brainstem (N. parabrachialis, dorsal n. of the vagus) • significance -presences of CRF in brainstem and spinal cord (N. tractus solitarius (NTS), LC ...) indicates its role in the regulation of autonomic nervous system activity (respiration, blood pressure etc.)

Answer 20

• 2 subtypes, 70% homology • 7 putative transmembrane helices • 5 putative extracellular glycosylation sites • multiple phosphorylation sites • gs-protein coupled -> adenylate-cyclase • can also interact with other g-proteins

Answer 21

• dense - hypothalamus (n. paraventricularis (PVN), n. suprachiasmaticus ((SCN)), bed nucleus of stria terminalis • moderate - cortex • low - thalamus, basal ganglia, hippocampus, amygdala, septum, brainstem, spinal cord

Answer 22

• CRF1–widelydistributed - several subtypes (CRF1α-h) - e.g.neuroendocrine regulation of pituitary function • CRF2α-distinct distribution - neuroendocrine actions in hypothalamus, regulation of behavior (e.g. food intake) and autonomic nervous system • CRF2β – peripheral and central nervous (in CNS in non-neuronal structures) - endothelial actions • CRF2γ-?

Answer 23

• CRF1 - cortex, septum, amygdala - pituitary (anterior and intermediate lobe) • CRF2α - lateral septum, PVN, ventromedial hypothalamus (VMN), n. supraopticus (SON), limbic system, bulbus olfactorius, raphe nuclei, n. tractus solitarius (NTS) • CRF2β - plexus chorioideus - cerebral arterioles • CRF2γ - limbic system, cortex

Answer 24

- down regulation gastric acid secretion - down regulation gastric emptying - down regulation gastrointestinal motility

Answer 25

- upregulation heart rate - upregulation blood pressure - downregulation peripheral resistance -> uncoupling of the baroreceptor-reflex action via - blockade of preganglionic vagal nuclei - stimulationof preganglionic sympathetic neurons - ! Independent from HPA! !only in awake animals - maybe result of general arousal?

Answer 26

- upregulation physical activity - upregulation O2 consumption - upregulation plasma-glucose - upregulation glucagon - mediated via sympathetic nerve - !independent from HPA!

Answer 27

- upregulation locomotor activity - independent from dopamine! - antigenic effects (participation of LC and amygdala) - downregulation food and water intake - alterations of sleep architecture (down regulation slow wave sleep) - down regulation reproduction - !independent from HPA!

Answer 28

• anorexia, bulimia • depression and anxiety disorders • Alzheimer’s disease

Answer 29

• Reduced sensitivity of the glucocorticoid-receptors (GR) lead to increased release of CRF and loss of the suppressing action of dexamethasone at the pituitary

Answer 30

• can possess different/distinct actions dependent on - distribution - receptor affinity • sauvagin - philomedusa sauvagii • urotensin I, urotensin II - teleosteer • urocortin, urocortin II - mammalia

Answer 31

• contains the largest number of noradrenergic neurons in the CNS • function - attention - orientation - stress • a little comment - locus coeruleus (latin: ‚dark blue place‘) contains melanin (at least in humans)

Answer 32

• compact nucleus in the pons • largest number of noradrenergic perikarya in the CNS • widespread, mostly ipsilateral efferences, innervating e.g. - cortex, cerebellum, various nuclei of the hypothalamus, spinal cord and nuclei of the brainstem (involved in autonomic functions) • noradrenergic afferences of neocortex and hippocampus are exclusively LC-projections

Answer 33

• LC is innervated by CRF-ergic afferences (amongst others), e.g. from n. paragigantocellularis, n. prepositus hypoglossi) • CRF-axon-terminals possess synapses on dendrites of catecholaminergic neurons • release of CRF in or in vicinity of the LC activates noradrenergic neurons • integration of autonomic functions, behaviour and anxiety

Answer 34

• afferences - nucleus praepositus hypoglossi - nucleus gigantocellularis • efferences - brainstem, both mesencephalon and rhombencephalon - cortex - cerebellum - thalamus - hippocampus - hypothalamus - spinal cord

Answer 35

• immortalised cell lines • primary cells • organotypical tissue culture • explants (e.g. hypothalamus) • isolated organs • intact organism

Answer 36

immortalised cells • ‚unlimited‘ cultivation • results might not be applicable to ‚normal‘ cells primary cell culture • usually fetal tissue • enzymatic digestion of tissues, cells become dispersed • three dimensional structure is lost • artificial medium

Answer 37

organotypic tissue culture • stable for weeks • three dimensional structure is kept intact explants • stable for hours or days under static conditions or perifusion • three dimensional structure is kept intact

Answer 38

Set a hypothesis and design an experiment/experiments to test it • what parameters need to be measured? • how will that be done? - species, strain, genetic modification - number(statistics!) - technique(s) - surgery - methods to measure parameters of interest - pharmacological intervention

Answer 39

• best possible design!!! • least invasive technique; optimised pain control • best equipment available for surgery • decent technical execution - experience of the experimenter - habituation of the animals to the experiment

Answer 40

guiding principles for more ethical use of animals in testing • replacement: methods which avoid or replace the use of animals in research • reduction: use of methods that enable researchers to obtain comparable levels of information from fewer animals, or to obtain more information from the same number of animals • refinement: use of methods that alleviate or minimize potential pain, suffering or distress, and enhance animal welfare for the animals used

Answer 41

• species - comparability - availability - size - costs • strain - ‚healthy‘ or with metabolic/endocrine defect - ability to learn - ... • transgenic - tissue specific or general - inducible - ...

Answer 42

• techniques - microinjections into the central nervous system - other ways of application (i.v., i.p., s.c., oral, implantation of drug-carriers/dispensers ...) - electrical stimulation of neurons • substances - receptor agonists or antagonists (important for physicians: function tests) - hormone antibodies - antisense Oligonucleotides - RNA Interference (RNAi), shRNA - other drugs Surgery/other interventions • examples: lesions, food / water restriction, sleep deprivation, stress, ...

Answer 43

• tests whether ACTH (and consequently release) can be induced • performed to test for anterior pituitary insufficiency

Answer 44

• tests whether ACTH (and cortisol), growth hormone and prolactin can be stimulated

Answer 45

former pregnancy test: • HCG in urine of pregnant women induces release of spermatocytes in frogs and ovulation in rabbits

Answer 46

• measurement of metabolic and endocrine parameters - hormones - body weight, food- and water intake - body temperature, heat production - ... • measurement of cardiovascular and respiratory parameters - blood pressure - heart rate - ... • monitoring of neuronal activity - microdialysis - electrophysiology • behavioral experiments - motivation - learning, memory - anxiety - locomotion - ...

Answer 47

• measurement of heat dissipation -> determination of heat production → energy expenditure with the help of • Thermonetics Seebeck Envelope Calorimeters(SEC) • or the ‚PMC‘

Answer 48

• sufficient anesthesia and analgesia • inhalation or injection anesthesia • not longer than necessary • in neuroendocrinology usually experiments in awake (freely moving) animals

Answer 49

Guide cannula, Dummy canula, Internal cannula

Answer 50

• possible in awake (freely moving) animals • little trauma • frequent sampling possible - monitoring of time courses - reduction of animal numbers • drug application through microdialysis probe possible • dialysis of interstitial fluid • monitoring of neurotransmitter release • analysis by - high performance liquid chromatography (HPLC) (e.g. catecholamines) - immunoassays(e.g.peptides)

Answer 51

• Cre-Recombinase (cyclization recombination) from bacteriophage P1 • Cre catalyses recombination between two loxP- sequences (locus of X-over P1) (‚flanked by loxP‘ = ‚floxed‘) • same direction/orientation loxP: excision • opposite direction/orientation loxP: inversion

Answer 52

Mouseline 1 • Cre is under the control of a cell/tissue specific promotor Mouseline 2 • target gene is floxed Crossing mouseline 1 x mouseline 1 -> floxed gene is excised by Cre

Answer 53

ligand-inducible Cre-recombinase • e.g. by fusion of Cre with a modified ligand binding domain for the estrogen receptor; this domain is binding tamoxifen (synthetic anti-estrogen) • only upon binding of tamoxifen modified estrogen receptors translocate cytoplasm to nucleus • estrogen receptor associated Cre excises floxed gene

Answer 54

• DA neurons in the VTA will express a light-sensitive protein → the blue light-activated cation channel-rhodopsin-2 (ChR2) • light stimulation through a laser connected to an implanted optic fiber will determine dopamine release into the Nucleus accumbens

Answer 55

• receptors which can only become activated by a synthetic substance (Designer Receptor Exclusively Activated by Designer Drugs (DREADD)) • allows activation of non-natural (designed) G-protein receptors (developed by mutagenesis) with a high spacial and temporal resolution • activation by low molecular weight synthetic, but not natural, ligands (e.g. Clozapine N- oxid (CNO) in designed muscarinergic receptors)

Answer 56

Expression of a stimulatory DREADD (hM3Dq) in Agouti related protein (Agrp) expressing cells (hM3Dq depolarises neurons via Gq pathway) • Agrp-IRES-Cremice • Cre-recombinase–dependent adeno-associated virus (AAV) with hM3Dq–construct (fusioned with mCherry) (AAV-hM3Dq-mCherry) • stereotaxic injection of AAV-hM3Dq-mCherry in the ARC of AgRP-Ires-Cre mice

Answer 57

direct calorimetry • determination of dry heat loss indirect calorimetry • determination of oxygen consumption of an organism • calculation of energy expenditure: energy expenditure = oxygen consumption × caloric equivalent • caloric equivalent can be calculated from respiratory quotient (RQ) (necessary when food composition is unknown) IDEALLY, BOTH METHODS ARE USED SIMULTANEOUSLY

Answer 58

Advantage • direct und exact method • no need to make assumptions • if no heat storage takes place: heat production = metabolic rate Disadvantage • elaborate experimental setting, e.g. to keep environmental temperature constant • equipment is expensive (and for mice and rats not commercially available anymore) • evaporative heat loss is not measured

Answer 59

• Radiation (R) dependent on temperature difference between animal and calorimeter and surface characteristics • Convection(C) transfer via movement of liquid or gas • Conduction (K) by direct contact – of little importance in calorimetric systems, often avoided by construction details • Evaporation(E) heat loss by evaporation of water (evaporative heat loss, EHL) (~ 2,43 kJ/g = ~580 cal/g) • R + C + K = DHL (dry heat loss) • DHL + EHL = THL (total heat loss)

Answer 60

• if (like usually in a calorimeter) no physical work is taking place (basal metabolic rate), heat production (HP) equals metabolic rate (MR) HP = MR • according to the First law of thermodynamics, when no heat is stored: MR = HP = THL

Answer 61

two general principles • compensation of the measuring effect - phase transformation (Lavoisier and Laplace) - thermoelectric compensation (Peltier elements) • measuring of a difference in temperature (temporal or spacial) - heat flow from the calorimeter is conveyed through a solid body Solid body consists of thermoelements or they are attached/part of it (spacial) (our system) - temperature change over time (temporal) (tea cup calorimeter)

Answer 62

• a temperature difference between two dissimilar electrical conductors or semiconductors produces a voltage difference at the junctions of the two substances (Seebeck effect) • a thermopile consists of some/many (thermo)couples of semiconductors or metals with different thermoelectric coefficient • thermocouples are connected usually in series

Answer 63

R= U / I P =U * I -> P = U2 / R

Answer 64

• total body mass • lean body mass • a function of body mass (e.g. 3⁄4 power of body mass) • regression analysis of energy expenditure against body composition •...

Answer 65

• to eliminate influences of body size variation on energy expenditure, data can be related to the 3⁄4 power of BW • appropriate for many species incl. rats • however only, when animals are adult and have a normal body composition (the assumption is made, that all tissues have an equivalent metabolic demand) • better, but only feasible when a large number of animals (and experiments) is available: regression analysis of energy expenditure against body composition data

Answer 66

- Core body adiposity (Hyperglycaemic action) - Diabetes-like metabolism (Hyperglycaemic action) - Arterial hypertony (Hypertonic action) - Moon face, central obesity (Hypertonic action) - Immune suppression (immunosuppressive action) - Skin atrophies, striae rubrae (Proteolytic & feedback effects) - Osteoporosis (Proteolytic & feedback effects) - Muscle fatigue (Proteolytic & feedback effects) - Depression

Answer 67

- Anorexia (Hyperglycaemic action) - Spontaneous hypoglycaemia (Hyperglycaemic action) - Hypotonia (Hypertonic action) - Osteoporosis (Hypertonic action) - Feaver / autoimmune diseases (immunosuppressive action) - Skin pigmentation (also of mucosa) (Proteolytic & feedback effects) - Muscle and joint pain (Proteolytic & feedback effects) - Fatigue, loss of appetite

Answer 68

- are highly lipophilic (Poor solubility in blood / good membrane passage)

Answer 69

- Capsule - Cortex – produces steroids - Medulla – produces catecholamines

Answer 70

Co-factor (anabolic) - NADPH

Answer 71

CRH: Corticotropin releasing hormone; corticoliberin - 41 AA long peptide - made in the PVN of the hypothalamus (pulsatile circadian and/or stress-induced) ACTH: Adrenocorticotropic hormone; adrenocorticotropin - 39 AA long peptide - Cleavage product of proopiomelanocortin (POMC) - made in the frontal lobe of the pituitary (pulsatile circadian and/or stress induced)

Answer 72

- binds in blood to transcortin - acts similar to glucagon and opposite to insulin - anabolic on the heart (mehr Gluconeogenesis, mehr Glycogenolysis und weniger Glucose uptake) - catabolic on the muscle (mehr Proteolysis, weniger Glucose uptake) - catabolic on fat cells (mehr Lypolysis, weniger Glucose uptake) - increases the addiction risk - a multi-rythmic hormone

Answer 73

- biosynthesis in the pineal gland (epiphysis) - "Hormon mit Taktgefühl" -> SCN controls the rythmic secretion -acute suppression of melatonin levels by lights

Answer 74

- 41aa long - Cleavage product of a 196-aa prepro-hormone - Origin: parvocellular neuroendocrine cells of the PVN - Target: eminentia mediana - But also: production in the placenta Target: labor induction at the end of pregnagncy

Answer 75

- (pyro)Glu-His-Pro-NH2 - Cleavage product of a 242-aa prepro-hormone - Origin: medial neurons of the PVN - Target: anterior pituitary - But also: production in gastrointestinal system and pancreas Target: modulation of epithelial transport and ß-cell maintenance

Answer 76

- pyroGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro- Gly-NH2 - Cleavage product of a 92-aa prepro-hormone - Origin: nucleus preopticus - Target: eminentia mediana - But also: production in placenta and gonads Target: regulation of tumor development (mammary, ovary, prostata, endometrium)

Answer 77

Wake phase - Off: VLPO, eVLPO - On: LC, TMN, Raphe Sleep phase - On: VLPO, eVLPO - Off: LC, TMN, Raphe

Answer 78

Orexin A - 33 aa Orexin B - 28 aa Targets: Appetite, Thermogenesis, Wakefulness -> Orexin deficiency causes narcolepsy -> Orexin acts as a sleep switch

Answer 79

• Many hormones show multiple rhythms (e.g. cortisol). • The circadian rhythm center is the SCN. • Melatonin is SCN- and light-regulated. • The main hormonal axes show circadian and pulsatile rhythmicity. • Sleep/wake centers of the CNS: VLPO, LC and Orexin neurons. • Orexin deficiency causes narcolepsy.

Answer 80

- in contrast to cortisol a primarily behavior-driven hormone

Answer 81

→ weight loss → hair loss → diarrhea → heat intolerance → tachycardia → HAND TREMOR → ANXIETY → INSOMNIA

Answer 82

→ weight gain → dry brittle hair → dry skin → cold intolerance → muscle cramps → constipation → irregular cycles → DEPRESSION → MEMORY PROBLEMS -> Usually all reversible after normalization of thyroid hormone levels.

Answer 83

Brain - Development - Function - Motor Skills - Hearing - Color Vision Pituitary - Prolactin Regulation (Lactation) - Growth Hormone Synthesis Cardiovascular - Heart Rate - Contractile Force Metabolism - Temperature Regulation - Basal Metabolic Rate - Fat and Glucosemetabolism Bone - Strenght

Answer 84

• prevalence of 1 in 3600 newborns • if not detected and treated immediately, mental retarda1on (cretinism) • reason for newborn screening since the 70s

Answer 85

• Special case of hypothyroidism: lack of iodine • often in 3rd world countries • extremely severe form of cretinism (as mother is also affected) • severe and irreversible mental retardation • muscle weakness • growth problem • deaf muteness • around 7 Mio affected each year • very tragic: could be completely avoided with iodinated table salt

Answer 86

Special case of hypothyroidism: iodine and selenium deficiency 3 deiodinases (selenoenzymes) regulate tissue T3/T4 levels • iodine and selenium deficiency (Congo & Zaire) • extremely severe case of cretinism • selenium deficiency affects also other proteins, involved in redox-reactions (free radicals)

Answer 87

• Pax8-/- Knockout: no thyroid gland • no thyroid hormone after birth • severely growth retarded • deaf • ataxic • die after three weeks • all reversible by T4 treatment

Answer 88

• TRα1TRβ double KO have enlarged thyroid glands • clinical phenotype of hypothyroidism incl. growth retardation, despite high levels of T3/T4 • but in contrast to Pax8-/- viable and fertile • the absence of the hormone is worse than the lack of the receptors! • reason is the so called aporeceptor activity (apo-TR)

Answer 89

basal level (no TRs) -> activation (TR + T3) -> suppression (app-TR) -> no hormone

Answer 90

• Thyroid hormones act in all tissues, especially the brain. • The thyroid gland is tightly regulated by the HPT axis, thyroid hormone action is additionally fine-tuned by deiodinases and receptors. • Adult hyper/hypothyroidism has many symptoms, however most of these normalize after correct treatment. • Defects during development however can cause severe and irreversible damage (iodine deficiency and cretinism). • Thyroid hormone are extremely important in fetal development, during the first half of pregnancy they are provided by the mother. • Maternal hypothyroidism can be damaging for the offspring. • The effects of thyroid hormone are mediated by 2 receptors, which stimulate or suppress gene expression. Mutations in the receptor lead to thyroid hormone resistance with tissue specific phenotypes. • The cellular import of thyroid hormone occurs by specific thyroid hormone transporters. Defective transport e.g. in MCT8 can have severe consequences for affected individuals.

Answer 91

• embryo starts own production of thyroid hormone in second half of pregnancy, before that the mother needs to provide the hormone • pregnancy puts pressure on the maternal thyroid, as it needs to produce for 2 • if there is iodine deficiency or a preexisting hypothyroid condition (even if clinically not obvious), the thyroid might not be able to cope • 12.3% of all pregnant women have hypothyroidism, 2.6% hyperthyroidism • not routinely evaluated, so often undetected • maternal hypothyroidism can have severe consequences for fetal development • loss of few IQ points • associated with autism and epilepsy • often with vegan mothers that refuse fish or dietary supplements as non natural

Answer 92

• passive diffusion through cell membrane = wrong concept! • MCT8 is a very specific thyroid hormone transporter on neurons

Answer 93

• X-linked mental retarda1on due to defective MCT8 allele • no thyroid hormone import into brain possible

Answer 94

• over 1000 patients to date, mutations all over TRβ • mutated TRβ does not bind T3 => permanent apo-TR - high T3/T4, not suppressed TSH - functional TRα but defective TRβ - hyperthyroid in TRα tissues (tachycardia, high metabolic rate, high thyroid hormone in brain = ADHS, tremor, insomnia) - hypothyroid in TRβ tissues (high TSH/TRH, high cholesterol) - complex phenotype, often misdiagnosed

Answer 95

• first case in 2012, after long search • to date over 30 patients identified • growth retardation, large head & short legs • cognitive and motoric defects • severe constipation All defects resemble hypothyroidism, but are limited to TRα tissues.

Answer 96

• synthesised and secreted in/by adipose tissue • many can act auto-, para- and/or endocrine • many are involved in glucose and/or lipid metabolism in the periphery • some possess central nervous actions, e.g. in energy homeostasis

Answer 97

- Visfatin, FGF21, Leptin, Adiponektin, NUCB2/Nesfatin

Answer 98

- food and water intake - energy expenditure - blood pressure

Answer 99

- mainly synthesized by visceral adipose tissue • can (most likely) pass the BBB • also synthesised in brain (dogs)

Answer 100

• i.v. administration reduces plasma glucose independently from insulin secretion (also in mice with type 2 diabetes) • chronic ‘administration’ (visfatin adenovirus) slightly lowered plasma glucose and insulin • insulin-sensitiser Rosiglitazone (thiazolidindione) (a PPAR𝛾 agonist) increases visfatin mRNA expression (in obese OLETF rats) • stimulates glucose uptake in adipocyte- and muscle cell culture • suppresses glucose release from cultured hepatocystes; mediation via insulin receptor (IR) • activates IR signal transduction, however, does not compete with insulin

Answer 101

• detected in plasma (humans, mice), although primary amino acid sequence does not comprise a signal sequence • correlates with fat mass • also evidenced in nucleus and cytoplasm • explanation: visfatin is secreted by adipocytes via a highly-regulated non-classical secretory pathway

Answer 102

• visfatin increases the expression of proinflammatory cytokines and enzymes of prostaglandin synthesis (TNFalpha, IL1b, Cox2, mPGES1) in hypothalamus • indomethazin inhibits Cox (prostaglandin-synthesis enzyme) -> thermogenesis is mediated via prostaglandins • reduction of food intake is independent of prostaglandins

Answer 103

• highly expressed in liver, pancreas and white adipose tissue (WAT) • not expressed in the CNS

Answer 104

• induced by PPAR alpha activation in liver • PPAR alpha is activated by fasting, fatty acids, pharmacological ligands (fibrates) • induction by cold stress (most likely independent of PPAR alpha) • overexpression prevents diet induced increase in body weight • also expressed in WAT and brown adipose tissue (BAT); in WAT, expression is induced by PPAR gamma

Answer 105

• most important receptor: FGFR1c, expressed in many tissues • co-receptor betaKlotho is needed for binding at the FGFR1c • betaKlotho expression only in distinct tissues (amongst others in liver, WAT, pancreas, testes) -> tissue specific action • both FGFR1c and betaKlotho are expressed in hypothalamus

Answer 106

• effects in CNS and periphery • CNS effects are hardly investigated • can pass the BBB • no expression in CNS

Answer 107

• induces lipolysis (unequivocal findings), hepatic fatty acid oxidation, ketogenesis • blocks growth hormone signal transduction • improves insulin sensitivity and reduces plasma insulin, glucose, triglycerids

Answer 108

• induces PPAR gamma receptor co-activator PGC-1alpha in the liver PGC1alpha is a transcriptional regulator of metabolism PGC1alpha participates in TRANSDIFFERENCIATION OF CELLS IN THE WAT INTO BAT(LIKE) • s.c. application INCREASES THERMOGENESIS (UCP1 upregulation in WAT and BAT), fatty acid oxidation is increased (reduction of respiratory quotient (RQ)) • s.c. administration REDUCES BODYWEIGHT, adipose tissue in particular • s.c. administration does not affect food intake • i.c.v. administration INCREASES THERMOGENESIS and FOOD INTAKE, bodyweight and body composition unaffected • s.c. application INCREASES AGRP AND NPY EXPRESSIONin hypothalamus – is discussed as compensation of increased thermogenesis • FGF21 SENSITIES FOR TORPOR and reduces physical activity (hungry/underweight animals?)

Answer 109

• data on direct effects of FGF 21 on WAT lipolysis and BAT thermogenesis are unequivocal • distinct functions of FGF 21 in obesity and fasting? • prolonged fasting: FGF 21 -> thermogenesis down regulation • well nourished condition or obesity: FGF 21 -> thermogenesis upregulation • pharmacological activation of PPAR (which is physiologically activated e.g. by fasting): -> induction of hepatic FGF 21 -> body temperature downregulation

Answer 110

• precursor: NUCB2/nesfatin • synthesized in white adipose tissue (and elsewhere) • can cross the blood-brain-barrier (BBB)

Answer 111

expressed (among other regions) in • hypothalamus (ARC, PVN, SON, LH) • limbic system(NAc, amygdala, VTA) • brainstem (NTS, dorsal motor nucleus of the vagus)

Answer 112

• located in secretory vesicles in perikarya, but not in axon-terminals → dendritic release (autocrine or paracrine action?)

Answer 113

• involved in the regulation of food and water intake and also energy expenditure: • CNS application reduces food intake • application of nesfatin-1 antibody (CNS) increases food intake

Answer 114

• precursor of nesfatin-1 • first discovered in human acute lymphoblastic leukemia cell line (KM3) and, because of its characteristic features, originally named DNS binding/EF-hand/acidic amino rich region (NEFA) • NUCB2’s EF hand domains can bind Ca++ and thus, as a golgi resident protein, is implied in Ca++ homeostasis • ‘rediscovered’ in hypothalamus of rodents

Answer 115

• some neurons in PVN and ARC respond to nesfatin-1 • increases c-Fos expression in PVN, ARC, SON, locus coereuleus, raphe pallidus, NTS, ventrolateral medulla

Answer 116

• nesfatin-1 induces Ca2+ influx – can be blocked by pertussis toxin → G-protein coupled receptor, not identified yet

Answer 117

• in hypothalamus: interaction of NUCB2/nesfatin and melanocortin (MC)-system - melanocortin receptor (MC) 3/4 blockade abolishes nesfatin-1 induced anorexia and its effects on blood pressure - i.c.v. administration of α-MSH increases NUCB2/nesfatin expression in PVN • however: anorexigenic effect of nesfatin-1 is not dependent on direct agonistic activity at the MC-receptors • MC systems of hypothalamus and brainstem are involved in thermogenesis

Answer 118

• nesfatin-1 and oxytocin are often/mostly co-localized • oxytocin reduces food intake • nesfatin-1 depolarises oxytocinergic neurons • nesfatin-1 stimulates oxytocin-release from magnocellular and parvocellular PVN neurons, these project to the NTS • blockade of oxytocin-receptors inhibits nesfatin-1 effects on food intake and blood pressure • α-MSH induces dendritic release of oxytocin (via a Ca2+-dependent mechanism)

Answer 119

Nesfatin-1 recruits the melanocortin system to increase energy expenditure - Nesfatin 1 increases thermogenesis in brown adipose tissue - Nesfatin 1 Ab administration into the PVN increases food intake and decreases energy expenditure

Answer 120

• identified in 1994 by Zhang et al. • synthesized in white adipose tissue (and elsewhere) • can cross the blood-brain-barrier (BBB) • feedback signal from adipose tissue to brain • crucially involved in (longterm) bodyweight regulation - increases energy expenditure

Answer 121

• ob/ob mouse -> mutation in leptin-gene • db/db mouse, S1138 mouse -> mutation in leptin-receptor gene • fa/fa (Zucker) rat -> mutation in leptin-receptor gene

Answer 122

• characterized by Coleman before mutation was identified - down regulation body temperature - down regulation energy expenditure - upregulation food intake - downregulation immune system - downregulation fertility • Coleman performed parabiosis experiment

Answer 123

• members of class I cytokine receptors • different isoforms - Ob-Rb o longest isoform o fully functional signaltransduction (all pathways) o expressed in hypothalamus (e.g. ARC) - other isoforms (Ob-Ra, c, d) o differ in length of intracellular domain o expressed in hypothalamus, chorioid plexus, various peripheral organs o blood-brain-barrier (BBB) transport protein, but longer forms possess also certain signal transduction capabilities (at least theoretical) - soluble isoform (Ob-Re) o shortest isoform, modulates circulating leptin levels

Answer 124

• central nervous administration of leptin reduces body weight • i.c.v. administration is more potent than peripheral application

Answer 125

• participation of ObR • however: also involvement of another transport system • saturable • temperature dependent • specific • serum-leptin is proportional to adipose tissue • significant correlation between CSF- and serum-leptin - in lean - but not in obese humans o in obese, CSF/serum quotient decrease • saturation of BBB transport at ~ 25 ng/ml • higher serum levels do not lead to proportional increase in CSF

Answer 126

• develops with increasing adipose tissue -> reduction of leptin transport across the BBB -> peripheral application of leptin becomes ineffective • central nervous application remains active • additionally, centralnervous leptin resistance is discussed

Answer 127

• central nervous leptin target area

Answer 128

in humans too: brown-adipose- tissue activity as assessed by PET–CT with 18F-FDG

Answer 129

Intranasal application can circumvent the blood brain barrier

Answer 130

- Leptin i.n. reduces body weight and food intake in lean and diet induced obesity (DIO) animals -> Leptin treatment doesn't work in "normal" obesity -> useful to treat lipodystrophy

Answer 131

• 5 known types of melanocortin receptors • MC3-5 are expressed in CNS • MC4 is widely distributed within the CNS (e.g. cortex, thalamus, brainstem, spinal cord, amygdala, hypothalamus) • within hypothalamus: ARC, PVN, DMN, VMN, MPO...... • distribution indicates an involvement of MC4 in the control of food intake • MC4-/- -mice develop hyperphagia, hyperinsulinemia, hyperglycemia and obesity • MC4- and POMC-mutations are associated with obesity in humans • importance of MC3 for the regulation of food intake and bodyweight is less clear

Answer 132

Ligands for melanocortin-receptors are (amongst others) products of the proopiomelanocortin (POMC) gene

Answer 133

• alpha-MSH is (a) physiological ligand of MC3 and MC4 - anorexigenic action • centralnervous application of ACTH reduces food intake • ACTH binds to MC4 with similar affinity as alpha-MSH

Answer 134

• normally only expressed in skin • acts in skin as MC1-receptor antagonist -> blocks alpha-MSH-action • in Ay, Avy, Aiy, Asy –mice, ubiquitous expression, incl. CNS • acts in CNS at MC3- and MC4-receptors - expression in hypothalamus (PVN, VMH, DMN and nuclei in medial hypothalamus) -> blocks alpha-MSH-action • induces - obesity - hyperglycemia - hyperinsulinemia - increases longitudinal growth • expressed physiologically in the ARC of the hypothalamus • acts as an antagonist for alpha-MSH at MC3- and MC4-receptors • downregulated in well fed animals • increased expression as consequence of low leptin

Answer 135

• belongs to the pancreatic polypeptide (PP) family • potently stimulates food intake and decreases energy expenditure via interaction with the noradrenergic system • important for food intake: - NPY Y1 receptor - NPY Y5 receptor • NPY-synthesizing neurons are located e.g. in - brainstem (e.g. LC) - hypothalamus (ARC, DMN) - in the ARC, NPY is colocalized with AgRP • hypothalamic NPY-neurons are involved in the regulation of food intake - NPY inhibits BAT thermogenesis via reduced SNS outflow - NPY increases adipogenesis and decreases lipolysis via reduced sympathetic outflow

Answer 136

- Acute i.c.v. administration of NPY increases food intake - Chronic PVN administration of NPY increases food intake and promotes body weight gain and adiposity - NPY in the Arc of WT and NPY-/- mice affects TH hydroxylase expression in PVN and LC

Answer 137

- Food intake suppresses NPYa mRNA expression of the hypothalamus in Nile tilapia

Answer 138

• hungersignal • increases pre-prandial (= before a meal) • synthesized and released in gastrointestinal system • circulating ghrelin is reduced in obesity • exists in two forms: acyl- and desacyl ghrelin • both act via ghrelin receptor 1a

Answer 139

b) increases blood pressure

Answer 140

d) Overproduction of growth hormone during adulthood

Answer 141

e) obesity in ob/ob mice can be treated by leptin administration

Answer 142

b) The basal secretion of melatonin is age-dependent