Neuroendocrinology Flashcards

1
Q

Hormones - definition

A
  • highly potent specialised organic molecules which control biological functions by interacting with specific receptors on/in responsive cells
  • traditional definition: hormones are synthetised within specialised endocrine glands, secreted into circulation and to act at their target cells
  • more recent, broader, definition: hormones are synthetised in tissues, secreted into circulation and to act at their target cells
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2
Q

Hormones - two different principles

A

• involvement in homeostatic control (e.g. uptake and release of carbohydrates, proteins, fatty acids, electrolytes, water in tissues)
• morphogenetic actions (e.g. control of changes during growth, differentiation, development)

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3
Q

Example of hormone actions

A

• control of enzyme activity
• control of gene expression
• regulation of transport across membranes
• control of the secretion of other hormones

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4
Q

Classification based on chemical nature/structure

A
  • protein- and peptide hormones
  • aminoacid-derivatives
  • steroids
  • fatty acid derivatives, retinoid acid…
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5
Q

“Classical” definitions

A

Hormones
• synthesis in endocrine cells
• release into circulation
• act at specific receptors

Neurotransmitters
• synthesis in neurons
• localized in presynapsis
• release triggered by neuronal activity
• act at specific receptors (post- or presynaptic)

BUT NEURONS CAN ALSO HAVE ENDOCRINE ACTIONS

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6
Q

Peptide hormones

A

• synthesis in a great number and variety of cells, including neurons
• short biological half life
- some are also neurotransmitters

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7
Q

Different ways of secretion

A
  • autocrine action
  • paracrine action
  • Neuroendocrine action -> neuron secretes peptide hormone into bloodstream
  • endocrine action: neurosecretory cell -> hormone -> endocrine tissue -> hormone -> target cell (can inhibit neurosecretory cell via negative feedback)
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8
Q

“Classical” neurotransmitters vs Peptide neurotransmitters (neuropeptides)

A

“Classical” neurotransmitters
• acetylcholine
• aminoacids
• monoamines
• noradrenaline
• adrenaline
• dopamine
• serotonine (5-HT)

Peptide neurotransmitters (neuropeptides)
• neuropeptide Y (NPY)
• opiods
• hypothalamicreleasinghormones (CRF, TRH, LHRH…)
•…

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9
Q

Neuroendocrinology

A

• many physiological processes are controlled by both nervous and endocrine systems
• interactions serve to coordinate both systems
• occasionally, the same substances are involved in both systems

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10
Q

Hypothalamus - pituitary - organ systems

A

• central endocrine system in vertebrates
• controlsmanyphysiologicalprocesses:
- reproduction
- growth
- intermediary metabolism
- metamorphosis
- behaviour
- osmotic balance
- stress reaction
- blood pressure
- immune response
- …

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11
Q

Hormones of the hypothalamus-pituitary system

A

Hypothalamus
• thyreotropin releasing h. (TRH)
• gonadotropin releasing h. (GnRH, LHRH)
• corticotropin releasing h. (CRH, CRF)
• growth hormone releasing h. (GHRH)
• somatostatin (SS,GHIH)
• PROLACTIN RELEASING H. (PRH)
• prolactin inhibiting H (PIH)

Pituitary, anterior lobe (adenohypophysis)
• adrenocorticotropic h. (ACTH)
• thyroid-stimulating h. (TSH)
• follicle-stimulating h. (FSH)
• luteinizing h. (LH)
• growth h. (GH)
• prolactin (PRL)

pituitary, posterior lobe (neurohypophysis)
• oxytocin
• (arginine) vasopressin, antidiuretic h. (AVP,ADH)

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12
Q

Hypothalamus

A

• afferent and efferent connections with various brain structures
• control of pituitary hormones
• feedback regulation
• integration of internal and external input

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13
Q

Pituitary (hypophysis)

A

• best investigated neurosecretory system
• consists of two functional and structural differing parts
neural ectoderm -> neurohypophysis = posterior lobe = eminentia mediana
outer/oral ectoderm (German: epidermal) -> adenohypophysis = anterior lobe

DEVELOPS FROM BOTH NEURAL AND ECTODERMAL TISSUE

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14
Q

Endocrine hypothalamus (magnocellular neurons)

A

• cell bodies in n. supraopticus (SON) and n. paraventricularis (PVN)
• mainly projecting to the posterior lobe of the pituitary (neurohypophysis)
• contain antidiuretic hormone (ADH) and oxytocin

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15
Q

Neurohypophysis - how does it work?

A

similar to neurons
• neurons in the hypothalamus (SON und PVN) produce ADH and oxytocin
• peptides are packaged into vesicles
• axonal transport to the posterior lobe of the pituitary
• release from axon terminals

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16
Q

Oxytocin

A

• induceslabour
• elicits milk ejection reflex
• affects behaviour (social interaction, reproduction, food intake)

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17
Q

Antidiuretic hormone (ADH)

A

• most import antantidiuretic hormone
• increases water reabsorption in the kidneys
• hereby participates in osmoregulation
• also known as (arginine)-vasopressin (AVP)

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18
Q

Diabetes insipidus (centralis)

A

• production and/o rrelease of ADH is reduced
• symptoms:
- polyuria->polydipsia
- serum Na+ upregulated, osmolality upregulated
- urine Na+ downregulated, osmolality downregulated

DI renalis (rare): kidneys do not respond to ADH

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19
Q

Hypothalamus - adenohypophysis system

A

Adenohypophysis is under hypothalamic control
• hypothalamic neurons synthetize releasing and inhibiting factors/hormones
• release factors from axons into capillaries of the pars tuberalis in the pituitary
• capillaries lead to portal veins
• transport via portal veins to adenohypophysis
• control of pituitary hormone release

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20
Q

Endocrine hypothalamus (parvocellular neurons)

A

• cells mainly contain hypophysiotropic hormones, which control adenohypophysis
• releases hormones into the portal system
• cell bodies are located in PVN and SON (like the magnocellular neurons)

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21
Q

Other neuroendocrine nuclei of the hypothalamus

A

• anteriorhypothalamus
• N. periventricularis
• N. arcuatus(ARC)
• N. preopticusmedialis

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22
Q

Prolactin-inhibiting hormone = dopamine

A
  • neurotransmitter and (here:) hormone
  • inhibition of prolactin secretion
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23
Q

Prolactin (PRL)

A

• controls the development of mammary glands
• stimulation of milk production

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24
Q

Gonadotropin-releasing hormone (GnRH)

A

• 10 AA, multiple isoforms
• stimulates luteinizing (LH) and follicle stimulating hormone (FSH) release
• mainly synthetized in n. preopt. and n. arcuatus (ARC)
• aka gonadoliberin, gonadorelin, luteinizing hormone releasing hormone (LHRH )

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25
Q

Luteinizing hormone (LH)

A

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

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26
Q

Follicle stimulating hormone (FSH)

A

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

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27
Q

Growth hormone-releasing hormone (GHRH)

A

• 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

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28
Q

Somatostatin (SS, GHIH)

A

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

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29
Q

Growth hormone (GH)

A

• 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

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30
Q

Growth hormone - diseases

A
  • 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
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31
Q

Thyrotropin-Releasing Hormon (TRH)

A

• 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

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32
Q

Thyreocyte stimulating hormone (TSH)

A

• control of thyroid hormone synthesis

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33
Q

Thyroid hormones (T3, Thyroxin (T4)) - actions

A

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

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34
Q

Corticotropin-Releasing hormon (CRH, CRF)

A

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

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35
Q

ACTH (Corticotropin) - actions

A

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

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36
Q

Glucocorticoid - actions

A
  • increased in stress
  • hyperglycemic
  • inhibit synthesis of proteins and fat
  • inhibit immune system
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37
Q

Cortisol related diseases

A

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

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38
Q

Cortisol feedback

A

• 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)

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39
Q

CRF - physiological functions

A

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

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40
Q

CRF - peripheral distribution

A

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

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41
Q

CRF - centralnervous distribution

A

• 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

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42
Q

CRF - Distribution in subcortical structures

A

• 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

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43
Q

CRF - system

A

• 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.)

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44
Q

CRF - types of receptors

A

• 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

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45
Q

CRF - receptors: central nervous distribution

A

• 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

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46
Q

CRF - receptor-subtypes

A

• 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-?

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47
Q

CRF - receptor subtypes: central nervous distribution

A

• 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

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48
Q

CRF - gastrointestinal effects

A
  • down regulation gastric acid secretion
  • down regulation gastric emptying
  • down regulation gastrointestinal motility
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49
Q

CRF - cardiovascular effects

A
  • 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?

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50
Q

CRF - metabolic effects

A
  • upregulation physical activity
  • upregulation O2 consumption
  • upregulation plasma-glucose
  • upregulation glucagon
  • mediated via sympathetic nerve
  • !independent from HPA!
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51
Q

CRF - behavior

A
  • 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!
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52
Q

CRF - pathophysiological significance

A

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

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53
Q

Pathological DEX/CRF test in depression

A

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

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54
Q

CRF - related peptides

A

• can possess different/distinct actions
dependent on
- distribution
- receptor affinity

• sauvagin
- philomedusa sauvagii
• urotensin I, urotensin II
- teleosteer
• urocortin, urocortin II
- mammalia

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55
Q

Locus coerulus

A

• 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)

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56
Q

Locus coerulus - neuroanatomy

A

• 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

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57
Q

Locus coerulus - anatomy/function

A

• 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

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58
Q

Locus coerulus - projections

A

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

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59
Q

Model systems

A

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

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60
Q

Cell culture

A

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

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61
Q

Organotypic tissue culture, explants

A

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

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62
Q

Designing an animal experiment

A

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

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63
Q

Performing an animal experiment (here in particular: involving surgery)

A

• 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

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64
Q

The “3R” by Russel and Burch (1959)

A

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

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65
Q

Selection of the appropriate animal model

A

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

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66
Q

Manipulations of the endocrine system - Applications, stimulations

A

• 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, …

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67
Q

Pituitary function test (example): CRF test

A

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

68
Q

Hypothalamus function test: insulin-hypoglycemia test

A

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

69
Q

Human chorionic gondaotropin (HCG) - bioassay

A

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

70
Q

Animal experimental methods

A

• 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
- …

71
Q

Direct calorimetry

A

• measurement of heat dissipation
-> determination of heat production → energy expenditure

with the help of
• Thermonetics Seebeck Envelope Calorimeters(SEC)
• or the ‚PMC‘

72
Q

Surgery - anesthesia

A

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

73
Q

Microinjection

A

Guide cannula, Dummy canula, Internal cannula

74
Q

Microdialysis

A

• 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)

75
Q

Cre/loxP-recombination system

A

• 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

76
Q

Tissue specific knockout

A

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

77
Q

Conditional knockout

A

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

78
Q

Optogenetics to study the involvement of nesfatin-1 in “liking”

A

• 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

79
Q

DREADD-system

A

• 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)

80
Q

DREADD - example

A

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

81
Q

Direct vs indirect calorimetry

A

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

82
Q

Direct calorimetry - advantages and disadvantages

A

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

83
Q

Heat loss - different means of “transportation”

A

• 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)

84
Q

Determination of metabolic rate in a calorimeter

A

• 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

85
Q

Measuring principles of calorimeters

A

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)

86
Q

Thermoelectric effect, thermopile

A

• 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

87
Q

Calibration with an electric resistor

A

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

88
Q

Metabolic energy expenditure and heat loss can be related to

A

• 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
•…

89
Q

Kleiber’s law

A

• 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

90
Q

Morbus Cushing

A
  • 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
91
Q

Morbus Addison

A
  • 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
92
Q

Steroids - lipophil oder lipophob?

A
  • are highly lipophilic (Poor solubility in blood / good membrane passage)
93
Q

Adrenal anatomy

A
  • Capsule
  • Cortex – produces steroids
  • Medulla – produces catecholamines
94
Q

Cytochrome P450 oxidoreductase -> Cofactor?

A

Co-factor (anabolic) - NADPH

95
Q

The HPA axis

A

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)

96
Q

Cortisol

A
  • 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
97
Q

Melatonin

A
  • biosynthesis in the pineal gland (epiphysis)
  • “Hormon mit Taktgefühl” -> SCN controls the rythmic secretion
    -acute suppression of melatonin levels by lights
98
Q

Corticotropin-releasing hormone/ CRH (or CRF)

A
  • 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
99
Q

Thyreotropin-releasing hormone/ TRH (or TRF)

A
  • (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
100
Q

Gonadotropin-releasing hormone/GnRH (or LHRH)

A
  • 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)
101
Q

The flipflop model of sleep

A

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

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

102
Q

Orexin / hypocretin

A

Orexin A - 33 aa
Orexin B - 28 aa

Targets: Appetite, Thermogenesis, Wakefulness

-> Orexin deficiency causes narcolepsy
-> Orexin acts as a sleep switch

103
Q

Hormones -> Summary

A

• 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.

104
Q

Leptin

A
  • in contrast to cortisol a primarily behavior-driven hormone
105
Q

Symptoms of Hyperthyroidism

A

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

106
Q

Symptoms of Hypothyroidism

A

→ 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.

107
Q

Target Tissues -> Why are there so many symptoms?

A

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

108
Q

Congenital Hypothyroidism

A

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

109
Q

Endemic Cretinism

A

• 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

110
Q

Myxedemic Cretinism

A

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)

111
Q

Animal model for Cretinism

A

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

112
Q

TR double KO mice

A

• 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)

113
Q

TR aporeceptor activity

A

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

114
Q

Thyroid hormones -> Summary

A

• 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.

115
Q

Maternal Hypothyroidism

A

• 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

116
Q

T3/T4 Transporter

A

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

117
Q

Allan Herndon Dudley

A

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

118
Q

Resistance to TH (RTHbeta)

A

• 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

119
Q

Resistance to TH (RTHalpha)

A

• 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.

120
Q

Adipokines - defintion, functions

A

• 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

121
Q

Adipokines with known central nervous actions

A
  • Visfatin, FGF21, Leptin, Adiponektin, NUCB2/Nesfatin
122
Q

What are the central nervous actions?

A
  • food and water intake
  • energy expenditure
  • blood pressure
123
Q

Visfatin - CNS and BBB

A
  • mainly synthesized by visceral adipose tissue
    • can (most likely) pass the BBB
    • also synthesised in brain (dogs)
124
Q

Visfatin - blood glucose homeostasis

A

• 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

125
Q

Visfatin - secretion

A

• 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

126
Q

Visfatin - core body temperature

A

• 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

127
Q

FGF 21 - expression / localization

A

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

128
Q

FGF 21 - expression / induction

A

• 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

129
Q

FGF 21 - receptor - FGFR1c

A

• 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

130
Q

FGF 21 - effects

A

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

131
Q

FGF 21 - lipid and glucose metabolism

A

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

132
Q

FGF 21 - food intake and thermogenesis

A

• 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?)

133
Q

FGF 21 - a complicated story

A

• 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

134
Q

Nesfatin 1

A

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

135
Q

Nesfatin 1 - CNS - expression

A

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

136
Q

Nesfatin 1 - intracellular localisation

A

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

137
Q

Nesfatin 1 - food intake

A

• 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

138
Q

Nucleobindin 2 (NUCB2) - first description

A

• 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

139
Q

Nesfatin 1 - hypothalamus and more

A

• 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

140
Q

Nesfatin 1 - receptor

A

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

141
Q

Nesfatin 1 and the melanocortin system

A

• 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

142
Q

Nesfatin 1 and oxytocin

A

• 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)

143
Q

How does nesfatin-1 increase energy expenditure?

A

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
144
Q

Leptin

A

• 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

145
Q

Leptin - animal models

A

• 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

146
Q

ob-gene deficiency in mice (ob/ob)

A

• 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

147
Q

Leptin - receptors

A

• 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

148
Q

Leptin - central nervous actions

A

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

149
Q

Leptin - transport into CNS

A

• 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

150
Q

Leptin-resistance at the blood-brain-barrier (BBB)

A

• 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

151
Q

Arcuate nucleus (ARC) -> target area

A

• central nervous leptin target area

152
Q

white fat can turn brown

A

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

153
Q

Intranasal application

A

Intranasal application can circumvent the blood brain barrier

154
Q

Leptin intranasal application (mouse)

A
  • 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
155
Q

Melanocortin receptors

A

• 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

156
Q

Melanocortin receptor and POMC gene

A

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

157
Q

POMC processing products alpha-MSH and ACTH

A

• 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

158
Q

Agouti-protein (Agp)

A

• 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

159
Q

Neuropeptide Y (NPY)

A

• 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

160
Q

Neuropeptide Y administration

A
  • 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
161
Q

NPY and Nile tilapia

A
  • Food intake suppresses NPYa mRNA expression of the hypothalamus in Nile tilapia
162
Q

Ghrelin

A

• 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

163
Q

Central nervous application of corticotropin releasing factor (CRF)…
a) possesses antidepressant actions
b) increases blood pressure
c) induces milk ejection
d) induces hypothermia
e) increases food intake

A

b) increases blood pressure

164
Q

Acromegaly is caused by:
a) Overproduction of ACTH during childhood
b) Overproduction of growth hormone during childhood
c) Adrenal tumors during adulthood
d) Overproduction of growth hormone during adulthood
e) Adrenal tumors during childhood

A

d) Overproduction of growth hormone during adulthood

165
Q

Which of the following statements is correct?
a) ob/ob mice only become obese on feeding with high-fat diet
b) obesity in db/db mice can be treated by leptin administration
c) fa/fa (Zucker) rats have been developed by genetic manipulation
d) db/db mice have been developed by genetic manipulation
e) obesity in ob/ob mice can be treated by leptin administration

A

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

166
Q

Which statement on melatonin is WRONG?
a) Melatonin secretion is independent of the activity pattern
b) The basal secretion of melatonin is age-dependent
c) In shift workers, melatonin secretion is often suppressed
d) The duration of nocturnal melatonin secretion is age-independent
e) Melatonin has anti-oxidative action

A

b) The basal secretion of melatonin is age-dependent