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Anna's > CENTRAL PATHWAYS REGULATING ENERGY HOMEOSTASIS > Flashcards

CENTRAL PATHWAYS REGULATING ENERGY HOMEOSTASIS Flashcards

1
Q

Describe how the brain senses glucose

A

Through glucose excitatory and glucose inhibitory neurons

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2
Q

How can the hypothalamus sense nutrients

A

The hypothalamic arcuate nucleus has a fenestrated blood brain barrier meaning hypothalamic neurons have direct access to circulating metabolic cues

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3
Q

How does a glucose inhibitory neurone work?

A
  • Glucose enters the cell and is converted to ATP. The reduced ATP:ADP ratio causes INCREASED ACTIVATION OF AMPK
  • This inhibits the Cl- CHANNEL
  • There is neuronal depolarisation
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4
Q

Give evidence of what happens in obesity in terms of fuel sensing?

A

In obesity, POMC neurons lose their ability to sense glucose shown by the reduction in alpha MSH produced as a percentage of baseline at increasing glucose concentrations.

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5
Q

Another piece of evidence about nutrient fuel sensing in obesity in rats

A

Altered glucokinase mRNA in diet-induced obese rats study

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6
Q

Human obesity fuel sensing evidence

A

Altered glucose induced hypothalamic activation in obese versus normal humans on fMRI

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7
Q

How can fatty acid sensing take place?

A

Enzymes involved in fatty acid oxidation and lipogenic enzymes present in hypothalamic nuclei involved in appetite

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8
Q

How does fatty acid sensing take place overall?

A

Inhibition of CNS FAS reduces appetite → Thought to work via ARC neurons, increasing POMC and decreasing AGRP

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9
Q

How does fatty acid sensing take place molecular level?

A
  • Inhibition of FAS pathway→metabolites that mimic the fed state.
  • Malonyl-CoA inhibits CPT-1 reducing the entry of LCFA-CoA’s into the mitochondria.
  • This mechanism controls the switch from fatty acid to glucose oxidation.
  • Malonyl-CoA and Long chain fatty acid-CoA are metabolites that reflect energy status. →High in fed state
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10
Q

What experimental evidence is there for fat sensing?

A

ICV injection of Oleic acid decreases food intake. • Pharmacological or genetic inhibition of CPT-1 increases LCFA-CoA reduces NPY, appetite and body weight.

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11
Q

Evidence for how amino acids affect food intake

A

ICV leucine injections reduce food intake and decrease AGRP expression

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12
Q

How do amino acids sense?

A

Leucine activates mTOR→Phosphorylation of p70 S6kinase→ reduced appetite and increased insulin sensitivity

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13
Q

What non-hormonal way is there to communicate food eaten?

A

Stretch receptors in the stomach that communicate via the vagus nerve

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14
Q

Within the hypothalamus what are the stimulatory and inhibitory neutrons? What receptors do they have?

A

STIMULATORY (NPY/AGrP neurons)
INHIBITORY (POMC)
Both sets of neurons extend to other hypothalamic nuclei. They have Leptin receptors and MC3R.

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15
Q

What do NPY/ AGrP neutrons release? What is evidence for this?

A

GABA. Injection of GABA into the arcuate nucleus increases food intake

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16
Q

Where does Leptin signal

A

Inhibits NPY Y1/Y5 receptor

Stimulates POMC–> alphaMSH–> MC4 receptor

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17
Q

What do NPY deficient mice have?

A

Normal food intake and body weight

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18
Q

What do Y1 KO mice have?

A

Y1 KO mouse is moderately obese and hyperinsulinaemic but no hyperphagia. Y5 normal development but develop late onset obesity.

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19
Q

Which mutations have never been found in humans?

A

NPY/AgrP

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20
Q

What is AGRP?

A

Is an ENDOGENOUS ANTAGONIST of the MC4R that blocks the effects of ALPHA MSH from POMC.
It is expressed in the same neurons as NPY

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21
Q

Evidence concerning AGRP?

A

Icv AGRP causes increased food intake and energy expenditure, increased x18 in starvation

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22
Q

What happens in NPY/AGRP KO?

A

NPY/AGRP KO no changes. Important in day to day regulation? 3 papers say yes. Can get developmental compensation due to plasticity. Bewich 2005 used ataxia 3 to kill off AGRP neurons and result was lean hyperphagia phenotype. Same result using diphtheria toxin, minimal effects in neonates compared to adults

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23
Q

What does the Paraventricular nucleus do?

A

Incorporates autonomic responses with endocrine, connects sns to spinal cord–> regulation of respiratory quotient, BMR, thermogenesis, thyroid and adrenal axis. Trh neurons, wings vasopressin and oxytocin releasing.
Expresses Y1,5 MC3,4 receptors. Oxytocin neurons express melanicortin receptors and intra PVN injections reduced appetite. corticotrophim RH reduces appetite in PVN via CRH2R

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24
Q

What does the lateral hypothalamus do?

A

Is poorly characterised. Medial forebrain bundle passes through that connects forebrain with the mid brain.
Has 2 major OREXIGENIC neuropeptides = OREXIN and. MELANOCORTIN CONCENTRATING HORMONE in distinct neuronal populations

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25
Q

What is the dual centre hypothesis?

A

Damage to the ventromedial leads to hyperphagia and obesity. Therefore is the satiety centre.
Damage to the lateral hypothalamus leads to decreased food intake and body weight. Therefore is the feeding centre. Since superseded.

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26
Q

What is a craniapharyngioma?

A

Tumour that lies close to the pituitary and the hypothalamus (usually at a young age) which is normally benign but can cause neuro endocrine problems and obesity

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27
Q

What is the brain stem composed of?

A

medulla oblongata, pons and the midbrain

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28
Q

What are areas important for appetite regulation?

A

-area postrema (AP)
-dorsal motor nucleus of the vagus (DMV)
-nucleus of the solitary tract (NST). Vagus nerve inputs
AP lies directly above NST which is outside the protection of the BBB.

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29
Q

What does the vagus nerve do?

A
  • provides motor to the larynx and pharynx
  • sensory to ear, pharynx, larynx, trachea and oesophagus, thoracic and abdominal viscera.
  • inner ages gi tract down to the transverse colon(final part parasympathetic from splanchnic)
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30
Q

Which area of the brain stem is important in appetite regulation and what is it composed of?

A

The DORSAL VAGAL COMPLEX, composed of the AP (area postrema), NTS (nucleus of the solitary tract) and the DMV (dorsal motor nucleus of the vagus)

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31
Q

Where is the AP?

A

Lies directly above the NTS outside of the protection of the blood brain barrier

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32
Q

What does the NTS do?

A

Meal related afferents that travel via the VAGUS which terminates in the NTS. It also receives inputs from the area postrema

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33
Q

What is the dorsal motor nucleus of the vagus?

A

Arises from floor of 4th ventricle and is the area where parasympathetic that innervate GI tract originate.

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34
Q

Overall, how does the brain stem communicate?

A

Extensive reciprocal connections exist between the brain stem and the hypothalamic nuclei that control appetite. This means that peripheral signals can communicate to the hypothalamic feeding centre directly via the arcuate nucleus or indirectly via the brain stem.

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35
Q

Pancreatic polypeptide: where produced? What stimulates release?

A

PP cells of the Islet of langerhans. Release is stimulated by food intake and is proportional to the amount of calories injested.

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36
Q

What is pancreatic polypeptide part of?

A

The ileal brake that slows gastric emptying and decreases exocrine secretions

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37
Q

What does pancreatic polypeptide bind to?

A

To members of the y family, strongest to Y4

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38
Q

How does pancreatic polypeptide communicate?

A

Via vagus nerve and brain stem (VAGOTOMY studies and In situ hybridisation found in all areas of the DVC). IV PP decreased firing of vagus nerve. It could act via the AP/NTS to reduce feeding or gut motility via the DMV. But also via the hypothalamus, hence the y4 binding

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39
Q

What does pancreatic polypeptide lead to?

A

PP reduces expression of the hypothalamic signals of orexin and NPY by 60%
Has DOSE DEPENDENT ANORECTIC EFFECTS.

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40
Q

Where is ghrelin released?

A

A cells of the gastric fundus

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41
Q

For PP, what did the vagotomy studies show?

A

Sham and PP - reduced food intake. Vagotomy and PP, no effect on food intake.

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42
Q

What does ghrelin bind to?

A

GHS R1, especially found in the arcuate nucleus. Works via the blood stream and the brain stem.

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43
Q

Where is gherlin found? Evidence

A

NTS, AP, and DMV (brainstem) through cfos activity

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44
Q

What else does it require for action? How did you know that the Ghrelin was working?

A

Vagus nerve (through vagotomy studies and chili pepper), where afterwards unable to stimulate food intake. As it was able to stimulate GH release.

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45
Q

Evidence that ghrelin works in the hypothalamus?

A

If five rats mono sodium glutamate to destroy the ARCUATE nucleus then ability of GHRELIN to stimulate food intake is attenuated. If inject GHRELIN into rats then increased c fos activity in ARCUATE nucleus, dose dependent manner

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46
Q

What does ghrelin do? Evidence

A

Increases food intake. If injected into the ARC, PVN then increases food intake in a dose dependent manner.

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47
Q

Specifically which neurons is ghrelin found on?

A

Found on NPY/AGRP neurons and leads to the release of GABA into POMC

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48
Q

How do you activate and deactivate ghrelin?

A

GOAT is responsible for the binding of OCTANOIC ACID that leads to the ACTIVATION of GHRELIN
To inactivate des-aceyl GHRELIN

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49
Q

What receptors do POMC, NPY and AgRP bind to?

A

NPY - Y1/Y5 and is STIMULATORY
AGRP - MC4R and is INHIBITORY
POMC - MC4R and is STIMULATORY

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50
Q

Which is the active form of PYY and what does it bind to?

A

PYY3-36 and binds to Y2

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51
Q

Describe PYY. Where is it secreted? What does it cause? How does it act peripherally versus centrally

A

As you move distally in the gut more and more PYY is secreted, which causes:
- increased illeal fluid and electrolyte absorption
- increased pancreatic and gastric secretion
-decreased gastric emptying
-decreased gall bladder contraction
-peripheral vasoconstriction
-decreased GFR
-decreased plasma renin and aldosterone
BUT ACTS LIKE NPY CENTRALLY

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52
Q

When is PYY secreted? What factors such as obesity affected this

A

But PYY is secreted after meals.
Increased after an ideal resection eg for crohns or gastric bypass, Decreased in obesity
• From VAGOTOMY studies acts via the vagus nerve and the blood stream

  • Y2RKO mice are resistant to PYY
  • PYY thought to bind to Y2R and block the effects of NPY and AGRP
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53
Q

What does PYY act as? Evidence?

A

Seems to act like a ANOREXIGENIC hormone that decreases food intake. If injected into the ARCUATE nucleus then decreases food intake (intra ARCUATE antagonist blocks peripheral PYY)

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54
Q

What happens in Y2RKO mice?

A

They are resistant to PYY. PYY is thought to bind to Y2R and block the effects of NPY and AGRP

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55
Q

What is the problem with giving PYY?

A

It causes nausea and vomitting

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56
Q

What is the ob/ob mouse like?

A

It is the model of starvation - reduced growth and immune function, infertillity

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57
Q

What does leptin do in terms of hypothalamic neurons?

A

It activates POMC and inhibits ArRP and NPY, also activates the SNS and thyroid. Principally signals to arc, PVN, DMH, VMH and LH. (these genes express the early gene cfos in response to peripheral leptin)
Leptin specifically injected into the hypothalamus reduced endogenous cannabinoids. Defective leptin have increased cannabinoid levels. Then administration of cb1 antagonist then reduced food intake.

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58
Q

Which pathway does leptin involve

A

The Jak/ stat pathway since it has no intrinsic tyrosine kinase activity of its own so uses cytoplasmic associated kinases of the janus family.

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59
Q

One minor way that leptin and insulin are similar?

A

Both activate POMC neutrons

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60
Q

Give another way leptin affects the brain?

A

Neuronal firing, plasticity by modulating inputs. Leptin changes AFFERENT inputs to neurons and MAY CHANGE threshold for response for other key hypothalamic neurons to stimuli.

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61
Q

What phrase describes why leptin cannot be used as a weight control drug?

A

It is a hormone of absence

62
Q

What is an adipocyte factor? 4

A

Synthesised exclusively in fat, inproportional to the fat stores, signal to receptors in the hypothalamus to reduce food intake.

63
Q

Evolutionarily why might insulin be considered an adipostat factor?

A

In evolutionary animals, insulin was more about energy expenditure than homeostasis

64
Q

Unlike leptin what does insulin not circulate at levels proportional to?

A

Fat

65
Q

In what ways might insulin and leptin be considered similar?

A

In obesity, there is hyperleptinaemia and hyperinsulinaemia and resistance to their actions.

66
Q

Can insulin cross the blood brain barrier? Where does it then signal to?

A

Only attached to IR so is an active process. To mainly neurons, especially hypothalamic ARCUATE ones. Insulin receptor is expressed in most tissues in the body. In Cns, the highest expression is in the olfactory bulb, cortex and hypothalamus

67
Q

What does insulin do to hypothalamic neurons?

A

Insulin increases hypothalamic NPY mRNA expression and normalises the fasting decrease in POMC mRNA expression.

68
Q

What does insulin do to body weight? What shows that is essential for normal regulation of adiposity?

A

Reduces food intake but is hard to separate from effects of hypoglycaemia or hyperglycaemia, would need to keep patients euglycaemic. Central and persipheral administration leads to a marked reduction in food intake and energy expenditure. Mice lacking insulin receptor in brain have increased body fat content, it is ESSENTIAL FOR NORMAL REGULATION OF ADIPOSITY

69
Q

Adipostat plan

A
  1. Describe the four things that make an adipostat factor
  2. Describe leptin, leptin deficienty and perhaps leptin is the adipostat factor
  3. Describe leptin in relation to the 4 rules
  4. But leptin resistance. Hormone of absence, not anti-obesity, so not 100% adipostat factor
  5. Describe the effects of insulin on carbohydrate metabolism, what it is released in proportion to.
  6. Evolutionarily in the C. elegans. Describe whether insulin follows the 4 rules (has to be transported across BBB actively, where highest expression is, what the role in the CNS is)
  7. The leptin receptor versus the insulin receptor
  8. Conclude that there is cross talk but leptin may cause affect neuronal plasticity
70
Q

What does POMC undergo?

A

Post translational modification to form ACTH (then aMSH), as well as BLPH, JP and NT

71
Q

Where is POMC expressed?

A

ARC and NTS

72
Q

Where are the melanocortin receptors? 1-5

A

MCR1- melanocytes (coat colour)
MCR2 - adrenal cortex and adipocytes (ACTH selective)
MCR3- hypothalamus and LIMBIC system
MCR4 - hypothalamus, LIMBIC system,cortex, brain stem: FOOD INTAKE
MCR5- low in Cns but high in peripheral nervous system

73
Q

What two general sources of fuel does the CNS sense?

A

Stored fuels and available fuels

74
Q

What is AMPK? How is it activated?

A

Sensor of energy status and co-ordinates body processes with energy stores. Activated by increasing AMP and decreasing ATP. Activates catabolic pathways that increase ATP in states of negative energy such as fasting. It increases NPY/ AgRP expression

75
Q

What action to AMPK and MTOR have on each other?

A

AMPK inhibits MTOR

76
Q

What are the two colour pigments and what molecule causes either one or the other colour? What is a well known mutation of this?

A

Phaeomelanin is yellow and eumelanin is brown. This direction is alpha MSH and the other direction is Agouti. The agouti mouse which is yellow and fat due to agouti antagonising the binding to MCR1 and 4.

77
Q

What is the MCR4 KO mouse like?

A

Is obese and hyperphagic but has a normal coat colour. Could have therapeutic ligand this way? They eventually develop hyper insulinaemia.

78
Q

What are both agouti and AGRP?

A

Antagonists of the melanocortin receptor. Overexpression of both of these leads to obesity

79
Q

Where is AgRP an antagonist?

A

McR3 and 4

80
Q

What is the AGRP over expressing mouse like?

A

It is an antagonist at the MCR3 and 4 receptor but retains its wild type coat colour and the mouse is obese. Confirms the importance of AgRP in controlling food intake.

81
Q

What experiment could you do to see the role of Agrp?

A

See food intake when you give saline, aMSH, AgRP and then them together. Or measure 24 hour food intake when giving AGRP versus saline.

82
Q

What are AGRP projections like?

A

AGRPir mirror POMCir mutations

83
Q

What are POMC knock out mice like? The human equivalent?

A

Obese, altered pigmentation and defective adrenal development. POMC mutations have red hair and obesity (alpha msh and pomc deficiency)

84
Q

What are the two human melanocortin mutations?

A

POMC mutations leading to red hair and obesity and MCR4 that leads to hyperphagia and obesity

85
Q

What is energy expenditure composed of?

A

BMR - 60-70%, thermic effects of food 10% the rest is thermic cost of activity

86
Q

What are the three types of energy expenditure?

A

Thermogenesis, adaptive and diet induced

87
Q

What is thermogenesis?

A

THERMOGENESIS is required to maintain CORE body temperature:

OBLIGATORY accompanies all METABOLLIC processes

88
Q

What is adaptive thermogenesis?

A

This occurs in response to cold or feeding that goes rapidly up and down. Occurs in the brown adipose tissue, uncoupling protein 1 important

89
Q

What happens in diet induced thermogenesis?

A

Thermogenesis is the regulatory increase in energy expenditure that goes up in response to hyperphagia to minimise deposition of excess fat and occurs in BAT

90
Q

Where is brown adipose tissue and what is it composed of? What is the blood supply like?

A

Mainly inter scapular and is multi lobular adipocytes with many mitochondria. Good blood supply. Important in neonates, 5% of body weight, have less and less as you get older

91
Q

What is BAT interspersed with?

A

Collagen, reticular fibres and fibroblasts

92
Q

What is the innervation of BAT like?

A

It has a good nervous supply. Sympathetic via the b-adrenoceptors, and thyroid receptors, that work synergistically and help conversion from T4-T3

93
Q

How is the heat dissipated in BAT?

A

Through uncoupling protein 1. Normally the electron transport chain couples heat production to ATP synthase but uncoupling protein 1 stops this

94
Q

What do thyroid hormones do?

A

They increase uncoupling protein 1

95
Q

Where are some of the THR located and what is their role in starvation?

A

In the PVN, TRH are innervated by aMSH and AgRP. This means that during starvation BMR is reduced

96
Q

What evidence is there about ob/ob mice?

A

lower metabollic rate. Lower temperature ( reduced thermogenesis), reduced motor activity and gain excess weight without greater food intake.

97
Q

Describe white adipose tissue

A
  • Unilocular adipose- one vacuole (lipid droplet)
  • Less mitochondria, less capillaries
  • Each ADIPOCYTE surrounded by collagen, fibroblasts and reticular fibres
  • Loosely connective tissue comprised of adipocytes and white fat cells
  • Functions- insulation, shock absorbance, energy store and endocrine organ
  • 30-40% ADIPOCYTE genes code for secreted proteins
98
Q

What to types of effects do adipokines have?

A
  • para/autocrine effects on fat vasculature and macrophages

- endocrine: vasculature, muscle, brain and liver

99
Q

Name the main adipokines

A

Leptin, adiponectin, resistin, TNF alpha and visfatin

100
Q

What is the most abundant adipokine?

A

Is adiponectin, produced by mature adipocytes

101
Q

What causes adiponectin to increase and decrease?

A

Decreased in obesity and diabetes and increases for weight loss

102
Q

What is its structure like?

A

Has a collagen and globular domain and self associates into larger molecules and circulates in blood as large multimeric molecules

103
Q

What is the receptor for adiponectin like?

A

It is a 7 transmembrane domain that is different to a g protein

104
Q

What do the adiponectin receptors do?

A

They mediate the photosphorylation of AMPK. Adiponectin enhances hypothalamic AMPK in the ARC via ADIPO R1 to stimulate food intake and increase energy expenditure. Levels thus increase during fasting and decrease during feeding

105
Q

What beneficial action does adiponectin have?

A

Has INSULIN SENSITIZING activity. Globular form increases FA oxidation and glucose uptake in muscle. increases longevity.

106
Q

What does peripheral adiponectin cause?

A

Decreases body fat but has to be injected IV. BUT HAS DIFFERENT CENTRAL AND PERIPHERAL EFFECTD

107
Q

What diabetes drug may interact with adiponectin?

A

THiazolidinedione that may increase adiponectin

108
Q

What is the adiponectin KO like?

A
  • ↑plasma glucose, ↑FFA
  • IR with high fat diet
  • Reversed with adiponectin replacement
  • IR attributed to ↑TNFa
  • NB adiponectin opposes TNFa action and synthesis
109
Q

How is adiponectin linked to inflammation and what are the implications of this?

A
  • Inhibits NFKB → anti-inflammatory
  • Therefore ↓ adiponectin in obesity may contribute to inflammatory response and endothelial dysfunction that leads to atherosclerotic vascular changes
110
Q

What is the difference between the 2 adiponectin receptors?

A
  • ADIPORI 1: abundant in muscle and binds to globular form with high affinity but low affinity for full length adiponectin.
  • ADIPOR2 is mainly in liver and has intermediate affinity for the two receptors.
111
Q

What happens to resistin levels in obesity?

A

They increase

112
Q

How has resistin been linked to diabetes? Evidence

A

Steppan et al 2001. Circulating resisting levels were decreased by anti diabetes drug rosiglitazone and higher in obesity. Normal mice given resistin develop glucose intolerance.

113
Q

What evidence of a potential benefit from resistin?

A

Anti-Resistin drug improved blood glucose and insulin action in DIO mice.

114
Q

What is the mechanism behind resisting?

A

Inhibits the IRS pathway and the translocation of glut 4 to the cell membrane.

115
Q

What effect does central administration of resistin have?

A

Decreases food intake

116
Q

What is the problem with all these models for resistin

A

Human and mice resistin only has 60% homology. Human resistin is not expressed by adipocytes but infiltrative macrophages.thus no correlation between circulating levels and adiposity or insulin resistance

117
Q

What produces TNF Alpha? What is its role?

A

Macrophages and adipocytes. It has a dual role in immunity and metabolism

118
Q

When in TNF alpha elevated and what may this signify?

A

Thought to reflect ↑ macrophage accumulation and low grade inflammation that occurs in adipose tissue with ↑ adiposity

119
Q

What are the 3 actions of tnf alpha?

A
  • INHIBITS ADIPOGENESIS AND PROMOTES LIPOLYSIS
  • INIHIBITS GLUCOSE UPTAKE AND FATTY ACID METABOLISM IN MUSCLE
  • INTERFERES WITH IRS PATHWAY
120
Q

What evidence is there for the activity of tnf alpha?

A

• Immunoneutralisation studies in obese rodents increases insulin sensitivity

121
Q

What is the difference between mice and humans when it comes to TNF alpha?

A

In rodents antibodies to TNF alpha reverse insulin resistance but in man Tnf alpha isn’t released into the circulation and only acts as an auto or paracrine factor. Short term studies in man blocking Tnf alpha increases adiponectin, blocks inflammatory cascade but has no effect on insulin resistance.

122
Q

What is visfatin?

A

a PROTEIN secreted from VISCERAL FAT that MIMICS the effects of INSULIN

123
Q

What are visfatin levels equal to?

A

Circulating insulin levels but they are a magnitude lower and are unchanged by feeding or fasting. It has a possible autocrine or paracrine effect in adipose tissue, stimulating adipogenesis and lipogenesis. Found that not all preparations bind to and activate the insulin receptor

124
Q

Which 2 enzymes do adipose tissue express?

A

CYTOCHROME p450 DEPENDENT AROMATASE (conversion of androgens to oestrogens) and 11b HYDROXYSTEROID DEHYDROGENASE

125
Q

What do aromatase KO mice have?

A

increased adiposity. Oestrogen is responsible for female pattern of fat distribution. Absence of oestrogen causes TRUNCAL OBESITY

126
Q

What hypothesis is there concerning fat types?

A

Visceral fat causing more problems that subcutaneous

127
Q

What does adiponectin do and how is it thought to do it?

A

It is an insulin sensitiser, it inhibits tnf alpha

128
Q

What are the cannabinoid receptors?

A

CB1 (most abudant in mammalian brain, mediates the CNS effects of cannabinoids) and CB2 which is mainly in peripheral tissue. 7 Transmembrane domains.

129
Q

What are the 3 opioid receptors? Where are they located?

A

Mu, Kappa and Delta. Mu and Kappa implicated in food intake Largely distributed in areas involved with food intake and reward.

130
Q

What is the precursor of serotonin?

A

Trypophan

131
Q

How is 5HT signalling inactivated?

A

The re uptake of serotonin by SERT.

132
Q

What does serotonin bind to?

A

7 families, mainly transmembrane receptors termed 5HTR1-7

133
Q

Where are the serotonin cell bodies found?

A

The cell bodies are in the RAPHE nucleus of the BRAIN stem, with ascending and descending projections to other areas, particularly ARC, NTS and PVN.

134
Q

What actions is serotonin involved in?

A

appetite regulation, aggression, anger, sleep, depression, anxiety and migraine

135
Q

What experimental evidence is there concerning serotonin?

A

Depletion of brain serotonin causes hyperphagia. ICV injection of an inhibitor of tryptophan hydroxylase causes hyperphagia. Equally serotinergic neurotoxin

136
Q

What other experimental evidence is there concerning serotonin?

A

Drugs that increase serotonin cause anorectic effects such as SSRIs or MAOs.

137
Q

For serotonin’s effects, which receptors are specifically involved?

A

5HT2CR. Agonists decrease food intake. The anorectic effects of fenfluramine (increases serotonin) are blocked by an antagonist. KO mice are hyperphagic and develop late onset obesity.

138
Q

What are the drugs that effect serotonin?

A

Fenfluramine, ectasy and LSD all increase it.

139
Q

Which other serotonin receptors are involved?

A

5HT1BR. Agonists decrease food intake. KO increase body size.

140
Q

What affect does serotonin have on neurons?

A

Some AgRP neurons have 5HT1BR and serotonin inhibits AgRP.

Some POMC neurons have 5HT2CR. Fenfluramine and (presumably serotonin) activate POMC.

141
Q

What serotonin drugs are there?

A

Fenfluramine but causes pulmonary hypertension and heart valve problems. SIbutramine is a serotonin reuptake inhibitor and has a modest effect on food intake but causes slight hypertension and tachycardia. Future may be specific agonists.

142
Q

What are the cannabinoid ligands like?

A

They are a group of lipid ligands that are not stored in ligands instead made after a specific stimulus. After binding to the cannabinoid receptor they are rapidly re-uptaken.

143
Q

What are the 3 endogenous ligands?

A

beta-endorphin, enkephalin and dynorphin

144
Q

Which cannabinoid receptors are implicated in food intake for which ligands?

A

MU - endorophin/ enkephalin

Kappa - dynorphin

145
Q

What evidence is there for the effects of cannabinoids?

A

Anandamide injected into the CNS increases food intake.

146
Q

What specific effect does leptin have on cannabinoids?

A

Leptin specifically injected into the hypothalamus reduced endogenous cannabinoids. Defective leptin have increased cannabinoid levels. Then administration of cb1 antagonist then reduced food intake.

147
Q

Where is CB1 mRNA colocalised with?

A

CRH, CART, Orexin and MCH.

148
Q

What effect do opioids have?

A

When injected into the CNS, they decrease food intake. Blockade of opioid receptors decreases food intake, decreases NPY, AgRP and orexin

149
Q

What is a hypothesis concerning opioids?

A

They mediate the down stream effects of AgRP. When giving AgRP and in combination with mu and kappa blockade, its appetite increasing effects are attenuated

150
Q

Opioid and cannabinoid receptors are found where?

A

In the reward circuitry

151
Q

What cannabinoid therapy is there?

A

Rimonabant, cannabinoid receptor antagonist but since withdrawn, e.g. with depression.

Anna's (16 decks)

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