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Anna's > PERIPHERAL SIGNALS OF ENERGY HOMEOSTASIS > Flashcards

PERIPHERAL SIGNALS OF ENERGY HOMEOSTASIS Flashcards

1
Q
  • Leptin and insulin neuropeptide signalling
  • Ghrelin, PYY, PP and appetite
  • Adiponectin and the adipocytokines
A

See the central pathways regulating energy homeostasis slides

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2
Q

What do neural stimuli act via and humeral stimuli act via?

A

Neural stimulus- vagal afferents to nucleus of solitary tract
Humeral stimulus acts on the area postrema via the circulation

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3
Q

What does pre-proglucagon form?

A

GLP1, GLP2, glucagon and oxyntomodulin

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4
Q

What does GLP2 do?

A

GLP-2 is a trophic hormone in the gut, meaning if a part of the gut is chopped out, GLP-2 modulates and makes other part of gut take over.

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5
Q

Where is GLP 1 produced?

A

From L cells of the distal gut and small intestine.

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6
Q

What stimulates production of glp1?

A

Fats and carbohydrates, up to 3 times after a meal

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7
Q

What are GLP1s actions?

A

It engages the ileal break to slow gastric absorption, induces early satiety and weight loss. It is a potent INSULINOTROPHIC

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8
Q

How does glp1 act?

A

Also via the brain stem, abolished by vagotomy. Administration of GLP1 causes a c-fos marker of neuronal activity in the PVN and CEA which are areas important in feeding. Also ARCUATE, blocked by EXENDIN 9-39

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9
Q

What is the ileal brake?

A

Its a feedback mechanism, will ingested food activated distal GI signals that inhibit GI motility and gastric emptying. Neuro humeral and interacts with satiety

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10
Q

What does GLP1 inhibit?

A

Glucagon release

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11
Q

What therapeutic effects occur if you inject GLP1?

A

Normalise glucose in T2DM and decrease post prandial glucose rise and there are no side effects or loss of function

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12
Q

What has GLP1 been shown to do in animals?

A

Increase islet cell mass and delay the onset of t2dm

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13
Q

One potential problem with GLP1 that was not recognised before?

A

Can cause hypoglycaemia

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14
Q

What are the cardiac effects of GLP1?

A

Improved endothelial and left ventricular function in patients with end stage heart failure. Causes a small but significant increase in BP. May also improve neurological symptoms such as memory

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15
Q

What is an evolutionary sign of GLP1 significance?

A

100% homology with animals

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16
Q

What neurological effects does GLP1 have?

A

Stimulates vagal afferents

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17
Q

What evidence is there for the effects of GLP1?

A

Reduces food intake icv in obese zucker rats. Has dose dependent weight loss effects in patients in normal, obese and diabetic (continuous iv or subc).

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18
Q

What is the hypothesis for how GLP1 works?

A

Circulating GLP 1 accesses the AREA POSTREMA and signals to the PVN to stop eating, peripheral circulating factor accessing CNS directly, stimulate vagal afferents directly

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19
Q

What have ko studies shown on glp1

A

GLP 1 KO in mice had no significant effects so may not be important in humans
GLPIRKO FASTING HYPERGLYCAEMIA AND GLUCOSE INTOLERANT

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20
Q

What study was there to assess GLP1 as weight reducer?

A

GLP-1 or saline for 7 days- caused wt loss
Exendin 9-39 or saline for 3 days- gained wt
Exendin 9-39 plus NPY or NPY alone for 8 days- gained wt (mean daily fd intake 20%>)
Thus, GLP-1 not only satiety factor but also seems
physiological regulator of wt

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21
Q

What is exentin 4?

A

potent and long acting agonist of the GLP1 receptor, t1/2 is 30 minutes. Reduces fasting glucose and no hypoglycaemia, particularly post prandially. 19% reduction in food intake and no nausea ( initially may be some but effects reduced with time), using subjects and a free choice buffet lunch and visual analog scale. From gila monster

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22
Q

What GLP drugs are available in the UK?

A

Exenatide, once daily injection. Liraglutide.

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23
Q

What is exendin 9-39?

A

(from gila monster) specific antagonist that blocks the effects of glp1→ no effect on fasting state but increased feeding on sated state and increased NPY induced feeding. Lead to increased weight. In rats halved post prandial insulin and caused glucose intolerance.

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24
Q

What does bariatric surgery do?

A

increased GLP1, increase PYY and increased OXYNTOMODULIN

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25
Q

What breaks down GLP1? Drug?

A

DPPIV is an enzyme that breaks down GLP1 and GIP–> antagonist to this are GLIPTINS

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26
Q

Why might GLP1 be an endogenous satiety factor?

A

Rises after a meal

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27
Q

What is further clinical evidence that GLP1 is beneficial?

A

It increases after bariatric surgery

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28
Q

When is oxyntomodulin secreted?

A

Co-secreted with GLP1.

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29
Q

Where does oxyntomodulin bind?

A

It is a dual agonist at the GLP1 and glucagon receptor

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30
Q

What effects does oxyntomodulin have? Evidence

A

Reduces food intake, increases energy expenditure and may act as INCRETIN factor ( OXYNTOMODULIN self administered pre prandially for 4 weeks reduced weight by 2.3 kg). It is elevated in certain diseases associated with weight loss such as tropical sprue

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31
Q

How does oxyntomodulin compare to GLP1?

A

Reduces food intake and may have similar potency to GLP 1, also no nausea

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32
Q

What other factor might oxyntomodulin be linked to?

A

GHRELIN causes a 44% reduction

33
Q

What happened in the rat model treated with oxyntomodulin?

A

core temp, WAT and BAT

34
Q

What therapeutic potential is there with oxyntomodulin?

A

Make an analogue that has an increased duration of action

35
Q

What happened in human studies with oxyntomodulin?

A
  • 3 times daily s/c injections to obese volunteers for 4 weeks
  • Weight loss 1.8 kg vs control
  • No nausea or alteration in food palatability
36
Q

What is the incretin effect?

A

Oral glucose causes much more insulin to be released that intravenous- main regulator must be something released from your gut when you eat

37
Q

What is the final hormone of this series?

A

Glucose-dependent insulinotrophic peptide. First isolated in the 1979s and administration lead to greater insulin release than glucose alone, the effect is GLUCOSE DEPENDENT.
• However immuno neutralisation studies abolished 20-50% of the effect showing other incretins must be present

38
Q

What is a pathological change in obesity?

A

METASTATIC FAT DEPOSITION in fat, liver and pancreas.

39
Q

What are the changes occurring with high cortisol?

A
  • Centripetal obesity and increased appetite
  • Insulin resistance and steroid diabetes accompanied by hyperinsulin
  • Hypertension
  • Dislipidaemia
  • Skeletal muscle and adipose tissue: reduced insulin mediated vasodilation, reduced translocation of glut 4 to the cell surface, inhibit lipoprotein lipase and augment lipolysis
40
Q

In adipocytes, which pathways predominate?

A

lipogenic pathways

41
Q

In skeletal muscle, which pathways predominate?

A

Oxidative metabolism

42
Q

What do glucocorticoids do in the liver?

A

Augment gluconeogenesis, stimulating PEPCK and glucose-6-phosphatase

43
Q

How does excess glucocorticoids lead to the metabolic syndrome?

A
  • Increase fat Mass by promoting differentiation into pre adipocytes
  • Induces insulin resistance
  • Increase lipolysis
  • Increase blood free fatty acids leading to fatty liver and pancreas etc
  • Increase gluconeogenesis and blood glucose
  • Increase appetite
44
Q

What is an important differentiation in obesity regarding cortisol?

A

THERE IS LITTLE EVDIENCE TO SHOW THAT CORTISOL IS INCREASED IN OBESITY BUT MAY BE THE WAY THAT TISSUES HANDLE CORTISOL

45
Q

What animal evidence is there concerning glucocorticoids in obesity?

A

In ZUCKER rats, 11bhsd1 expression is increased in adipose tissue and decreased in hepatic tissue. Expression increases with High fat feeding. 1bHSD1 KO are resistant to high fat diet induced obesity

46
Q

Which nuclear receptors are there in the liver?

A
  • PPAR alpha: FA oxidation and fasting response

- LXR: lipogenesis

47
Q

What nuclear receptors in fat?

A

PPAR alpha: adipogenesis and lipogenesis

-ERR alpha: energy uncoupling and fatty avid oxidation

48
Q

What nuclear receptors in muscle ?

A
  • PPAR alpha: regulation of insulin sensitivity
  • PPAR gamma: fatty acid oxidation
  • ERR alpha: FA oxidation
49
Q

What was the ligand for FXR thought to be and what is it?

A

Farnesyl but only super physiological concentrations. It is bile acids (involved in bile acid homeostasis)

50
Q

Thus were is FXR expressed?

A

In enterohepatic tissue such as liver, gall bladder and intestine

51
Q

What does FXR do?

A

FXR SUPPRESSES BILE ACID SYNTHESIS AND INDUCES LIVER BILE ACID EXPORT GENES and INDUCES INTESTINAL BILE ACID BINDING PROTEIN. After a meal, bile acids emulsify fats. 5% excreted and 95% reabsorbed in terminal ileum. FXR prevents conversion from cholesterol to bile acids. FED STATE RECEPTOR THAT INHIBITS AUTOPHAGY IN LIVER

52
Q

What does a FXRKO mouse do?

A

High bile acids and develops liver cancer.

53
Q

What does FXR regulate expression of?

A

FGF15/19 in the intestine

54
Q

What does FGF19 do?

A

FGF19 stimulates post prandial protein synthesis, stimulates glycogen synthesis and total liver glycogen and inhibits gluconeogenesis. Is a LONG ACTING INSULIN MIMETIC.

55
Q

What can FXR agonists be used to treat?

A

can be used to treat diseases of bile acids as well as steatohepatitis, portal hypertension.

GASTRIC BYPASSES EFFECTs seem to be FXR Mediated

56
Q

What is PPAR alpha?

A

FASTING STATE receptor that INCREASES AUTOPHAGY

57
Q

What do PPar alpha and FXR do?

A

PPARalpha and FXR COMPETE FOR BINDING ON SHARED AUTOPHAGIC GENE PROMOTERS

58
Q

What does PPAR a do? KO model

A

PPARalpha is active during STARVATION, inducing genes for fatty acid uptake and beta oxidation. (PPAR alpha KO in starvation leads to severe hypoglycaemia)

59
Q

What does PPAR alpha regulate?

A

FGF21

60
Q

What evidence is there for FGF21?

A

increases energy expenditure but not food intake so weight reduction. Improves insulin sensitivity, increases sympathetic nerve activity to brown adipose tissue

61
Q

What does FGF21 do?

A

FGF21 leads to inhibited growth, longevity, FA oxidation, gluconeogenesis and ketogenesis.
Female reproduction. Defect in lack of LH SURGE

62
Q

What is another way insulin could be acting as an adipostat factor?

A

Neuron specific insulin receptor knockout mouse: lots of insulin receptors are in the brain, but the brain metabolises glucose in an insulin independent manner however insulin receptor knockout mice were still: hyperphagic, obese, hyperleptinemic, insulin resistance, high TG reduced fertility 2ndry to hypothalamic hypogonadism (females mostly effected) – role in limiting reproduction in times of food deprivation?

63
Q

What is the role of BAT in insulin resistance?

A

Brown adipocyte insulin receptor knockout mouse: progressive deterioration of glucose tolerance, progressive loss of Beta cell mass and function

64
Q

What is an additional risk for beta cell function?

A

Polymorphisms in the zinc transporter, required for beta cell function

65
Q

What happens when glucose enters the cell?

A

After entering the cell, glucose is phosphorylated by hexokinase and either stored as glycogen via the activation of glycogen synthase, or oxidized to generate ATP via activation of enzymes such as pyruvate kinase

66
Q

What two forms of reward are there?

A

Primary and secondary

67
Q

What can rewards direct?

A

Work for a reward and elicit approach and consummatory behaviour, goal directed responding, subjective internal states of pleasure–> reinforcing

68
Q

What is the role of dopamine in rewards?

A

Dopamine neurons encode REWARD PREDICTION ERROR. They are spontaneously active at 4hz, but there is burst of activity with reward. Burst when predictor of reward but not when they reward actually given. This process helps to maximise rewards through Learning.

Dopamine has dual roles in STRIATUM and CORTEX:

1) modulating synaptic plasticity- learning
2) modulating neuronal activity - behaviour and attention

69
Q

What do food seeking behaviours do?

A

Generally food seeking behaviours increase dopamine such as ghrelin, glutamate and OREXIN. Negative - GABA, Leptin and insulin

70
Q

How can food seeking behaviour be linked to dopamine?

A

Addictive drugs all increase dopamine: cocaine/ amphetamine ( blocks reuptake), opiates -opioid receptor, cannabis ( cannabinoid receptor), nicotine (nicotinic ach receptor) and alcohol. Dopamine changes can also be seen in obese patients . Drug induced plasticity in meso cortico-LIMBIC system. Addiction changes occur in striatum.

71
Q

What was given way back in the 1800s as a weight control drug? Followed by and what problems?

A

Thyroxine. -1930s dinitrophenol that increases the METABOLLIC rate, transports protons across the mitochondrial membrane that uncouples oxidative phosphorylation meaning energy lost as heat, however causes cataracts and neuropathy

72
Q

What was a traditional chinese supplement?

A

ephedrine: a traditional Chinese sympathomimetic that increases noradrenaline release (dopamine and serotonin). But cvs problems. Illegal unless in dietary supplements

73
Q

What drug was there for serotinergic transmission?

A

-fenphen: moderate weight loss when taken alone, considerable together but increase pulmonary hypertension
Fenfluramine enhances serotinergic transmission but causes pulmonary hypertension

74
Q

What drug was the second part of fenphen?

A

Phenteramine enhances dopamine and noradrenaline release (amphetamine like)
-phenylpropanolamine:releases noradrenalin. Founding cold cures and causes a moderate weight loss but stroke and cerebral haemorrhage.

75
Q

What was the main cannabinoid one?

A
76
Q

What is sibutramine?

A

-SIBUTRAMINE that inhibits reuptake of serotonin and noradrenalin. Reduces appetite and increases energy expenditure but associated with ht (non fatal heart attacks and strokes)

77
Q

What current weight loss medication is available? Problems with it?

A

-ORLISTAT: GASTRIC AND PANCREATIC LIPASE INHIBITOR that reduces dietary fat absorption by 30%. Not the highest weight loss and high attrition rates. Fatty stool, faecal urgency, oily spotting and faecal incontinence. Potential deficiency of fat soluble vitamins.

78
Q

What are most new weight loss drugs?

A

Most of the new drugs are combinations of old drugs so you don’t get as bad side effects

79
Q

What are future targets for weight loss?

A 
CBIR
MC4R agonists
MCHIR Antagonists
Y1/Y5 receptor antagonists 
Y2 and Y4 agonists
Central amine 5 ht2c agonists
Gut hormones eg GLP1/ OXYNTOMODULIN

Anna's (16 decks)

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