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Molecular Neuroscience III > 1 - Obesity I > Flashcards

1 - Obesity I Flashcards

1
Q

True or false? Obesity is increasing worldwide among ALL age groups

A

True

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2
Q

How is body mass index calculated?

A

kg/metres of height squared

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3
Q

What is a better indicator of obesity than the BMI?

A

Abdominal fat thickness

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4
Q

What percent of Canadian’s are overweight or obese?

A

62%

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5
Q

What are the three most common causes of obesity?

A
  • Lifestyle (eg. diet)
  • Disease (cushings, GH deficiency, hypothyroidism, psychiatric disorders, Cohen’s etc.)
  • Genes (energy homeostasis)
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6
Q

What are four consequences of obesity?

A
  • Increased blood pressure
  • High blood pressure
  • Atherosclerosis
  • Diabetes mellitus type II
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7
Q

What area of the brain primarily controls food intake?

A

Hypothalamus arcuate nucleus

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8
Q

What two appetite-stimulating hormones are found in the hypothalamus arcuate nucleus?

What neurons do these hormones active?

A
  • Neuropeptide Y
  • Agouti-related protein (AgRP)

Activate pro-opiomelanocortin (POMC) neurons, which reduce food intake

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9
Q

What are the key appetite inhibiting hormones?

A
  • Leptin

- Insulin

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10
Q

What effect on appetite does activation of neurons in the paraventricular nucleus (PVN) have?

A

Reduce food intake

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11
Q

Activation of neurons in what two areas stimulates food intake?

A
  • Lateral hypothalamic area (LHA)

- Perifornical area (PFA)

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12
Q

Neurons from all involved structures involved in feeding project to where in the hindbrain?

A

Nucleus tractus solitary (NTS)

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13
Q

True or false? Most energy balance-related mediators (eg. hormones) discovered so far, signal hunger, rather than satiety

A

False.

Most energy balance-related mediators (eg. hormones) discovered so far, signal satiety, rather than hunger.

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14
Q

What are the appetite inhibiting brain-originating mediators? (6)

A
  • POMC/MSH
  • Serotonin
  • Histamine
  • Ciliary neurotrophic factor (CNTF)
  • Cocaine and amphetamine regulated transcript (CART)
  • Pituitary adenylate cyclase activating polypeptide (PACAP)
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15
Q

What are the appetite stimulating brain-originating mediators? (6)

A
  • Neuropeptide Y (NPY)
  • Agouti-related protein (AgRP)
  • Melanin-concentrating hormone (MCH)
  • Orexins (Acting via Ox)
  • Syndecans
  • Cannabinoids
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16
Q

What are the inhibiting periphery-originating mediators? (12)

A
  • Leptin
  • Insulin
  • Cholecystokinin (CCK)
  • Peptide YY (PYY)
  • Enterostatin
  • Nesfatin-1
  • Glucagon like peptide-1 (GLP-1)
  • Oxyntomodulin
  • Pancreatic polypeptide (PP)
  • Adiponectin
  • Tumor necrosis factor α (TNF-α)
  • Interleukin-6 (IL-6)
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17
Q

What are the stimulating periphery-originating mediators (2)

A
  • Ghrelin

- Gastric inhibitory peptide (GIP)

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18
Q

What percent of total glucose utilization does the brain account for?

A

50%

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19
Q

What is energy intake balanced between (two processes). What will result if there is disruption of the balance?

A

Spending

  • Metabolism
  • Heat spending

Imbalance consequence

  • Obesity
  • Starvation
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20
Q

What are two main methods for thermogenesis?

A
  • Shivering

- Brown fat heat from mitochondria and uncoupling proteins (UCP)

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21
Q

How do mitochondria produce thermogenesis from ATP metabolism?

A

Fatty acid and glucose are oxidized to generate NADH and FADH2, which donate electrons to the electron transport chain
- Energy from electrochemical gradient of protons can be either involved in ATP synthesis (by ATPase) or leaks as a heat by action of uncoupling proteins (UCP)

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22
Q

What is the consequence for mice lacking uncoupling protein 1 (UCP-1)?

A

Not hyperphagic and obese, but extremely sensitive to cold

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23
Q

True or false? Calcium cycling can produce heat

A

True

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24
Q

What are myokines and what produces them? (8)

A

Skeletal muscle produces myokines

  • Involved in control of adipose tissue buildup
  • Increases muscle hypertrophy
  • Increases adipose oxidation
  • Increases insulin sensitivity
  • Promotes osteogenesis
  • Promotes anti tumour defense
  • Promotes pancreas function
  • Causes browning of fat

Myokines decrease risk of chronic disease and premature mortality

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25
Q

How can working out decrease the risk of chronic diseases and premature mortality?

A

By promoting myokine release from skeletal muscles.

Myokines increase adipose oxidation, anti inflammation, anti tumour defence and browning of fat (among other things)

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26
Q

How are brown and white adipocytes different morphological?

A

Brown: Multiple small lipid granules

White: Single fat droplets that constitute the majority of the cell volume

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27
Q

Brown adipose tissue is innervated by what type of neurons? What receptors do they act on?

A

Adrenergic sympathetic neurons

Act via β3 receptors

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28
Q

How do β3 KO mice survive cold?

A

Increased shivering and increased β1 adrenergic signaling

β3 receptors are on brown adipose tissue

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29
Q

What effect does β3 adrenergic agonist (CL316,243) have (in terms of weight change)?

A

Inhibited weight gain in rodents kept on high fat diet

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30
Q

How can white adipocytes be turned to brown adipocytes? When is this effect not observed? Why?

A
  • Exposing an animal to prolonged cold
  • CL316,243 β3 agonist also induces white adipose differentiation

Not observed in β3 adrenergic KO mice because these receptors are on brown fat

31
Q

If stimulating β3 receptors induces white adipose differentiation into brown fat, what happens when you stimulate β1 receptors?

A

Increases the number of preadipocytes, but not brown fat.

32
Q

What does cold exposure cause, physiologically?

A
  • Expression of thermogenic genes (UCP1, PGC01 and C/EBP) in the WAT/BAT
  • Also resulted in increased density of brown preadipocytes
33
Q

In adult mice, satellite cells (adult stem cells) differentiate usually to myocytes. They differentiate into brown adipose when they express what two transcription factors?

What counteracts stem cell differentiation into brown adipose tissue?

A
  • Pax7 and Myf5

miRNA-133 silences Prdm16, this counteracting stem cell differentiation into brown adipose tissue. Prdm16 is a zinc-finger transcription factor that is specifically expressed in BAT and Perilipin A is a marker of differentiated adipocytes. In vitro Prdm16 expression (and a PGC1α-peroxisome proliferator-activated receptor gamma coactivator-1α, which is a Prdm target) is silenced by miRNA-133

34
Q

Cardiotoxin injection (CTX to induce satellite cell activation) combined with mRNA-133 inhibition does what?

A

Induces expression of UCP1 in mice muscles (causing thermogenesis)

35
Q

Inhibition of miRNA-133 expression by antisense oligonucleotide (ASO) results in what?

What do these results indicate?

A

Increase of UCP, thermogenesis and decrease of weight gain in animals fed high fat diet

Indicates that modulation of miRNA-133 expression can be used in therapy of obesity

36
Q

How can satellite cells be converted to brown adipocytes (marked by UCP1) without using drugs or changing transcription factors)?

A

Exposition of mice to cold for at least a week

UCP1 can be used as a marker for brown adipose tissue

37
Q

In the CNS, which neurons inhibit food intake (1) and which stimulate feeding (2)?

A

Inhibit
- POMC/Melanocortin

Stimulate

  • Agouti-related protein (AgRP)
  • Neuropeptide Y(NPY)
38
Q

In the PNS, what are the peptides released for acute hunger signals (3)? And which reflect long term nutritional state (2)?

A

Acute (released on demand)

  • Cholecystokinin (CCK)
  • Ghrelin
  • Peptide YY (PYY)

Long term

  • Leptin
  • Insulin
39
Q

What do melanocortins, such as anterior pituitary peptides (ACTRH) and its fragments, do to food intake?

Through what type of receptors?

A

They inhibit it through Gs G protein-coupled receptors.

(MC1R, MC2R, MC3R, MC4R and MC5R).

40
Q

What are the two non-neuronal melanocortin receptors?

A
  • MC1R (melanocytes and melanoma cells)

- MC2R (ACTH receptor localized in adrenal cortex)

41
Q

What type of melanocortin receptor is found in the hypothalamus and limbic system? What effect does it have on metabolism?

A

MC3R, inhibits food intake when stimulated

42
Q

What type of melanocortin receptor is found in the CNS, most densely in the hypothalamic PVN?

A

MC4R, plays a role in inhibiting food intake

Mutations in MC4R have been identified in humans. These lead to dysregulation of energy homeostasis and early onset obesity.

43
Q

Mutation in which melanocortin receptor is associated with early onset obesity?

A

MC4R

44
Q

What happens when NPY or its agonist are injected into the brain?

A

Increased food intake.

45
Q

Where is the highest density of NPY neurons found?

A

The hypothalamus

46
Q

How is NPY affected in patients with anorexia?

A

High levels of NPY found in CSF of patients with anorexia

This is counterintuitive, as NPY stimulates hunger.

47
Q

What stimulates the releases of NPY from the hypothalamus?

A
  • High fat, high carbohydrate diet

- Repeated stress

48
Q

What are the five Y receptors that mediate actions of NPY, and what to other peptides act on them?

A

Y1 and Y5 (stimulate feeding)

Y2 and Y4 (inhibit appetite)

Y6 function in appetite not clear

  • Peptide YY (PYY)
  • Pancreatic polypeptide (PP)
49
Q

What two peptides belong to the pancreatic polypeptide (PP) family (not including NPY), and what do they do?

A
  • peptide YY (peripheral PYY)
  • pancreatic polypeptide (PP)

Blood levels of PYY are dependent on the volume and kind of food eaten. High PYY inhibits appetite

50
Q

What cells synthesize peptide YY?

A

L cells of gastrointestinal tract

51
Q

What receptors does PYY act on? (4)

A

Y1, Y2, Y4, Y5

52
Q

What two types of endogenous PYY exist in the body, and at what times are each dominant in the blood?

A

PYY(1-36): Fasting state. Binds to Y1R, Y2 and Y5.

PYY(3-36): After a meal predominates in blood. Acts on Y2R receptors to inhibit NPY and AgRP neurons.

53
Q

Where are Y2R receptors, which are bound by PYY(3-36) most dense?

What happens when these receptors are stimulated? Knocked out?

A

Hypothalamic arcuate nucleus

Activation of Y2R inhibits adenylyl cyclase via Gi protein. Mouse knockout of Y2R is insensitive to exogenous PYY anorexic effect

54
Q

What is leptin? What does mutation of this protein cause?

A

A protein produced by leptin gene (LEP) in white adipose, whose name is derived from the greek word, Leptos, meaning thin.

Mutation in the mouse LEP gene results in absence of leptin, causing obesity, hyperphagia, hypothermia, extreme insulin resistance and infertility. Administration of leptin restores WT phenotype.

55
Q

Which neurons does leptin act on to inhibit feeding?

A
  • AgRP
  • POMC

Leptin activates the signal transducer and activator of transcription 3 (STAT3), which binds to POMC and AgRP promoters, stimulating POMC expresssion and inhibiting AgRP.

Leptin and insulin signalling pathways converge on phosphoinositide 3-kinase (PI3K). The pathway which leads to phosphorylation and inactivaiton of forkhead box protein O1 (FoxO1), a repressor of POMC expression.

Phosphorylation of FOxO1 provokes its nuclear export and allows STAT3 to bind to POMC and AgRP promoters. Inhibition of AMP-activated protein kinase (AMP-an energy sensor) by leptin is mediated by mTOR. It has been reported that leptin action depolarizes (activates) POMC and hyperpolarizes (inhibits) AgRP neurons

56
Q

What evidence shows that autophagy may play a physiological role in hypothalamic energy homeostasis?

A

Mice that lack the autophagy-related gene 7 (Atg7) in POMC neurons are obese, and show increased food intake whereas Atg7-KO in AgRP neurons promotes body weight loss.

57
Q

How does ghrelin stimulate appetite via a central mechanism?

A
  • Ghrelin is a gastrointestinal hormone
  • Acts on the growth hormone secretagogue receptor to stimulate food intake via AgRP/NPY-dependent pathway
  • Stimulates NPY release from brainstem
  • Stimulates dopamine release from VTA
  • Stimulates NPY and AgRP release from hypothalamus
58
Q

What is the precursor of ghrelin called?

A

preproghrelin

59
Q

What is BSX?

A

The main transcription factor activated by ghrelin. Part of appetite stimulation and locomotor activity.

60
Q

Where is the highest density of growth hormone secretagogue receptor (GHS-R, aka ghrelin receptor) found?

A

The arcuate nucleus in the hypothalamus

61
Q

What does a lack of cholecystokinin signalling lead to? (2)

A
  • Hyperphagia
  • Obesity

Otsuka-Long-Evanc-Tokushima Fatty (OLETF) rats are spontaneous knockouts of CCK-1 (Cholecystokinin-1). They become obese and develop non-insulin diabetes mellitus. OLETF rats have elevated hypothalamic NPY mRNA expression and this can be prevented by increased physical activity.

62
Q

In humans what does cholecystokinin and its antagonist do?

A

CCK: Decrease food intake

CCK Antagonist: Increase food intake

63
Q

What are melanin concentrating hormone neurons (MCH) and what do they do for appetite?

A
  • Stimulates appetite
  • Is present in hypothalamus and acts via MCH1R and MCH2R
  • MCH neurons are inhibited by GABAergic, cholinergic, aminergic and POMC inputs.
  • Glutamatergic and orexinergic neurons stimulate MCH neurons
  • Circulating leptin inhibit MCH neurons, whereas glucose stimulates MCH neurons
64
Q

What is orexin A (hypocretin 1) and orexin B (hypocretin 2) produced from (precursor)?

A

prepro-orexin

by prohormone convertase

65
Q

What are the two main orexin receptors and which G proteins are they coupled to?

What does stimulation of each cause?

A

OX1R: Gq (phospholipase C pathway), Increased food intake

OX2R: Gq and Hi, decreased high fat food intake (but not low fat)

66
Q

Which molecules do the two orexin receptors have the highest affinity for?

A

OX1R: Orexin A

OX2R: Orexin A and B

67
Q

What does noradrenaline and serotonin do to orexin neurons?

A

Hyperpolarizes them (inhibits) through activation of G-protein regulated inwardly rectifying K (GIRK or Kir3) channels via α2-adrenoceptors and 5HT1a receptors.

68
Q

What are orexin neurons role in feeding?

A

To sense the nutritional status of the body. The most important mediators of orexin neurons are glucose, ghrelin and agouti-related protein

69
Q

What suggests allosteric regulation of food intake by OX1R and ____ receptors?

A

OX1R and CB1 cannabinoid receptors have been found as heterodimers

70
Q

How does sleep deprivation augment obesity? (3)

A
  • Increases ghrelin
  • Increases hunger
  • Decreases leptin

All through HPA axis dysregulation

71
Q

What is the safest method for treating obesity?

Most effective?

A

Safest

  • Reduce caloric intake
  • Increase physical activity

Most effective
- Surgery, to reduce size of stomach (gastric bypass) or implanting small balloon

72
Q

What is orlistat (xenical)?

A

The most commonly used medication to treat obesity, inhibitor of pancreatic lipase.

73
Q

What is belviq (lorcaserin)?

A

Obesity treatment

A 5-HT2c agonist. Probably decreases appetite by stimulation of POMC neurons

74
Q

What is Qsymia?

A

Increases satiety/reduces appetite (teratogenic in animal and human studies)

Molecular Neuroscience III (8 decks)

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