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Molecular Neuroscience III > 2 - Obesity II > Flashcards

2 - Obesity II Flashcards

1
Q

Knockout of which genes is associated with obesity in mice?

A
  • CEP19 (ciliary protein 19)

- MeCP2 (methyl-CpG-binding protein 2)

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2
Q

What is the most common side effect with drugs that try to treat obesity by modulating hunger?

A

Depression and other mood disorders

Drugs that modulate this are often modulating the HPA axis (hypothalamo-pituitary-adrenal axis)

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3
Q

Chronic stimulation of the HPA axis is connected with what metabolic consequence?

A

Increased obesity from overfeeding

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4
Q

List the obesity-associated genes (7)

A
  • Fat mass and obesity associated (FTO) gene
  • Ciliary protein 19 (CEP19) gene
  • Methyl-CpG-binding protein 2 (MeCP2) gene
  • Melanocortin 2 receptor accessory protein 2 (MRAP2)
  • Kinase suppressor of Ras 2 (KSR2)
  • Ras homolog enriched in brain 1 (Rheb1)
  • Mercapturic acid pathway transporter RLIP76
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5
Q

How is FTO gene associated with obesity?

A

Fat mass and obesity associated (FTO) gene encodes the 2-oxoglutarate dependent demethylase, which is involved in:

  • pre-mRNA processing,
  • amino acid sensing,
  • mTORC1 (mammalian target of rapamycin complex 1 - an energy sensor) regulation and
  • leptin receptor clustering.

FTO gene polymorphism correlated with increase BMI index in both children and adults

Also associated with ADHD, major depression disorder and Alzheimer’s disease.

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6
Q

What does knockout of the FTO gene in mice cause? What does overexpression cause?

A

Postnatal growth retardation, a lean phenotype and increased energy expenditure.

Global overexpression causes obesity due to an increased food intake.

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7
Q

How is the CEP19 gene associated with obesity?

A

This gene encodes the ciliary protein CEP19. Polymorphism is associated with obesity and KO exhibits

  • obesity
  • hyperphagia
  • decreased energy expenditure
  • glucose intolerance
  • Insulin resistance
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8
Q

How is MeCP2 gene associated with obesity?

A

Methyl-CpG-binding protein 2 (MeCP2) modulates transcription. Mutation has been associated with Rett syndrome.

  • MeCP2 is a positive regulator of POMC expression in the hypothalamus and MeCP2 KO in hypothalamic POMC neurons exhibit hypermethylation of the POMC promoter, resulting in reduced POMC expression and increased food intake, reduced burning of fat and higher body weight in KO mice.
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9
Q

How is MRAP2 gene associated with obesity?

A

melanocortin 2 receptor accessory protein 2 KO causes mice to develop severe obesity at a young age. Mrap2 interacts directly with melanocortin 4 receptor (MC4R) and it enhancces MC4R-mediated generation of cyclic AMP. In humans, genetic variants in MRAP2 have been associated with severe, early-onset obesity.

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10
Q

How is the KSR2 gene associated with obesity?

A

Kinase suppressor of Ras 2 gene codes for an intracellular scaffolding protein, which deletion induces obesity in mice. In humans, mutations connected with hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance.

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11
Q

How is the mercapturic acid pathway transporter RLIP76 gene associated with obesity?

A

Important for receptor mediated endocytosis. KO resistance to high fat diet can result in body weight loss, hypolipidemia and hypoglycemia

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12
Q

How the Rheb1 gene associated with obesity?

A

The Ras homolog enriched in brain 1 gene is an activator of mammalian target of rapamycin complex 1 (mTORC1) activity in the brain. Deletion of Rheb1 in the brain impairs normal food intake, induces hypoglycemia and increased lipid mobilization in adipose tissue and ketogenesis in the liver

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13
Q

Which two peptides involved in feeding can effect behaviour?

A
  • Anorectic peptides (eg. α-MSH) which can produce anxiety causing factors

Orexigenic peptides (eg. NPY), which can produce anxiety relieving factors

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14
Q

How can stress lead to increased body weight?

A

HPA axis

  • Neurons in hypothalamic PVN produce corticotropin releasing hormone (CRH)
  • CRH acts on receptors present in the anterior pituitary to stimulate adrenocorticotropin releasing hormone into the blood
  • ACTH stimulates receptors on adrenal cortex to induce release of corticosteroids

The negative feedback induced by increasing glucocorticoid levels is mediated through hippocampal and hypothalamic corticosteroid receptors, which suppress hypothalamic CRF expression.

The amygdala also has excitatory effects on PVN CRF neurons (ie. emotional stress)

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15
Q

How can corticosteroids contribute to obesity?

A

Cortisone is the inactive form of cortisol. It is transported in blood bound to corticosteroid-binding globulin.

When 11β-hydroxysteroid dehydrogenase (11β-HSD) enzyme converts cortisone to cortisol in the periphery, cortisol can induce adipose cell differentiation.

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16
Q

What is Cushing’s syndrome?

A

The pathological hypercortisolism associated with obesity, glucose intolerance, and hypertension. Adrenalectomy in cushing’s syndrome patients reverses glucose intolerance and obesity.

Genetically obese mice and rats demonstrate hypercorticosteronemia. Adrenalectomy in rodents reduces food intake and can be reversed by glucocorticoids.

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17
Q

What is Addison’s disease?

A

The hypoactivity of adrenal cortex, associated with low body weight and hypotension.

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18
Q

How can low birth weight be associated with higher risk of obesity later on?

A
  • Starvation during the first half of pregnancy can lead to low birth rate
  • The baby is predisposed to obesity due to elevated blood cortisol levels (inversely proportioned to birth weight) from activated HPA axis
  • Antenatal betamethasone (corticosteroid) increases insulin resistance
  • The effect can persist to the second generation
  • Low birth weight can be associated with increased risk of type 2 diabetes and also increased risk of developing dyslipidemia and hypertension
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19
Q

Placental administration of what can inactivate maternal cortisol and prevent obesity from low birth weight?

A

Placental 11β-HSD2 (11 beta hydroxysteroid dehydrogenase, type 2)

Converts cortisol to cortisone (11β-HSD1 does the opposite)

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20
Q

Elevated cortisol levels early in pregnancy can lead to low birth weight, but later obesity. What is late cortisol increase important for?

A

Required to induce lung maturation

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21
Q

What effect does serotonin have on food intake?

A

Serotonin inhibits food intake

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22
Q

What does tryptophan hydroxylase inhibitor and serotonergic neurotoxin induce in mice? (in regards to metabolism)

A
  • Induces hyperphagia and body weight increase

- Indicates that 5-HT has a anorexigenic function in regulating feeding behaviour

23
Q

How is serotonin transporter related to obesity?

A

Overexpression: Weight decrease

KO: Weight gain

Neither of these involve hyperphagia

24
Q

How can serotonin receptors modulate body weight? (4)

A

5-HT1b KO: elevated food intake and body weight

5-HT2c KO: hyperphagia and late onset obesity

5-HT6 KO: do not develop obesity on high fat diet

5-HT2c activation: Activates POMC neurons. Activation of 5-HT1b receptors inhibit both GABAergic tone at POMC neurons and AgRP tone at MC4R (melanocortin 4 receptor) neurons

25
Q

How can histamine reduce food intake? (4)

A
  • H1 KO mice develop age-related obesity and hyperphagia, likely from disruption of sleep/wake cycle from effects on hypocretin neurons
  • Histamine autoinhibitory receptor (H3) antagonist suppresses food intake and H1 agonists increase food intake
  • Histamine increases the expression of uncoupling protein-1 (UCP-1) mRNA in adipose tissue, which means it increases energy expenditure
26
Q

How can ciliary neurotrophic factor reduce food intake? (4)

A

Similar to leptin.

  • Ciliary neurotrophic factor (CNTF) is a neurocytokine expressed by glial cells in CNS and PNS. Stimulates cell proliferation and enhances cell survival
  • Administration of CNTF induces tis-11 primary response gene in the arcuate nucleus, suggesting that this cytokine may be involved in feeding control
  • CNTF significantly reduces body fat accumulation in mice lacking leptin (ob/ob) or leptin receptor (db/db)
  • Ciliary neurotrophic factor gene polymorphism is associated with obesity in men, but not women
27
Q

How can CART (cocaine and amphetamine regulated transcript) be involved in feeding behaviour?

A

It is expressed in four brain structures involved in feeding behaviour control:

  • Mesolimbic reward system
  • Hypothalamus
  • Hindbrain
  • Pituitary
28
Q

CART levels are positively correlated with ___ levels (2). It is regulated by ____ and regulates ___?

A

Positively correlated with leptin and high fat diet

Regulated by glucocorticoids and regulates HPA axis activity through a CRF-dependent mechanism

29
Q

What does CART injection into the hypothalamus do?

A
  • INcreases thermogenesis and energy expenditure
30
Q

What does a missense mutation in CART gene cause?

A

Reduced resting energy expenditure and obesity

31
Q

What receptor are CART receptors colocalized with? Where?

A

CB1 cannabinoid receptors, also involved in feeding behaviour in the hypothalamic PVN, LH and DMN.

32
Q

True or false? CART’s role in obesity requires interactions with the environment or with developmental events. Why?

A

True. CART-deficient animals did not show an increase in body weight until after the 14th week of a high fat diet.

33
Q

In the human hypothalamus, CART colocalizes with what three other substances?

A
  • Orexigenic NPY
  • Orexigenic AgRP
  • Orexigenic MCH

CART colocalizes with α-MSH in rats, but not humans. In rats, the above is not observed. This demonstrates that CART may play different roles in regulation of feeding in humans than described in rodents and that hypothalamic feeding regulatory systems are different between the two species.

34
Q

What is syndecan-3? (4)

A

A molecule that stimulates feeding.

  • From a family of heparan-sulfate proteoglycans (HSPGs)
  • Syndecan-3 KO exhibits enhanced LTP and impaired memory
  • In mice, overexpression of syndecan-1 leads to obesity and type II diabetes
  • Genetic disruption of the endogenous syndecan-3 in the hypothalamus leads to decreased sensitivity to food deprivation and in vitro assays have demonstrated that this syndecan directly facilitates the action of endogenous melanocortin antagonists (AgRP). This mechanism of action is controversial because it was shown that posttranslationally modified AgRP (AgRP83-132) did not interact with teh syndecan-3
35
Q

What is nesfatin-1?

A

A novel hunger mediator that reduces food intake and weight gain.

  • Originates from nucleobinding-2 (NUCB2) protein. Antibody to NUCB2 stimulates feeding
  • Nesfatin-1/NUCB2 is present in the brain, especially in the hypothalamic PVN and supraoptic nuclei, arcuate nucleus and medullary A2 catecholamine cell group in the nucleus of the solitary tract (NTS) and dorsal motor nucleus of vagus (DMX) complex
  • Intracerebroventricular administration of nesfatin-1 in rats elevates both plasma adrenocorticotropin and corticosterone levels. Adrenalectomy evokes an increasing nesfatin-1/NUCB2 mRNA expression, indicating that adrenal steroids mediate the negative feedback of nesfatin.
36
Q

Nesfatin-1 is coexpressed with ___ in the stomach

A

ghrelin

37
Q

How does nesfatin-1 reduce food intake?

A
  • Melanocortin (MC3-4) and CRF2 signalling
  • Hyperpolarizing neurons containing orexigenic peptide NPY.
  • Activates the hypothalamic magnocellular oxytocinergic system which could reduce food intake and delay gastric emptying
  • Peripheral nesfatin-1 can reach the brain via the circulation and crossing the blood brain barrier and/or direct action on circumventricular organs, as well as modulation of vagal afferent activity.
38
Q

What two neurological/psychiatric disorders are associated with elevated nesfatin-1 plasma levels (food intake reducer)

A
  • Generalized epilepsy (normalized after treatment)

- Major depressive disorder. Also associated with depression self-rating, even in non clinically depressed subjects.

39
Q

What is glucagon-like peptide (GLP-1)?

A

Incretin hormone which is released from gut endocrine cells after meals, stimulating glucose dependent insulin secretion by activating a G protein-coupled GLP-1 receptor (GLP-1R) expressed on pancreatic islet cells. The receptor is also found within the CNS, heart and lung.

40
Q

The circulating levels of glucagon-like peptide (GLP-1) are lower or higher in obese patients?

A

Lower, and increase with weight loss.

41
Q

The feeding-inhibitory action of glucagon-like peptide (GLP-1) is rapidly terminated by what?

A

Dipeptidyl peptidase-4 (DPP-4)

42
Q

What are the most effective drugs in the treatment of diabetes mellitus type 2?

A

GLP-1 receptor agonists and DPP-4 inhibitors are the most effective drugs in treatment of diabetes mellitus type 2

43
Q

Where are GLP-1 receptors found and what happens when GLP is injected into these areas? What does the other incretin hormone, gastric inhibitory peptide (GIP), do?

A

GLP-1 receptors are present in hypothalamic nuclei and brain stem - areas known to be involved with energy balance.

When centrally injected in rodents, GLP-1 produces anorexia, induces satiety, and increases energy expenditure, leading to reduced body weight if given over a long period.

GLP-1 infusion in healthy volunteers caused a dose dependent reduction in caloric intake.

The other incretin hormone - gastric inhibitory peptide (GIP) increases adipogenesis, likely through direct actions on adipocytes.

44
Q

Which adipocytokines act as anorectic mediators? (5)

A
  • Leptin
  • Adiponectin (increases energy expenditure without decreasing food intake, protection against insulin resistance and atherosclerosis)
  • Resistin (increases insulin resistance)
  • TNF (correlated with body fat, inhibits feeding, increases metabolism, induces cachexia - loss of body mass)
  • IL-6 (increased energy expenditure)
45
Q

What is enterostatin? What is required to respond to it?

A

A satiety factor

  • Induces satiation in rats
  • Released from pancreatic procolipase by proteolytic activity in the small intestine after the ingestion of dietary fat
  • 5-HT1b and MC4R activities are required for the feeding response to enterostatin
46
Q

What is oxyntomodulin (OXM)? In what way does it work when administered?

A
  • A protein released from intestinal cells into circulation, in proportion to caloric intake. OXM inhibits gastric acid secretion, reduces food intake when administered centrally to rodents or peripherally in rodents and humans, and reduces body weight and fat mass when injected chronically.
  • The weight loss observed is greater than it would be expected by a reduction in food intake, indicating that OXM promotes increased energy expenditure.
  • In humans, OXM administration also reduces the levels of circulating ghrelin, which may contribute to it’s effects on an appetite.
47
Q

Is bacteria connected with obesity? (5)

A
  • Some evidences indicate that bacteria inhabiting intestines are able to digest and provide nutrients to the host from the food ingredients that are otherwise indigestible.
  • Different lines of germ-free (GF) mice show slower weight gain as compared
    to conventionally raised animals both when fed low fat diet but also when given Western high-fat high- sugar diet.
  • The germ-free animals show increased AMP-activated protein kinase (AMPK) which stimulation suppresses ATP-consuming anabolic pathways and stimulated ATP-producing catabolic pathways. The gut microbiota was shown to interact with host hunger/satiety signalling.
  • Recent studies indicate that some bacterial species contribute relatively more to energy intake than other commensal/symbiotic microbes.
  • A Gram- negative bacteria from Bacteroidetes phylum prevail in the lean mice whereas Gram-positive phylum Firmicutes are found in the obese ones. This suggests that controlling of bacterial microbiota composition may be useful in reducing weight gain.
48
Q

What happens when obese human bacteria is introduced to mice?

A
  • Mice receiving the obese twin microbiota showed an increase in adiposity, whereas those receiving the lean twin microbiota remained lean
  • When mice inoculated with the obese microbiota were co-housed with mice inoculated with the lean microbiota, the lean bacteria invaded the obese-infected animals and prevented their weight gain
49
Q

What are sodium-glucose transporters and how might inhibitors of them show potential in treatment of obesity? (3)

A
  • Under physiological conditions the renal sodium glucose co-transporters (SGLT1-2) are responsible for reabsorption of more than 99.5% of the glucose filtered by glomeruli in mammalian kidneys.
  • The urinary excretion of glucose was significantly increased in mice SGLTs-double knockout and males of this knockout also showed significantly reduced weight.
  • Studies on pharmacological inhibition of SGLTs in humans show their effectiveness in lowering glucose levels in diabetes type 2 patients, lowering the blood pressure and also decreasing the body weight.
    Canagliflozin (Invokana) is the first SGLT-2 inhibitor approved in 2013 by FDA in the USA.
50
Q

How does astressin-B effect CRF-OE mice?

A

CRF over-expressing mice accumulate visceral fat and show Cushing’s-like symptoms, and also develop alopecia (patches of skin without hairs). Nonselective CRF antagonist astressin-B but not astressin2-B (CRF2 receptor antagonist) blocks alopecia but without effect on visceral fat and Cushing’s symptoms. Might be useful to treat hair loss in men?

51
Q

What are the two main sites of convergence and integration of the central and peripheral signals that regulate food intake and energy expenditure?

A
  • Hypothalamic arcuate nucleus (ARC)

- Nucleus of the solitary tract (NTS)

52
Q

What type of signals regulate energy depots? (2)

A

These signals can be divided into short-term regulation (satiety signals) which determine the beginning and end of a meal and the interval between meals, and long-term regulatory factors (signals of adiposity) which help the body to regulate energy depots.

53
Q

Satiety signals from the periphery are transmitted primarily through ____ nerves to the NTS. While the signal of adiposity reach the median eminence via ___ or by crossing the ___ ___ ___ through saturable and non-saturable membranes.

A

Satiety signals from the periphery are transmitted primarily through VAGUS nerves to the NTS. While the signal of adiposity reach the median eminence via ARC or by crossing the BLOOD BRAIN BARRIER through saturable and non-saturable membranes.

54
Q

What do signalling components in obesity arise from? (long summary answer)

A

Signaling components in obesity include intracellular and secreted signaling molecules that are made in adipose tissues, various brain nuclei, particularly the hypothalamus, liver, skeletal muscle, and the pancreatic islets. The secreted signaling molecules that play a key role in food intake include neurotransmitters and peptide hormones from the brain (NPY, AgRP, POMC, 5-HT, HA), adipokines (leptin, adiponectin, resistin), cytokines from adipocytes (IL-6, TNF-a) and nutrients (glucose, free-fatty acids, polyunsaturated fatty acids and amino acids).

Molecular Neuroscience III (8 decks)

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