Animal Models of Feeding Behaviour and Body Weight Regulation

Question 1

Define obesity

Answer 1

Obesity results from prolonged imbalance between the level of energy intake and the level of energy expenditure, with the resultant surplus being stored as lipids

Question 2

Where does obesity come in global death risk

Answer 2

5th

Question 3

What is the energy calculation when discussing human physiology

Answer 3

Energy from the diet - the energy used in work and heat

Energy used during work and heat -
Resting metabolic rate
Physical activity
Diet-induced thermogenesis

Question 4

What can be used in the lab to show the expenditure of each organ/tissue type

Answer 4

MRI and X-rays = based on density and presence of fat, glucose turn over and protein metabolism.

Known as functional body composition

Question 5

What happens with active metabolic tissue with age

Answer 5

Decreases so need to reduce intake accordingly

Question 6

What does the brain do in excess glucose (food signal)

Answer 6

1) store the excess as fat
2) activate energy-consuming paths (Anabolism) and shut down E-producing
3) induce satiety

Question 7

What does the brain do in a deficiency of glucose (food signal)

Answer 7

1) release energy from stores in form of lipid
2) shut down metabolic paths that consume (anabolism) high amounts of energy and activate E producing ones (catabolism)
3) induce hunger to replenish that energy

Question 8

How does the vagus nerve communicate levels of hunger to the brain

Answer 8

The Vagus nerve communicates to the paraventricular and arcuate nucleus in the lateral hypothalamic area.

Question 9

Give 8 benefits of mice models

Answer 9

Mouse obesity and metabolic phenotypes are comparable to humans

Phenotype measured with standardized test

Easy study of the brain

Manipulate their genome

Use identical strains when inbreeding

Control of environmental factors

Accelerated lifespan 1/30

Cost-effective and efficient tool

Question 10

What do the animals (scientific procedures) act 1986 state regarding their 4 levels of regulation

Answer 10

Only approved personal can perform approved procedures under approved projects in approved facilities

Try to REPLACE the use of animals if possible
REDUCE the number of animals if possible
REFINE the experiment to reduce the suffering and improve welfare

Question 11

What are environmental models and what can they show about poor energy regulation by the brain

Answer 11

Used to mimic changes in the human food environment - e.g. access/restriction to food or macronutrient composition change.

Junk food - dopamine release causing compulsive behaviour
Maternal/early life - modulation of energy circuits during this time
Fat/sugar choice diets - hyperphagia
Scheduled meal events - temporal sections of the brain to initiate hunger around meals
Bing-type feeding - impulsivity, independent of energy balance

Question 12

What are chemical models and how do some affect eating behaviours, give some examples

Answer 12

Give an animal a drug/chemical to see the various effects of this drug on the animal -

Glucocorticoids - adipocyte differentiation, lipolysis, increased food intake, glucose impairment

Streptozotocin - chemical ablation of pancreatic B cells (diabetes)
Antipsychiotics - olanzapine fat deposition/FFAs

Question 13

Give some pros of environmental/chemical models

Answer 13

Suitable for the investigations of non-genetic lifestyle-dependent metabolic syndrome in humans
Inexpensive

Question 14

Give some cons of environmental/chemical models

Answer 14

Sometimes not complete reproducibility
Lack of standardized diets
Delayed onset of metabolic syndrome

Question 15

What have genetic models found out regarding the genomes role in obesity

Answer 15

248 genes have a role taht when modified with transgenes in rats - the energy balance is affected in the phenotypes.

Question 16

How do spontaneous mutations help us understand obesity

Answer 16

No phenotype in heterozygous genotype and very rare in human population.

However, as it usually affects a single molecule/protein - they have been crucial to understanding the pathophysiology of obesity

Question 17

Give an example of a spontaneous mutation that affects the energy balance

Answer 17

Leptin - is produced by the adipose tissue (fat). Leptin levels correlate to the amount of fat and the brain senses leptin through Leptin receptors. If absent - get fat rats as the brain cannot sense lipid levels.

Question 18

How do artificially induced mutations help us to understand genetic models of obesity

Answer 18

Not targeted mutations as done with UV or chemicals.
Difficult as need to screen the whole genome which is also expensive.

Has a look at specific gene mutations and their effect on obesity - helps to determine role of specific protein

Question 19

Give an example of an artificially-induced mutation that affected obesity

Answer 19

SMA1 + mutation in growth hormone receptor

Question 20

How do targetted mutations help us understand the genetic role in obesity

Answer 20

Looked into leptin - STAT3 regulates adiposity. If this is mutated it shows the same overweight phenotype but can be controlled with food restriction. Meaning that leptin is now known to regulate glycaemia as well as adiposity.

Question 21

Give two downfalls of targeted mutations

Answer 21

Can kill the samples in utero if the knockout gene is vital for growth

Since the animal develops and grows without a specific gene, compensatory mechanisms can appear.

Question 22

How are 4 viral tools used to target neurons that regulate weight

Answer 22

Viral particles - introduce transgene into mouse. Can be long term and cell-specific whilst helping to map out the target site and its specific neuron.

Chemogenetics - DREADD - designer receptors exclusively activated by designer drugs. Allows conditional knock-ins/outs of genes when a drug is introduced or removed.

Optogenetics

Photometry

Question 23

What is optogenetics

Answer 23

Opsins are light-gated ion channels or pumps that absorb light at specific wavelengths. Upon activation by light, these channels and pumps respond by opening or closing, which conducts the flow of ions into or out of the cell

That can modulate terminal projections to evaluate target regions in real-time.

Question 24

What is photometry

Answer 24

Calcium imaging enables neuroscientists to visualize the activity of hundreds of individual neurons simultaneously using fluorescent activity sensors. Changes in fluorescence indicate fluctuations in intracellular calcium, which is an indirect indicator of neural activity

Question 25

What is the role of leptin

EXTRA READING - BUETTNER 2006

Answer 25

Regulates -
Energy metabolism
Glucose homeostasis
Lipid metabolism
Reproductive function

Question 26

What happens to mice with leptin deficiency

EXTRA READING - BUETTNER 2006

Answer 26

Mice deficient in either leptin (ob/ob) or the leptin receptor (db/db) display hyperphagia and decreased metabolic rate, marked alterations in insulin action and lipid and carbohydrate metabolism, and infertility with hypothalamic hypogonadism

Question 27

How does leptin work

EXTRA READING - BUETTNER 2006

Answer 27

Leptin binds to a cytokine receptor which activates janus tyrosine kinase (jak2) and leads to phosphorylation of cytoplasmic target proteins, including signal transducer and activator of transcription (STAT) 3

Question 28

What happens to STAT3 knockout mice

EXTRA READING - BUETTNER 2006

Answer 28

Obesity and impaired glucose tolerance but can be treated, shows leptin is important in glycaemia.

Question 29

What did DREADD show regarding agouti-related protein (AgRP) neurons and their effects on feeding

WIDER READING - Krashes 2011

Answer 29

AgRP neurons rapidly and dramatically induces feeding, reduces energy expenditure, and ultimately increases fat stores. This returned to baseline when the stimulus of food was removed.

activating AgRP neurons potently increased motivation for feeding and also drove intense food-seeking behavior, demonstrating that AgRP neurons engage brain sites controlling multiple levels of feeding behavior.

Question 30

What did optogenetic activation of AgRP show in mice and how can this be used medically

WIDER READING - Essner 2017

Answer 30

AgRP stimulation suppresses amylin, CCK and LiCl (all appetite suppressants). Therefore AgRP stimulation can be used to increase food intake in homeostatic need e.g. non-inflammatory based appetite suppression.