Animal Models of Feeding Behaviour and Body Weight Regulation Flashcards
Define obesity
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
Where does obesity come in global death risk
5th
What is the energy calculation when discussing human physiology
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
What can be used in the lab to show the expenditure of each organ/tissue type
MRI and X-rays = based on density and presence of fat, glucose turn over and protein metabolism.
Known as functional body composition
What happens with active metabolic tissue with age
Decreases so need to reduce intake accordingly
What does the brain do in excess glucose (food signal)
1) store the excess as fat
2) activate energy-consuming paths (Anabolism) and shut down E-producing
3) induce satiety
What does the brain do in a deficiency of glucose (food signal)
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
How does the vagus nerve communicate levels of hunger to the brain
The Vagus nerve communicates to the paraventricular and arcuate nucleus in the lateral hypothalamic area.
Give 8 benefits of mice models
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
What do the animals (scientific procedures) act 1986 state regarding their 4 levels of regulation
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
What are environmental models and what can they show about poor energy regulation by the brain
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
What are chemical models and how do some affect eating behaviours, give some examples
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
Give some pros of environmental/chemical models
Suitable for the investigations of non-genetic lifestyle-dependent metabolic syndrome in humans
Inexpensive
Give some cons of environmental/chemical models
Sometimes not complete reproducibility
Lack of standardized diets
Delayed onset of metabolic syndrome
What have genetic models found out regarding the genomes role in obesity
248 genes have a role taht when modified with transgenes in rats - the energy balance is affected in the phenotypes.
How do spontaneous mutations help us understand obesity
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
Give an example of a spontaneous mutation that affects the energy balance
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.
How do artificially induced mutations help us to understand genetic models of obesity
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
Give an example of an artificially-induced mutation that affected obesity
SMA1 + mutation in growth hormone receptor
How do targetted mutations help us understand the genetic role in obesity
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.
Give two downfalls of targeted mutations
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.
How are 4 viral tools used to target neurons that regulate weight
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
What is optogenetics
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.
What is photometry
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
What is the role of leptin
EXTRA READING - BUETTNER 2006
Regulates -
Energy metabolism
Glucose homeostasis
Lipid metabolism
Reproductive function
What happens to mice with leptin deficiency
EXTRA READING - BUETTNER 2006
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
How does leptin work
EXTRA READING - BUETTNER 2006
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
What happens to STAT3 knockout mice
EXTRA READING - BUETTNER 2006
Obesity and impaired glucose tolerance but can be treated, shows leptin is important in glycaemia.
What did DREADD show regarding agouti-related protein (AgRP) neurons and their effects on feeding
WIDER READING - Krashes 2011
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.
What did optogenetic activation of AgRP show in mice and how can this be used medically
WIDER READING - Essner 2017
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.
