3. Obesity Flashcards
What other problems does obesity predisposes to?
Obesity also predisposes to:
- mental problems
- cancer
- cardiovascular disease
- reproduction (PCOS)
What is obesity?
Obesity - disproportionate body weight for height with an excessive accumulation of adipose tissue
Determined by BMI - but only a rough metric - same numbers not applicable to all ethnicities
Explain what are the possible differences in fat accumulation and what it predisposes to
Fat accumulation at >30 BMI:
- pear-shaped obesity - low risk of diabetes, metabolic syndrome
- apple-shaped obesity - high risk of diabetes and metabolic syndrome - visceral fat
What are the causes of obesity?
Obesity caused by dysregulation between energy intake and expenditure - body energy homeostasis disrupted:
- environment: carbohydrate intensive diet, low physical activity
- genetics: management of energy balance - predispose / protect from obesity - monogenic - ?? / polygenic - FTO locus
- epigenetics
What early human study lead to the conclusion that genetics is the main factor determining obesity risk?
Twin studies - compared identical vs fraternal twins in obesity - identical seemed very similar in adipose tissue accumulation - fraternal exhibited higher variation
Compared with separated twins - environment plays a smaller factor in obesity than genetics
Which form of cancer was observed to cause obesity?
Obesity developed in patients after thet developed hypothalamic tumours => hypothalamus regulates energy balance
What experiments where done to test the function of hypothalamus in obesity and suggest there is a circulating factor regulating body weight
- Hypothalamic lesions were introduced in mice -> became obese - wanted to further study the possibility of hormone influence
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Mice parabiosis (anatomical suture together - share blood circulation) experiments: in one of the joined mice hypothalamic lesion -> became obese while the other started losing weight until died; when both with hypothalamic lesions -> both became obese
=> circulating factor is regulating body weight
What are the two lines of mice genetically engineered to be obese?
Two lines of mice genetically made obese:
- ob/ob - obese
- db/db - diabetes
Explain the parabiosis experiments of genetically obese mice revealing a circulating factor regulating body weight
Parabiosis of ob/ob, db/db and +/+ WT mice:
- WT and db/db -> WT died of malnutrition, db/db became increased weight
- WT and ob/ob -> WT no changes, ob/ob slimmed down
- ob/ob and db/db -> ob/ob decreased food intake -> death, db/db increased weight
db/db - secretes a factor but can’t respond to it
ob/ob - can respond to the factor but can’t produce
What was the discoevered circulating factor regulating body weight?
Leptin
ob/ob can’t produce leptin - mutation - STOP codon
db/db can’t respond to leptin - no leptin receptors
Explain how leptin regulates body wieght
Leptin is a hormone produced by fat cells - adipocytes -> the more fat cells there are, the more leptin produced to downregulate hunger / the less fat you have the less leptin produced - the higher feeling for hunger
Leptin is produced by adipose (fat) tissue - acts on leptin receptors in hypothalamic region - regulates food intake levels
Define hyperphagia
Hyperphagia - excessive overeating - not feeling full
Explain the components of melanocortinergic system in body weight regulation
Melanocortinergic system: in hypothalamic region - neural populations in arcuate nucleus of hypothalamus which regulate appetite:
- Orexigenic (appetite stimulating) - NPY/AgRP neurons
- Anorexigenic (appetite suppressing) - POMC neurons
have receptors for fat cell secreted hormone leptin
Explain how melanocortinergic system works in body weight regulation
Leptin regulates activity of NPY/AgRP (orexigenic) and POMC (anorexigenic) neurons
- leptin inhibits NPY/ArGP -> AgRP antagonism signaling to paraventricular nucleus - negative response to MC4R neurons -> appetite ON -> food intake
- leptin stimulates POMC -> MSH agonism - positive response to MC4R neurons -> appetite OFF -> no food intake
=> a balanced dynamic system which is capable of responding to changes
MC4R does not act in ON / OFF manner - but in a dynamic level manner
What could be an example showing a point mutation influencing appetite and subsequent obesity?
A deletion found in canine POMC gene - associated with overall appetite increase and obesity in labrador retriever dogs
-> more trainable because more motivated for food - more likely to become guide dogs
What are the other hormones involved in regulating food intake?
Long term: leptin
Short term: GLP-1, chrelin, inslin, glucagon
Explain how other hormones atc on the melanocortinergic system works in body weight regulation
GLP-1 - positively stimulates POMC -> decrease appetite
What is the genetic influence on obesity?
Obesity - high genetic infleunce - can be both monogenic and polygenic caused obesity
Monogenic: strong phenotype, usually causes non-functional / complete block of the system => more rare, early-onset, high penetrance, minor environmental influence
Polygenic: milder mutations but more of them - affect activity of the system but not complete block => more common obesity type, many variants, environment plays an important role in obesity development
Obesity genetics research timeline
What are the two types of fat accumulated in obesity and what are their differences
Found in different parts of the body:
Subcutaneous fat: beneath the skin, pinchable fat, unhealthy appearance but less health risks
Visceral fat: deep in abdominal cavity - surrounding organs like liver, intestines, stomach, not visible from outside but higher risk of diabetes, heart disease, stroke
How were genes for polygenic obesity discovered?
GWAS studies - FTO locus + neighbouring genes found in higher freq in obese people
Explain the role of FTO locus in obesity
FTO locus found associated with polygenic obesity patients
In humans:
- SNP in FTO increases expression of IRX3 and IRX5 genes during adipocyte differentiation
- FTO required for high fat diet (HFD) - mutations contribute to induced leptin resistance
What are factors apart from genes influence obesity?
Factors influencing obesity:
- genetics: monogenic / polygenic
- epigenetics: epigenetic modifications can influence obesity related gene expression - ex. people concieved during Dutch famine - prenatal malnutrition
- environment: infleunce levels depends if monogenic / polygenic
How can obesity be treated?
In monogenic obesity:
- exogenous leptin administration - helps slim down
but can’t be used as a general anti-obesity drug because leptin resistance develops - de-sensitisation of leptin receptors
- Setmelanotide - selective MC4R agonist: mutations in POMC or PCSK1 - POMC or LEPR deficiency (essential for POMC function) -> absent MSH => setmelanotide adminsitration - substitutes MSH
- Semaglutide (Ozempic/Wegovy): incretin based drug - peptide similar to hormone glucagon-like peptide 1 (GLP1) produced by intestine - signals “I’m full” signal - diabetes drug (lower blood sugar, suppresses appetite)
In polygenic obesiity:
- bariatric surgery - gastric bypass surgery - creating a small pouch - person feels full after eating less + body doesn’t absorb all the calories from eating
What is bariatric surgery? Which form of obesity is it supposed to treat?
Polygenic obesity - bariatric surgery - gastric bypass surgery - creating a small pouch - person feels full after eating less + body doesn’t absorb all the calories from eating
How can simpler organisms act as models for obesity research?
Drosophila for research into genetic basis for obesity - 75% human disease genes conserved in Drosophila - can become obese, develop diabetes, heart disease => perfomr quicker functional gene screens
What are the key factors involved in regulating obesity?
