Obesity

Obesity Intro

Metabolic disorder associated with insulin resistance, type 2 diabetes, dyslipidemia and hypertension

Consequence of the imbalance between energy intake and expenditure

Growing prevalence worldwide - epidemiology

Risk factor for other major chronic disease: cardiovascular disease, type 2 diabetes and several cancers

Causes: genetics, epigentics, environmental - excess food intake, lack of physical activity, genetic x environmental, socio-economical factors

Obesity related traits - high BMI, unhealthy weight gain, high waist circumference, excess of body fat

Two types: Monogenic - mendelian obesity (early onset) and polygenic - common obesity

Obesity Causes

Evolution?

• Natural obesity in animals for hibernation/migration etc.
• is obesity in humans adaptive response in case of famine? No because approx 70% of population not obese. If it was positive selection then everyone would be obese

Evidence for genetic contribution

1.Inter-individual variation of BMI/body fatness studies: identical twins, adoptees (environment affect only), and family data in Canada, Denmark and Norway

• genetic factors: 25-40%
• non hereditary factor s (e.g diet/exercise): 60-75%

2. Animal models ob/ob mice

• mutation in ob (obese) gene results in severe obesity and type 2 diabetes
• Leptin (ob (or lep) gene product): satiety hormone produced in adipose tissue, decreases appetite, body fat stores and insulin production

see lecture 3 for image of how leptin works

Obesity Monogenic - Intro

Monogenic mutations lead to defects in the satiety (loss of leptin signaling) and appetite control centres in the brain

Four patterns of inheritence

• autosomal dominant
• autosomal recessive
• x-linked dominant
• x-linked recessive

Mutations Affecting Satiety Centre

1. Congential Leptin deficiency: extremely rare mutations in LEP gene = no leptin. Children with deficiency treated with Leptin rapidly lose fat mass and body weight but not lean mass (see lec 3)

2. Leptin Receptor deficiency (leptin resistance): rare mutations in LEPR gene = no response to leptin

Both autosomal recessive and result in excessive hunger leading to severe obesity, decreased production of hormones affecting sexual development and reproductive function, hyperinsulinemia (insulin resistance), onset in first few months of life

Mutations Affecting the Appetite Centre

POMC pathway

POMC = proopiomelanocortin (POMC) - extensively cleaved into multiple peptide hormones 

• ACTH (adrenocorticotropic hormone) stimulates cortisol release by adrenal gland 
• α-MSH and β-MSH (melanocyte stimulating hormone) -weight regulation and energy balance maintenance, skin pigmentation (melanin production) - used to identify the disease but doesn't affect the disease
• β-endorphin and met-encephalin - endogenous opiates

POMC deficiency

• autosomal recessive
• mutation in POMC gene - truncated version or absense of POMC = decreased levels/loss of above proteins, dysregulation of body's energy…