11. Physiology of appetite and weight Flashcards
Obesity
A medical problem
Aetiology: genetic & environmental
Homeostasis
Precise matching of energy intake and energy expenditure
- average decade of adult life
- ~10 million kcal consumed
- tendency towards slight average weight gain
Measurements
BMI - kgm^2 Waist circumference Skin-fold thicknesses Bioelectrical impedance analysis Ethnicity specific cut-offs BMI: <18.5 underweight 18.5 - 24.9 normal 25 - 29.9 overweight 30 - 39.9 obesity >40 morbid obesity
Medical problems
6% UK deaths attributable to obesity Metabolic syndrome/type 2 diabetes Cardiovascular disease Respiratory disease Liver Cancer Reproductive dysfunction Joint problems Psychological morbidity
Metabolic syndrome
constellation of closely associated cardiovascular risk factors:
- visceral obesity
- dyslipidaemia
- hyperglycaemia
- hypertension
Insulin resistance is the underlying pathophysiological mechanism
Obesity in relation to insulin resistance and metabolic syndrome
BMI vs body fat distribution: central vs peripheral fat distribution
Metabolic syndrome associated with central (visceral) fat, and BMI >30
Pathophysiology
Increase in free fatty acids (non-esterified):
- lipolysis of visceral fat -> gluconeogenesis, dyslipidaemia
Pro-inflammatory cytokines:
- TNF-a, IL-6 (from overladed with white adipose tissue) -> insulin resistance.
- Decrease in expression of GLUT-4 (insulin-sensitive glucose transporter)
- Decrease in tyrosine kinase activity of insulin receptor
Role of adipocytokines
Regulator of food intake
vasoconstriction, endothelial dysfunction, thrombosis
Anti-atherogenic effects
Type 2 diabetes mellitus risk factors and targets
Age, obesity, family history, ethnicity
Rich people in poor countries
Poor people in rich countries - source of socioeconomic inequality in health
What factors contribute to increased prevalence of T2DM?
Increased age population
increased obesity - getting more younger obesity
Increased detection/diagnosis - 50% of cases T2DM picked up on routine examination
Increased survival with T2 DM
Cardiovascular disease
Metabolic syndrome plus:
- increased blood volume and blood viscosity
- increased vascular resistance
- increased hypertension
- increased left ventricular hypertrophy
- increased coronary artery disease
- increased stroke
Respiratory system effects of obesity
Obstructive sleep apnoea
Hypoxia/hypercapnia
pulmonary hypertension - due to right heart failure
Accidents - daytime somnolence
GI/liver effects of obesity
Non-alcoholic fatty liver Non-alcoholic steatohepatitis May progress to cirrhosis, portal hypertension, hepatocellular cancer Gallstones Reflux
Cancer effects of obesity
~10% cancer deaths in non-smokers attributed to obesity
Types:
breast, endometrial, oesophagus, colon, gall bladder, renal, thyroid
Mechanisms: increased insulin, increased free IGF-I, increased oestrogen, adipo-cytokines, reflux
Reproductive system effects of obesity
Polycystic ovarian syndrome: oligomenorrhea, hirsutism, acne, subfertility, endometrial hyperplasia, insulin resistance
Male hypogonadism
Adverse pregnancy outcomes
Obesity effects on joints
osteoarthritis
gout
Psychological effects of obesity
Depression
eating disorders
Aetiology of obesity
Genetic factors
Environmental factors
Programming
Gut microbiome
Obesity associated syndromes
Rare:
Prader-Willi
Bardet-Biedi
Genetics in obesity
Commonly:
polygenic
susceptibility genes
heritability of weight is similar to the heritability of height
Other medical causes of obesity
Hypothyroidism
Cushing’s syndrome
Environmental factors on obesity
Diet: high fat high sufar Coca-colanisation of developing world Socioeconomic factors
Physical activity:
20-50% total energy expenditure
Obesity prevalence related to proxy measures of physical activity: car ownership, TV viewing
Socioeconomic factors
Social - more likely to be obese if friends are obese
Foetal programming
Stimuli/insults at critical periods have persistent biological effects
Stressors in utero:
?undernutrition, ?trace elements, ?other
Crudely represented by birth weight
Mechanism: epigenetic modification of gene expression
E.g. programmed adrenal axis overactivity in adulthood, causal factor for metabolic syndrome, increased vulnerability to coronary heart disease
Barker’s group evidence
Babies with lowest birth weight ended up with highest morning cortisol as adults
Life course model
Factors operating at every stage of life affect health outcomes later in life
Pathway of risk between events and health outcomes
Worst outcome associated with:
- Low birth weight
- Excessive weight gain in infancy/childhood
- Adult obesity
Gut microbiome
10^4 - 10^14 cells/g in colon, 10-100 times as many genes as human genome
Integral to host homeostasis (physiology):
absorption of nutrients in duodenum and jejunum
Reabsorption of bile acids in ileum
Fermentation of fibre & bile acid metabolism in colon
Influenced by diet: high fat, high fibre etc, chronic & acute (meal by meal)
Influence disease risk: obesity, T2DM etc
Gut microbiome in obesity and T2DM vs normal
Differences in gut bacteria can be induced by diet e.g. high fat diet
Transplantation of faecal material alters insulin sensitivity in mice and humans
Regulation of appetite and weight - slow acting
Leptin
Insulin
Signal % body fat to hypothalamus
-> decrease food intake, increase energy expenditure
Regulation of appetite and weight - fast acting
Rapid-acting peptides regulate meal sizes
released from GI tract cholecystokinin (CCK) inhibits eating ghrelin increases eating PYY inhibits eating up to 12 hours Act via hypothalamus
Hypothalamus
Accelerator neurons: NPY/AgRP neurons
Neuropeptide Y (NPY) encourages eating
Agouti-related peptide (AgrP) blocks melanocortin receptor
Brake neurons:
POMC neurons
Melanocortin peptides (alpha-MSH, CART)
discourage eating
Leptin mice
Ob/ob mouse - leptin deficient
Db/db mouse - mutation of leptin receptor
Ob gene product = leptin
Mouse models of obesity
Leptin treatment reduces obesity in ob/ob mouse
Leptin in humans
Starvation signal
Permissive effect on puberty/reproduction
Obese humans: - very rare leptin deficiency or mutation of leptin receptor - increased [leptin] with increased fat ? leptin resistant ? decreased CNS leptin transport
Treatment for obesity
lifestyle modification
pharmacological
surgical
public health/social
Diet modifications to treat obesity
500-1000kcal energy deficiency
Low energy density:
decreased saturated fat, decreased sugar
increased fruit and veg (sub for other foods)
Decrease portion sizes, decrease snacking
Structured meals/meal replacements may help promote greater weight loss
Physical activity to treat obesity
Exercise 7 days a week
30 mins moderate-high intensity or 60 mins low intensity
Target 10,000 steps/day, increase 500 step increments
Regardless of weight/weight loss, exercise increases health
Very low calorie diets (VLCD) and T2DM
Principle:
Primary care programme with T2DM patients diagnosed less than 6 years ago, put on a VLCD (830kcal/day) for 3-5 month
Initially, total diet replacement with formulae, then stopped food reintroduction (2-8 weeks), long-term maintenance with structured support
Outcomes:
12 month outcomes reported
24% of participants lost 15kg or more
46% induced remission of T2DM: normal HbA1c off all medication for 2 months, >10kg weight loss: 73% remission
Lifestyle modifications
USUAL TARGETS
• 10% weight loss (doesn’t equal ideal weight)
• 1-2 lb (0.5 – 1 kg) per week
• Some evidence that ‘ambitious’ goals promote more weight loss
PROBLEMS
• Most patients can achieve ~ 5-10 % weight loss / 1 year
• ‘Yo-yo’ dieting / regaining weight lost
• ‘Obesogenic environment’
• Weight loss results in increased hunger, decreased satiety, decreased metabolic rate
BEST HOPE
• Sustainable lifestyle changes
• Diet combined with exercise / physical activity
• Ongoing management is required to maintain weight loss
Pharmacological therapy for obesity
25 years research many products, only orlistat
Orlistat mechanism
Binds & inhibits lipases in lumen of gut, stops fat absorption
Prevents the hydrolysis of dietary fat into absorbable free fatty acids/glycerol
Excrete 1/3rd dietary fat
Orlistat adverse effects
Flatulence, oily faecal leakage, diarrhoea
stops absorption of fat soluble vitamins (ADEK), but can take supplement
Metformin
best 1st line agent for overweight/obese patients with type 2 diabetes
All other oral hypoglycaemic agents and insulin cause weight gain
used to prevent diabetes but not licensed for this use
NICE recommended in preventing type 2 DM in adults at high risk
Pharmacological therapy problems
Can only increase by 3-4 fold the proportion who achieve a 5% weight loss in a year
Weight re-gained after treatment stopped
Pharmacological therapy future
All identified gut peptides/neuropeptides/their receptors are potential therapeutic targets/options
Gut hormones in combination most likely way forwards
Surgical treatment for obesity
Laparoscopic adjustable banding
Roux-en-Y gastric bypass
Laparoscopic adjustable banding
restrictive only
Inject/withdraw saline to adjust the diameter of the band
Roux-en-Y gastric bypass
Restrictive, malabsorptive, alterations in gut hormones and bile acid flow contribute to weight loss
Endocrine factors important in effects: plasma from operated rats to sham-operated rates - ate 1/3rd less
Increased satiety seems to be key, shown by F-MRI studies
Roux-en-Y bypass complications
Micronutrient deficiencies - supplement with iron, B12, folate, calcium vitamin D
Dumping syndrome - GI & vasomotor symptoms
Advantages of surgical treatment
Weight loss 25-30%
Resolve or improve co-morbidities
Brings cost savings
Disadvantages of surgical treatment
Perioperative mortality / morbidity
-Depends on procedure and experience of surgeon
Long-term follow-up
- Micronutrient deficiencies
Some weight re-gain
- Patients will still be obese
Expense
- Though cost effective by 2 - 5 years, depending on co-morbidities and weight
Swedish obesity subjects (SOS) study
Ongoing, non-randomised, prospective, controlled study
2010 obese subjects who had bariatric surgery vs 2037 matched obesity controls
Banding & bypass operations
Outcomes were improved through bariatric surgery
UK position on bariatric surgery
NICE 2006 • After failure of other options if ○ BMI >40 kg/m^2 ○ BMI > 35 with co-morbid conditions • Or first line ○ BMI >50 kg/m^2 NICE 2014 • Recent onset T2DM: • Expedite bariatric surgery if BMI >35 • Consider surgery if BMI >30
UK position bariatric surgery: NHS guidelines
NHS England 2013
• As per NICE but…..
• Must have been obese for at least 5 years
• Must engage with non-surgical weight-loss programme for 12-24 months first
Public health/societal approaches to overcoming obesity
• Schools ○ PE, lunches, vending machines • Urban design • Marketing/media/social media ○ Food labelling, food advertisements
