anti obesity drugs Flashcards
what constitutes to being obese
bmi over 30
what diseases does obesity contribute to
coranary heart disease, type 2 diabetes, osteoarthritis, certain forms of cancer, impotence
how is meal number and size regulated
end of feeding is promoted by satiety factors that increase during feeding
these generate signals in brain through peripheral nerves innervating the nucleus of the solitary tract as well as directly activating their own receptors
information is then transmitted to hypothalamus and forebrain areas
what receptors are involved in regulation of meals
peripheral receptors in gut (distension and chemo-receptors) and metabolic changes send signals to brain via vagus nerve
receptors in CNS which detect circulating levels of nutrients
neuroactive factors which cross blood-brain barrier and/or are released in the brain
how is control of food take regulated centrally
via hypothalamic nuclei which:
maintains homeostasis
is site of release of numerous neurotransmitters (monoamines and peptides) that influence food intake
have strong links with central and autonomic nervous systems as well as endocrine system
several hypothalamic nuclei are involved in regulation of food intake, each nucleus contains peptidergic neurones with opposing effects on food intake
how does brain modification affect feeding
lesions of ventromedial hypothalamus causes obesity and overeating
lesions of laterhypothalamus causes reduction in food intake and bodyweight
injection of glucose antimetabolites into 4th ventricle induces feeding
what are key hypothalamic nuclei
arcuate nucleus: different sets of neurones;
one set in which neuropeptide Y and AgRP are colocalised
or set which uses POMC
both groups in arcuate nucleus are sensitive to leptin
these neurones have reciprocal connections with the paraventricular nucleus, dorsomedial nucleus and lateral hypothalamic area
how do brainstem nuclei regulate feeding
these are source of neurones that regulate hypothalamic function
neurones integrate and resond to afferent signals from digestive tract
neurones here are targets for leptin, especially the nucleus of the solitary tract which is innervated by vagal afferents
how are other central areas involved in feeding
amygdala involved in food intake; has emotional influence on hunger/satiety
nucleus accumbent: food intake associated with reward pathway, dopamine receptors effect motor activity and duration of feeding but not total food intake
what are central orexogenic factors, give examples
factors that increase food intake:
neuropeptide Y, AgRP(agouti related peptide), endocannabinoids
opioids
how does neuropeptide Y increase food intake
released from neurones w cell bodies in arcuate nucleus which project to paraventricular nucleus
these neurones are activated by declines in fat stores and ihibited by feedback caused by insulin and leptin
stimulation of these neurones reduces sympathetic outflow to brown adipose tissue and so lowers energy expenditure and stimulates lipogenesis
production of neuropeptide Y may be inhibited by leptin and desensitisation of NPYergic neurones may impair satiety and so regulation of meal size which may contribute to obesity
how does AgRP cause its effects
orexegenic
colocalised w NPY
is an antagonist of melanocortin system
disruption of AgRP synthesis reduces body weight and increases metabolism but does not effect food intake
how do endocannabinoids cause their effects
orexegenic
peripheral administration of anandamide increases food intake
expalins munchies associated with cannabis use
CB1 antagonists reduce food intake
fasting leads to accumulation of anandamide
what are central anorexegenic factors, give examples
factors that reduce food intake: melanocortins 5HT noradrenaline dopamine
how do melanocortins produce their effect
anorexogenic
they are derived from POMC (pre-opiomelanocortin)
potently reduce food intake and increase energy expenditure through activation of MC3 and MC4 receptors
e.g alpha-melanocyte stimulating hormone
how does 5HT affect food intake
anorexegenic
effects attributed to activation of 5HT2c receptors
actions mediated in paraventricular nucleus, possibly by inhibiting NPY
may suppress preference for fat intake
intake of carbohydrate can increase 5HT release in brain,via release of insulin which promotes uptake of tryptophan (5HT precursor) which may augment effects on satiety (controversial)
how does NA affect food intake
anorexogenic
noradrenaline: reduce food intake thought to rely on stimulation of alpha1 and beta receptors in hypothalamus
what are key peripheral mediators of food intake
leptin, insulin, gherkin, peptide YY, cholecystokinin, glucocorticoids, GLP-1
how does leptin effect feeding
anorexogenic
stimulates POMC, inhibits NPY in hypothalamus
stimulates GLP-1 in brainstem
thought to act on satiety centre of hypothalamus to reduce fat deposition and hence body weight by decreasing food intake and increasing energy expenditure
increase in fat stores increases leptin production, decline reduces production
mice lacking genes for leptin or its receptors are obese
how does ghrelin effect feeding
orexogenic:
secreted by stomach, regulated by leptin, secretion increase during fasting and falls after eating
inhibits 5HT release
how does insulin effect feeding
actions resemble leptin, stimulates release of leptin
enters brain through specific transporters, reduces NPY synthesis, stimulates POMC synthesis
under some circumstances insulin can also increase food intake
how do peptide YY, cholecystokinin, GLP-1 and glucocorticoids effect feeding
peptide YY: inhibits feeding, produced by gut
cholecystokinin: inhibits feeding, increases release of 5HT in thalamus, meal termination signal
glucocorticoids: orexogenic, are leptin/insulin antagonists
GLP-1: anorexogenic, incretin causes glucose lowering effect, GLP-1 analogues are anti-diabetic drugs, also caused sustained weight loss
what drugs are used to treat obesity
sibutramine, orlistat, lorcaserin, GLP-1 analogues
how does sibutramine cause weight loss
5HT/ noradrenaline reuptake inhibitor
is a prodrug, undergoes extensive first pass metabolism; 2 active metabolites which inhibit reuptake of 5HT and NA
promotes activation of beta 2 receptors in adipose tissue
adverse effects are due to increased sympathetic drive: increase in blood pressure
how does orlistat cause weight loss
inhibits pancreatic lipase; prevents breakdown of fat to fatty acids and glycerols
increases faecal fat and so patients must adhere to low fat diet to avoid unpleasant effects
only anti-obesity drug not to be withdrawn from market (d-flenfluramine and related drugs withdrawn)
low patient compliance due to unpleasant gastric effects
how does lorcaserin cause fat loss
5HT2c receptor antagonist
increases melanocortin production from POMC neurones
how are GLP-1 analgoues used to treat obesity
e.g liraglutide and exenatide
cross blood brain barrier, act on GLP-1 receptors
act on various regions such as hypothalamus and mesolimbic system to supress both reward driven and metabolically motivated food intake
they are peptide; have to be injected so are less attractive to patient and are relatively expensive
how is gastric bypass surgery used in treatment of obesity
most efficient weight loss treatment, however serious surgical risks and high cost
changes in GLP-1 system may underlie some of its beneficial effects
what are types of gastric bypass surgery
roux-en-Y gastric bypass: alimentary limb in connected to mid jejunum, leads to reduction in functional volume of stomach by over 90%
sleeve gastrectomy: does not alter route for nutrients, reduces stomack to about 15% of its original size by removal of large proportion of stomach along greater curvature
how does gastric bypass surgery effect GLP-1
fasting GLP-1 levels not altered
enhanced postprandial GLP-1 responses observed 1-3 days after surgery
GLP-1 response greater after roux-en-Y bypass than sleeve gastrectomy
enhanced GLP-1 response was not observed in patients who were calorie restricted
progressive increase in GLP-1 response during first year after surgery, persists long term, changes are much more than incretin counterpart which is not altered
what are consequences of gastric bypass surgery
CV: decrease in CV disease and hypercholesterolaemia
decrease in hypertension and inflammation
decrease in obstructive sleep apnoea
central: decreased appetite and increased satiety, increased cognitive function
GIT: altered bile acids, increased PYY, altered gut microbiota
increase GLP-1, decreased gherkin, increased insulin
what is summary of treatment
sustained life style changes such as balanced diet and exercise may be healthiest way to loose weight
surgery is most effective, however targeting circulating factors is easier, less risky and expensive
NT receptor targets are difficult to target due to side effects
