Obesity Flashcards
What is ghrelin?
Ghrelin is a hormone produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach, and is often called a “hunger hormone” because it increases the drive to eat.
What are the main effects of ghrelin?
Only known peptide hormone that stimulates food intake and gastric motility.
Increase food intake, appetite.
Promote Fat storage, decrease fat utilisation.
Energy expenditure.
Increases blood glucose levels by reducing glucose-stimulated insulin secretion.
Alters insulin sensitivity.
Interesting CNS effects: antidepressant effect, improve cognitive function. Established neuroprotective effect.
What triggers ghrelin release?
Food intake is the most important factor that influences ghrelin level.
Circulating ghrelin concentration rises before meal and falls after meal.
Total ghrelin level increases in night and decreases after breakfast.
What stops ghrelin release?
Ghrelin levels fall to a nadir level 1 hour after eating.
Postprandial fall in plasma ghrelin is proportional to ingested calories, with fat causing less suppression than carbohydrate or protein.
Role of GI hormone: CCK, GLP, Insulin reduce Ghrelin release.
What is leptin?
Leptin is a hormone predominantly made by adipose cells and enterocytes in the small intestine that helps to regulate energy balance by inhibiting hunger, which in turn diminishes fat storage in adipocytes.
What factors trigger leptin release from adipocytes?
Main stimulus - some plasma factors increased at time of food intake:
Insulin.
Glucose (to a less extend fructose).
Amino acids.
Food supplements like zinc and omega 3 fatty acids.
How does leptin act around the body?
Liver: reduce de novo fatty acid synthesis and gluconeogenesis, increase glycogen storage.
Pancreas: reduces insulin secretion and exocrine secretion of pancreatic enzyme.
Stomach: inhibits gastric and ghrelin secretion.
Skeletal muscle and some other tissues increase in FA oxidation capacity lowering triacylglycerol stores.
Brain: acts in concert with insulin to increase satiety, suppress food intake and increase body weight loss.
How does leptin act in the brain?
Leptin is transported from the blood microvessels to the brain tissue.
Like insulin, leptin interacts with several neuronal pathways to regulate energy intake particularly in the hypothalamus.
Leptin also regulates energy expenditure via activation of the sympathetic system.
Leptin negatively modulates the mesolimbic dopamine system to decrease the motivation and pleasure for food intake.
What effect does leptin have on metabolism?
Several leptin-deficient states, including complete leptin deficiency and lipoatrophy, are associated with insulin resistance and diabetes.
Obesity is associated with high levels of leptin but resistance to leptin receptors.
Leptin can improve insulin resistance.
Leptin activates signalling pathways that overlap with those of insulin.
This overlap suggests a common pathogenesis of leptin and insulin resistance in obesity and may prove significant in emerging therapies.
What happens in the adipose tissue of obese patients?
Significantly increased numbers of macrophages accumulate in adipose tissue in obese states.
This infiltration generates the production of proinflammatory factors.
What mechanisms can be involved in fatty acid-induced insulin resistance?
High levels of plasma TG increase levels of diacylglycerol (DAG) - inside the muscle which act as a second messenger leading to the phosphorylation of important protein interacting with insulin receptor (insulin receptor substrate) reducing glucose transporter function.
Saturated fatty acids, like palmitate, at high concentration, can activate Toll receptors - toll receptors are receptor involved in the recognition of microbial agents (part of the innate immune system) and are normally activated by lipo-polysacccharide-like molecule. Activation of them induce intracellular mechanism leads to the production of inflammatory molecules that impair insulin receptor signalling.
Palmitate (due to its accumulation) can be metabolised into ceramide a sphingolipid which can act as a signalling molecule promoting inflammation and impairing insulin receptor signalling.
How does chronic inflammation of adipose tissue progressively develop with obesity?
Paracrine loop involving free fatty acids and inflammatory cytokines establishes a vicious cycle between adipocytes and macrophages that propagates the inflammation.
Activation of inflammatory pathways in adipocytes impairs triglyceride storage and increases release of free fatty acids which will induce insulin resistance in muscles and liver.
How does orlistat work?
Orlistat binds irreversibly to the active sites of lipase
through covalent binding. Reduce GI absorption of one-third of triglyceride intakes.
Well tolerated, no systemic effects, but must be given with lipophilic vitamin supplements (A, D, E, and K) particularly in children, may reduce oestradiol level.
Limited but significant effect on weight.
How does metformin work?
Hypoglycemic agent used in the treatment of adults with type 2 diabetes.
Insulin sensitiser, with some hypophagic effects.
Beneficial effects on weight and well tolerated, good effect on glycemic control. Works particularly well in childhood obesity (even if not diabetic).
How do GLP-1 analogues work?
Incretin peptides used for TTD, potentiate insulin release and decrease glucagon release.
Has significant effect on food intake, and produced weight loss but at higher dosage than required for glycemic control (may induce nausea).
Most commonly administered: liraglutide (GLP analogue with long t 1/2 (13 hrs) associated with fatty acid allowing to be protected by serum albumin).
