adipocytes Flashcards
what is a major problem with using BMI to classify obesity?
muscle weighs more than fat, so highly muscular individuals could qualify as obese using this method
wasteline circumference and waist-to-hip ratio are becoming more commonly used
what is metabolic syndrome/syndrome X?
suite of conditions that often accompanies obesity
overall problem is excessive caloric intake
leads to:
1: obesity - increase in adipose tissue
2: dyslipidemia - increase in circulating FA and VLDL
3: hepatic steatosis - fatty liver (hepatocytes overloaded with TG)
4: atherosclerosis
5: insulin resistance
6: hypertension
describe a common progression to type II diabetes.
1: individual has positive energy balance = taking in more calories than needed
2: individual gains weight
3: excess fat causes insulin resistance in muscle
what are the theories as to why excess fat causes insulin resistance in muscle?
both theories converge at inhibition of the insulin receptor’s ability to tyrosine phosphorylate IRS-1 during insulin signal transduction cascade
inhibition mediated by activation of particular serine/threonine protein kinases that phosphorylate IRS-1 => inhibition of its ability to be tyrosine phosphorylated by the insulin receptor
inflammation theory: increased adipose mass => cytokine release => attraction of particular type of macrophage => secretion of more inflammatory cytokines (TNF-alpha and others) => activation of insulin-responsive tissues => activation of JNK kinase => phosphorylation of IRS-1
intracellular TG theory: increased TG in cells => increase intracellular TG metabolites (esp. DAG) = agonists of serine/threonine protein kinase PKC theta => phosphorylation of IRS-1
what is the difference between early and late type II diabetes? what treatment approaches would you take in each situation?
early: hyperglycemia and hyperinsulinemia but not complete insulin resistance yet?
can try to sensitize cells to insulin as treatment
late type II diabetes: hypoinsulinemia because pancreatic beta cells either die or lose ability to produce insulin - may be genetic component in transition
now requires insulin treatment
what is the difference between glucokinase and hexokinase?
glucokinase has a much higher Km for glucose
since it’s in the pancreatic beta cells, this means that the posphorilation of glucose entering the cell isn’t limited by the Km of the enzyme converting it to glucose-6-phosphate, which means that the amount of glucose-6-phosphate in pancreatic beta cells is directly correlated with the amount of glucose in the blood, allowing these cells to sense the blood glucose levels
what could the effect of intracellular TG in beta cells be?
increased TG could cause impaired insulin release by up-regulating the expression of an uncoupling protein (UCP-2) => dissipation of the H+ gradient across the mitochondria => inhibited ATP production
what factors lead to hepatic steatosis (fatty liver)?
1: increased chylomicron TG from diet
2: insulin resistance in adipocytes => HSL stays active => more FA in blood
3: trascription factors SREBP-1c and ChREBP in liver up-regulate transcription of FA synthetic genes
4: increased ACC transcription => increased malonyl-CoA production => increased FA synthesis and inhibited liver FA oxidation
combined effect of increased FA synthesis and decreased FA oxidation => TG buildup as intracellular lipid droplets and secreted VLDL
how can SREBP-1c lead to hepatic steatosis?
this transcription factor is activated by insulin - the effect of insulin isn’t reduced by insulin resistance, so even though diabetic patients are resistant, the insulin in their system will still act on insulin-regulated transcription factors
activation => increased synthesis of many enzymes involved in FA synthesis
how can ChREBP lead to hepatic steatosis?
transcription factor = carbohydrate response element binding protein
activated by glucose
1: increases synthesis of many of the enzymes involved in FA synthesis
2: increases synthesis of liver pyruvate kinase (L-PK) - L-PK drives glucose through Krebs cycle => citrate - needed for FA synthesis
what is orlistat and how does it work? what are the side effects?
currently the only approved drug for long-term obesity treatment
pancreatic lipase inhibitor - causes TG to stay in the gut and be secreted in the stool => reduction of fat absorption by 30%
side effects:
1: mal-absorption of fat-soluble vitamins - prevent with supplementation
2: loose, oily stools
what is rimonabant and how does it work? what are side effects?
cannabinoid receptor antagonist
acts in hypothalamus to suppress orexigenic effect of endogenous cannabinoids
anorexigenic
has been withdrawn from the market in europe due to side effect = depression - never approved in US
what is sibutramine and how does it work? what are the side effects?
aka meridia
originally antidepressant
blocks norepi and serotonin reuptake - both NTs have anorexic effects so blocking their reuptake extends the length of the their effect and so decreases appetite
appears effective at preventing rebound after weight loss, but has been taken off the market due to cardiovascular and stroke side effects, as well as depression
how can exercise affect insulin sensitivity?
1: more surface GLUT4 => enhanced glucose up-take into muscle
2: enhanced glucose and FA catabolism in muscle
3: longer-term enhanced transcription of several proteins including GLUT4
4: enhanced mitochondrial proliferation and FA storage
what activates AMPK? what are the effects/actions of AMPK?
activated by increase in AMP:ATP ratio effects= 1: increases ATP generation 2: decreases ATP utilization 3: targets ACC for phosphorylation => decreased ACC activity => increased FA oxidation, decreased FA synthesis
