HPA axis Flashcards
Lethal yellow mutant mouselethal to homozygotes, heterozygotes have yellow coat, mature onset obesity, type 2 diabetes high leptinectopic expression of agouti protein normally blocks α-MSH from binding to Mc1 R. in ___: melanocortin usu inhibits feeding behaviour, but agouti antagonises Mc4 R on some neurons –>appetite cannot be suppressed
hypothalamus
ob/ob obese mouse:doesnt express product of ob gene- leptin which suppresses appetite. no leptin–> insulin_______mice lose weight dramatically when given leptinmost obese humans have ___ leptin levels, show some leptin resistance
resistancehigh
db/db diabetic obese mouse:Lack of leptin ___- long form involved in signallingidentical phenotype to obese mousecannot treat their obesity with leptin
receptors
diet induced obesitysome strains more resistant to DIO than othersmice fed cafeteria diet had worse glycaemia, highest FFA levels, higher levels of infiltrating ____and altered islets
macrophages
PI3K pathway mediates lots of insulin responses e.g.GLUT4 translocationglycogenesisinhibition of_______pathway shows less activity in insulin resistance
lipolysis
MAPK pathway mediates proliferative effects. it is ___by insulin resistancein hyperinsulinemia, pathway may have atherogenic + carcinogenic effects
unaffected
brown adipose tissueNA acting on____receptors stimulates lipolysis and FAOproton gradient is wasted via ucp1Unlike white adipose tissue, brown:Multiocular TAG dropletslarger, higher density mitochondriahgh ___innervationcapillary network denser
β3sympathetic
mature adipocyte makes adipokines e.g. leptin, ______PPARγ2 needed for adipogenesis and adipocyte differentiationadipogenesis: smaller adipocytes, less ectopic deposition and improved insulin sensitivity
adiponectin
lipodystrophymay be genetic or acquiredoften have aspects of metabolic syndrome: insulin resistance, dyslipidaemia, hypertensionsymptoms can be alleviated with some__________
adipokines
Familial partial lipodystrophy 3progressive, gradual loss of subcut adipose tissue from extremities↑deposition of TAG in muscle and liver↑ TGLs, low HDL, severe insulin resistance –> diabetesdue to mutations in PPARG gene coding for_____dominant negative, haploinsufficiency
PPARγhaploinsufficiency:only 50% expression of functional gene productdominant negative: faulty copy expressed and translocated–> nucleus but interacts with PPARγ binding partners, inhibiting activity OR binds to DBD but doesnt increases expression
preadipocytes—> adipocytes stimulated by ___phosphorylation of Ser114 inhibits this activityMAPK pathway disrupted mutant PPARγ2 overactive–> ↑ differentiation of adipocytes–> obesity but lower insulin levels
PPARγ2
portal theory: visceral adipose tissueVAT: resistant to insulin, sensitive to adrenaline so releases more fatty acidscan–> liver insulin resistance, so liver produces more VLDL and ____
glucose
Adipokinesantiinflammatory and insulin sensitizing . hyperplasia of adipocytes good hypertrophy bad–> adipokines become pro-inflammatory and insulin desensitizing. more cell death- recruits _____
macrophages
Leptinsecreted by mature adipocytesreceptors in feeding centre of hypothalamus but also in peripherysecretion ↑ with body fat, fluctuates in response to insulin↑ with overfeeding ↓ with fastingleptin___ food intake and___ energy expenditure
increases, decreasesleptin is also a chemoattractant and has an effect on the reproductive system
Leptin resistanceobese ppl: leptin levels are low in __compared to high plasma levelsdietary fat and fructose don;t stimulate insulin and do not ↑ leptin secretion
CSF
Adiponectinnormally at high levels in plasma but lower in ____expression depends on PPARγ but is inhibited by ____lower in larger adipocyteslow levels: hyperinsulinemia, insulin resistance, future diabeteslevels are increased by weight loss, exercise and ligands to PPARγ e.g. ____
obesityTNF-αthizaolidinedones. duh
Adiponectin↑ levels–> ↑ insulin sensitivitymuscle has receptor AdipoR1. adiponectin causes an ↑ in glucose uptakeliver has AdipoR2: responds by ____gluconeogenesis and plasma glucoseanti-inflammatory- inhibits TNF-α
decreasing
Inflammation mild, but chronic↑ CRP, IL6,serum amyloid A levelsadipose tissue produces IL6, IL8, TNF-α, chemokines etc. these proteins____ preadipocyte maturationweight loss can decreases these proteins
inhibit
Inflammation Anti-inflammatory: IL10, adiponectin. less as obesity increases____ inhibits macrophage activation and stimulates them to produces a/i cytokines e.g.__Pro-inflammatory proteins: leptin, IL6, Angiotensin. levels predict onset of diabetes. inhibit adiponectin expressionsome aspects of inflammation are dependent on RAS–> which is ___in obese
adiponectinIL10overactive1/3 of circ IL6 produced by adipose tissue. IL6 causes liver to make inflammatory proteins e.g. CRP
Macrophage infiltration↑ in obesity–> clustered around dead adipocytes that have undergone necrosis forming CLS=”____ _____ ______”
crown like structures
Insulin resistancean inadequate response to normal levels of insulin. higher levels needed to maintain normoglycaemiadue to downregulation of receptor/proteins downstream in signalling pathwaymay be due to inflammatory pathways–> inhibition of insulin pathway e.g. Ser _____ of IRS___improves insulin sensitivity via AMPK,but its resistance not seen in obesity
Phosphorylationleptin
Insulin resistancein obese, correlates with ectopic lipid deposition e.g. in _____ and ____subcut adipocytes can’t handle load of fat storage so TAG spills over into ____adipose etcectopic deposition may → ↑ ceramide, that alters signalling p/w
skeletal muscle, livervisceral TZDs and adiponectin that increase adipogenesis can ↑ insulin sensitivity, w/o necessarily causing weight loss
Adiponectin and insulin resistanceadiponectin levels decrease with obesity. it activates AMPK which favours FAO in muscle via AdipoR1. This __ectopic lipid storage in muscle and ↑ insulin sensitivity It ↓ expression of PEPCK and G6Pase in liver so no excess ___it opposes TNF-α
decreasesgluconeogenesisother anti-inflammatory drugs e.g. aspirin may be able to decrease insulin resistance
Hypertensionendothelial cells can produce:vasodilators: NO, ___vascoconstrictors: ROS, endothelin-1, RAS components,smooth muscle ___ can ↑muscle stiffness and ↑ BPperivascular AT adipokine secretion altered by obesity.
prostacyclinproliferation
Hypertension + leptin stimulates sympathetic ↑ BP. not affected by leptin resistanceleptin induces endothelin-1 a _____promotes smooth muscle proliferationstimulates production of pro-inflammatory cytokines e.g._____ and ____
vasoconstrictorIL6 and TNF-α,
Hypertension + inflammation ↓ NO production↑ ___which further depletes NOEndothelin-1 expression enhances smooth muscle ____ RASAdipocytes produce more _____, more in obesity in visceral adipocytes in response to glucocorticoids
ROS proliferationangiotensinogen
Adiponectin, hypertensionlow levels correlate with high BPadiponectin __ NO productioninhibits TNF-α signalling so less adhesion molecules on ______adiponectin suppresses oxLDL from inhibiting eNOS activity
↑endothelial cells
Obesity and cancermore aggressive, more metastases, more resistance to chemo, higher mortalityplasma adiponectin levels are usu lower in cancer patientsadipose tissue also produces ____ ___that stimulate angiogenesisleptin can act as a __, tumours often express leptin receptor
growth factorsmitogen adiponectin suppresses proliferation, causes arrest of cell growth and favours apoptosis
Angiogenesisleptin promotes angiogenesisinfiltrating ____produce VEGF +synergise with leptin HGF, produced in adipose has angiogenic propertiesTNF-α can be angiogenic at low levels IL6 ↑ VEGF expression____is a chemoattractant for macrophages+ ↑ their TNF-α production_______ is anti-angiogenic
macrophages leptinadiponectinHGF: hepatocyte growth factorthe new BVs formed are hyperpermeable to small molecules , plasma fluid and proteinseasier for metastatic cells to invade and–> circulationinvasive cancer cells may express chemokine receptors and inflamed adipose produce CCL2, leptin aiding their survival in new locations
