HPA axis

Question 2

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

Answer 2

hypothalamus

Question 3

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

Answer 3

resistancehigh

Question 4

db/db diabetic obese mouse:Lack of leptin ___- long form involved in signallingidentical phenotype to obese mousecannot treat their obesity with leptin

Answer 4

receptors

Question 5

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

Answer 5

macrophages

Question 6

PI3K pathway mediates lots of insulin responses e.g.GLUT4 translocationglycogenesisinhibition of_______pathway shows less activity in insulin resistance

Answer 6

lipolysis

Question 7

MAPK pathway mediates proliferative effects. it is ___by insulin resistancein hyperinsulinemia, pathway may have atherogenic + carcinogenic effects

Answer 7

unaffected

Question 8

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

Answer 8

β3sympathetic

Question 9

mature adipocyte makes adipokines e.g. leptin, ______PPARγ2 needed for adipogenesis and adipocyte differentiationadipogenesis: smaller adipocytes, less ectopic deposition and improved insulin sensitivity

Answer 9

adiponectin

Question 10

lipodystrophymay be genetic or acquiredoften have aspects of metabolic syndrome: insulin resistance, dyslipidaemia, hypertensionsymptoms can be alleviated with some__________

Answer 10

adipokines

Question 11

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

Answer 11

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

Question 12

preadipocytes—> adipocytes stimulated by ___phosphorylation of Ser114 inhibits this activityMAPK pathway disrupted mutant PPARγ2 overactive–> ↑ differentiation of adipocytes–> obesity but lower insulin levels

Answer 12

PPARγ2

Question 13

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 ____

Answer 13

glucose

Question 14

Adipokinesantiinflammatory and insulin sensitizing . hyperplasia of adipocytes good hypertrophy bad–> adipokines become pro-inflammatory and insulin desensitizing. more cell death- recruits _____

Answer 14

macrophages

Question 15

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

Answer 15

increases, decreasesleptin is also a chemoattractant and has an effect on the reproductive system

Question 16

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

Answer 16

CSF

Question 17

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. ____

Answer 17

obesityTNF-αthizaolidinedones. duh

Question 18

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

Answer 18

decreasing

Question 19

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

Answer 19

inhibit

Question 20

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

Answer 20

adiponectinIL10overactive1/3 of circ IL6 produced by adipose tissue. IL6 causes liver to make inflammatory proteins e.g. CRP

Question 21

Macrophage infiltration↑ in obesity–> clustered around dead adipocytes that have undergone necrosis forming CLS=”____ _____ ______”

Answer 21

crown like structures

Question 22

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

Answer 22

Phosphorylationleptin

Question 23

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

Answer 23

skeletal muscle, livervisceral TZDs and adiponectin that increase adipogenesis can ↑ insulin sensitivity, w/o necessarily causing weight loss

Question 24

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

Answer 24

decreasesgluconeogenesisother anti-inflammatory drugs e.g. aspirin may be able to decrease insulin resistance

Question 25

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.

Answer 25

prostacyclinproliferation

Question 26

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 ____

Answer 26

vasoconstrictorIL6 and TNF-α,

Question 27

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

Answer 27

ROS proliferationangiotensinogen

Question 28

Adiponectin, hypertensionlow levels correlate with high BPadiponectin __ NO productioninhibits TNF-α signalling so less adhesion molecules on ______adiponectin suppresses oxLDL from inhibiting eNOS activity

Answer 28

↑endothelial cells

Question 29

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

Answer 29

growth factorsmitogen adiponectin suppresses proliferation, causes arrest of cell growth and favours apoptosis

Question 30

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

Answer 30

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