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Adipose tissue (Barbara Fielding) - Coggle Diagram
Adipose tissue (Barbara Fielding)
Postprandial fat metabolism
why is post-prandial fat metabolism important and how does post-prandial fat metabolism work? Can measure changes in fat metabolism
How?
enterocyte in small intestine jejunum absorbs dietary fat and forms CM which travel via lymph
CM have APO B48 (if defect, then CM accumulate in gut)
Some VLDL still leaves liver after food eaten. However, insulin activates LPL and inhibits intracellular lipases and secretion of VLDL (less competition between CM and VLDL)= helps body to transport dietary fat to AT.
LPL hydrolyses CM TAG to FA to absorb into AT to make TAG
Chylomicron remnants (smaller) go to liver to back again for LPL hydrolysis
Importance: postprandial lipaemia and metabolic consequences (ectopic fat/ visceral fat) and atherosclerosis
Measurements of arteriovenous difference in healthy people after meal eaten (non-fasting) of plasma NEFA:
drop in NEFA in arterial and adipose venous (venous always higher) after meal eaten (due to insulin)
Insulin drops and fatty acids start to increase again in blood
Measurements of arteriovenous difference in healthy people after meal eaten of Plasma TAG ‘removal’ in AT
Similar levels of TAG for arterial and adipose venous when fasting
As CM move into blood (arterial) and removed (venous), difference is how much TAG been hydrolysed by LPL (rises as LPL releases TAG post-prandially)
Regulation of LPL- how LPL is activated
Adipocyte makes LPL and is secreted as an activated dimer from an adipocyte
Shuttled across to capillary endothelium
GPIHBP1 secreted on other side of capillary endothelium and shuttles lPL across to access CM
Other regulators of LPL:
Apolipoproteins
Angiopoitin lipoproteins (ANGPTL) : Inhibit LPL (during fasting)
Typical postprandial metabolite concentrations
Plasma TAG: fasting levels low (mainly VLDL) then rise post-prandially (mainly CM) and drops again after 180 minutes
Plasma glucose: Rises post-prandially due to glucose in meal then drops after 120 minutes
Plasma insulin: Rises alongside glucose
Plasma NEFA: Drops post-prandially and rises again after 120 minutes
GLUCOSE DETERMINING INSULIN AND INSULIN DETERMINING LIPIDS
Postprandial metabolism in healthy lean and overweight individuals (arteriovenous difference study over 24 hrs)
Aim- look at glucose and insulin which controls fat metabolism in overweight compared to healthy
Glucose: rises and falls for both groups after each meal. concentration ok in both groups
Insulin: Overweight group have much higher insulin concentrations after each meal (insulin resistance in action) so this will affect fat metabolism
Adipose tissue blood flow: per 100g AT, blood flow corresponds to meal in lean (rises with each meal) but in overweight, remains fairly constant with little fluctuations (AT becoming dysfunctional)
TAG: TAG (CM and VLDL) starting higher baseline in overweight and rise to higher values after each meal
NEFA: NEFA not affected as both adequate insulin levels (down after each meal and then up again)
Arterial blood flow
Can calculate the ‘Transcapillary flux’ (FA into and out of the AT) over 24 hours
In lean, net uptake of FA after each meal clearly seen
In overweight, failure of AT to store FA (little movement of FA) = travels around the body for ectopic fat deposition
Ectopic fat deposition
In T2DM, ectopic fat deposition can be reversed when put on low calorie diet
why? Less DNL, liver fat, resistance to insulin, less TAG in pancreas - liver fat can reduced
Regulation of fatty acid esterification (synthesis of TAG in adipocyte)
Suppression of lipolysis
increased glycolytic flux and glycerol-3-phosphate production (to make TAG)
Glucose needed into AT to make glycerol-3-phosphate
When regulation goes wrong! LPL gene defect.
Severe hypertriglyceridaemia
(11 week old with upper GI bleeding and skin problems and plasma TAG 426mmol/l )
Fed formula containing 84% fat from medium chain TAG so plasma TAG fell to 4.2mmol/l
Medium chain TAG do not form CM. They go into liver and are oxidised there
Lactation
Fatty acids used to make TAG for milk come from the diet or de novo litogenesis
De novo liipogenesis: dietary sugar converted into fat . thioesterase enzymes stop this reaction early so produce shorter chain fatty acids
Effect of a 3 day high fat diet
Plasma TAG higher in diabetic subjects compared to non diabetic despite being both given high fat diet for 3 days . WHY? higher cho diet spares oxidation of fat and results in de novo lipogenesis
AT and breast milk composition in women from France and Mauritius:
higher amount of longer chain fatty acids in women from mauritius (due to diet)= shows whats in adipose tissue comes from diet
higher amount shorter chain fats higher in breast milk in both groups= evdience of de novo litogenesias producing fats for breast milk
Adipose tissue- understand processes involved in release of fatty acids from adipocyte in AT
Functions of adipose tissue
store energy as food in adipose tissue and then release when required
Storage: healthier to store subcutaneously. Not viscerally.
NEFA FA fatty acids muscle
Transport of dietary Triacyglycerol
CM: carry to liver from gut
VLDL: excess NEFA to liver and released from liver as VLDL during overnight fasting and LPL still breaking it down to bring FA into muscle and adipose tissue
Carried in lipoproteins around blood
How does perilipin regulate HSL and Adipose TAG lipase (ATGL)
SWITCH ON TAG BREAKDOWN/NEFA RELEASE: Perilipin can be phosphorylated and allows P-HSL to move in and ATGL to be activated by P and cofactor
Perilipin (protein) gaurds lipid droplet, preventing HSL from gaining entry. insulin signalling inhibits ATGL gene expression
Adipose tissue lipolysis (insulin inhibits ATGL and HSL). once food eaten, insulin stops NEFA release for fat to be taken up
Insulin released in response to food ingestion
AT very sensitive to small rises in insulin
Lipolysis turned OFF: insulin immobilises pHSL (deactivation by de-phosphorylation/ removal of the phosphate group)
HSL moves away from droplet into cytosol so not available to hydrolyse
Adipose tissue lipolysis fasting: what causes release of NEFA before insulin kicks in? / NEFA release pathway
Regulation of Hormone Sensitive Lipase and Adipose Triglyceride Lipase (ATGL)
synthesis of PK and elevation of cAMP activates phosphorylation of ATGL+ CGI-58 (Cofactor) and HSL
P-ATGL and P-HSL next to droplet to access TAG to release NEFA
During fasting, exercise or stress: catecholamines (ANP and BNP) and cAMP trigger Protein Kinases (PK’s) to trigger enzymes in cascade of TAG conversion glycerol, releasing 3 FA molecules
PK triggers enzymes (by adding a phosphate group): ATGL (Adipose Trigclyceride Lipase) , HSL (Hormone sensitive lipase) , and MAGL (Monoacylglyceride lipase)
Glycerol end product travels round circulation and taken up by liver as cannot be re-used by adipose tissue
Measurements of arteriovenous difference:
Turning over our fat stores: the key to metabolic health (2018). How insulin infusion clamp demonstrates switching ON/OFF of NEFA release from adipose tissue
Plasma NEFA much higher in adipose venous compared to arterial during fasting 2. After insulin infusion given, BOTH drop significantly. Therefore, possible to completely switch off TAG release from adipose tissue with insulin. Insulin regulates NEFA release.
adipose tissue blood flow- does not function as well in obese
HOW?
Vein cannulated draining from adipose tissue and artery cannulated flowing to adipose tissue 2. Can measure what is going in through artery and out through vein to determine what is happening in adipose tissue e.g. If TAG content higher in artery than vein, shows TAG being taken from blood
need to measure adipose tissue blood flow via radioactive xenon given subcutaneously
Fit to expand- can expand up to 3000 times original size.m
Conversion of TAG/ fatty acids and glycerol. Esteriification- make up of TAG. Lipolysis- breakdown of TAG
What are fatty acids used for? Cell-membranes, elongated