Metabolic adaptations to fasting & postpranidal states

up to 3-8 hours after a meal (duration depends on the meal)

physiological situation

nocturnal fasting/ short fasting—>8 to 13 hours after a meal (duration depends on the meal)

moderate fasting: 2-3 days

prolonged fasting: > 3 days

adaptive mechanisms, consumption of endogenous proteins

Cost-saving: yeast stops proliferation to reduce energy metabolism (stationary phase) & block energy consumption until better days

mobilization of energy stores: humans utilize energy stores to increase activity (hunting & gathering)

absence of insulin (low glycemia): inhibition of glucose uptake in insulin-sensitive organs

release if glucagon: activation of ß-oxidation in insulin-sensitive organs, mobilization of energy stores (glycogen and TG), TG main storage of energy —>increased lipidemia

release of adrenaline: activation of gluconeogenesis (hepatic production of glucose)

low blood glucose & no insulin present (GLUT4 inactive)—>low glucose flux & decreased production of G6P —>decreased glycolytic flux —> low glycerol (backbone TG) & pyruvate —>low production of Acetyl-CoA via PDH —>Krebs cycle low —>low efflux of intermediates (citrate) to the cytosol (could be converted into Acetyl-CoA as 1. step of lipogenesis but too low)—>further inhibited by inactivation of ACC by AMPK (active in absence of insulin)

adrenaline ß3 receptor coupled with Gs activating adenylated cyclase —> increase in cAMP —> activation PKA (main regulator TG lipase) —>cuts FA from glycerol backbone & FFA released from the cell to increase the level of FFA in periphery

adrenaline triggers PKA activation —>inhibition glycogen synthesis & activation glycogen breakdown

glycolytic influx inhibited (PFK & GAPDH) as FA from adipose tissue are taken up —>ß-oxidation in mitochondria —>high acetyl-CoA (inhibits PDH) —>high ATP production

AMPK active —> allows the use of FFA —>efficient transport via CPT-1 in mitochondria

muscles & heart mainly use fatty acids as an energy source

adrenaline binds adrenaline receptor —>increased level of cAMP activates PKA

—> inactivates glycogen synthetase & inhibits synthesis of glycogen

—> activates phosphorylase kinase —> activation phosphorylase A —>activation glycogen breakdown

adrenaline —> FFA released (from a small store of TG)

& glycogen breakdown —> ↑G6P & inhibition glycogen synthesis

—>increased blood lipids & ß-oxidation for energy production

lipogenesis inhibited due to active AMPK —> inactive ACC

FFA increases ß-oxidation —> high levels of acetyl-CoA (inhibition PDH) & high levels of ATP (PFK & GAPDH inhibited)

increased rate of the Krebs cycle also increases citrate that can go into cytosol —>cant be used to produce FFA —>used for pyruvate production

high levels of pyruvate in the absence of glycolytic flux reinforced by an influx of AA & glycerol

glucagon triggers PEPCK (phosphoenol pyruvate carboxykinase): oxaloacetate —> phosphoenol pyruvate —> PEP used to produce G6P—>specific for liver under fasting conditions

all pathways used to produce G6P —>converted into free glucose & released in the blood —>gluconeogenesis

crucial to maintain glycemia, inhibited after a meal (hyperglycemia), in diabetic patients inhibition of PEPCK unfunctional

high pool in free glucose by glucose-6-phosphatase & exported due to gradient

G6Pase is bound to the membrane of ER & its catalytic site faces the lumen

G6P transporter carries G6P from cytosol to lumen

export of glucose & Pi by glucose and Pi transporter into cytosol

non-insulin sensitive: low Km glucose transporter GLUT1, glucose uptake always close to Vmax, little/not affected by low glycemia

heart&muscles: decreased glucose uptake, inhibition glycogenogenesis & glycolysis, activation ß-oxidation

adipose tissue: decreased glucose uptake, inhibition lipogenesis, increased lipolysis (FFA released)

liver: decreased (stopped) glucose uptake (GLUT2), inhibition glycogenogenesis & glycolysis, activation ß-oxidation / gluconeogenesis, activation splanchnic extraction of AA

physiological condition following a meal

in humans vagal stimulation reducing skeletal muscle, cardio-respiratory & cognitive activities —>store energy (ACh has the opposite effect as adrenaline)

insulin production (high glycemia): increased uptake & utilization of glucose by insulin-sensitive tissues

absence of glucagon: inhibition of ß-oxidation in insulin-sensitive tissues

absence of adrenaline: increased glycogen & TG storage

—>increased chylomicrons

insulin-induced translocation of GLUT4—> G6P↑ —>increased glycolysis —> pyruvate ↑ —>acetyl-CoA ↑

also glycerol ↑ (from glycolysis)

uptake of FFA: lipoprotein lipase LPL cleaves them from Chylomicrons —>Chymlomicron remnants (increased density)

mitochondrial energy production high, citrate exported in cytosol & converted into acetyl-CoA

AMPK inhibited by insulin —> ACC active —> lipogenesis produces FFA

from FFA & glycerol triglycerides produced (increased energy storage)

no adrenaline —> TG lipase inhibited (no FA released)

due to insulin (GLUT4 active)—>glycolysis active

adrenaline absent —>glycogen stored & not broken down

PDH active due to low acetyl-CoA

AMPK inactive—> ACC active & malonyl-CoA produced —>CPT-1 doesn’t transport Acyl-CoA into mitochondria—>no ß-oxidation —>low Acetyl-CoA

use of glucose & not FFA

glucose imported via GLUT2 (low affinity) —> direction conditioned by gradient —> high flux after a meal

high cytosolic glucose —> glycerol & pyruvate synthesized by glycolysis

absence of glucogen: PEPCK inactive —> no gluconeogenesis

absence of adrenaline: TG lipase inactive

AMPK inactive —> ACC active —> lipogenesis from citrate (high activity of Krebs cycle), exported in cytosol & conversion into Acetyl-CoA

from glycerol & FFA formation of TG —>loaded onto CMR to produce VLDL (new lipoproteins with newly formed FA)

non-insulin sensitive: low Km glucose transporters (GLUT1), glucose uptake at Vmax, little affected by high glycemia

heart & muscles: increased glucose uptake, glycogenogenesis & glycolysis activation, inhibition ß-oxidation

adipose tissue: increased glucose uptake, activation lipogenesis, inhibition lipolysis, increased uptake of FFA from Chylomicrons

liver: increased glucose tissue, glycogenogenesis & glycolysis activation, inhibition ß-oxidation, inhibition gluconeogenesis