metabolic integration

three major sources of metabolic fuel for the body

proteins, carbohydrates, and lipids

key pathways required to convert metabolic fuels into ATP

amino acid metabolism, carbohydrate metabolism, lipid metabolism, the citrate cycle, and oxidative phosphorylation

pancreas

• secretes insulin in response to rising blood glucose levels

• secretes digestive proteases that degrade dietary proteins in the small intestine

  • trypsin

  • chymotrypsin

  • elastase

intestines

• small intestine

  • absorbs nutrients

  • secretes peptide hormones

• large intestine

  • absorbs water and electrolytes

stomach

• prepares food for small intestine by producing chyme

• secretes peptide hormones that control eating behaviors through neuronal signaling in the brain

liver

• central processing facility and metabolic hub

• determines what dietary nutrients and metabolic fuels are sent to peripheral tissues

• glucose regulator that removes excess glucose from blood when carb levels are high and releases glucose when carb levels are low

  • cntrolled by insulin and glucagon signaling

• portal vein directly delivers nutrients from the small intestine and inactivates toxins from the diet

the fate of glucose-6-phosphate depends on

the metabolic needs of the liver and peripheral tissues

fates of glucose-6-p

• converted into glucose-1-p for glycogen synthesis

• dephosphorylated to be released into the blood to be used by other tissues (brain)

• converted to 6-phosphogluconolactone in the PPP if NADPH is needed

• converted to fructose-6-p for glycolysis to make pyruvate and then make acetyl-CoA for OXPHOS

skeletal muscle

• uses fatty acids, glucose, or ketone bodies depending on physical movement required (rapid burst of activity or endurance)

• can be used as an energy source for the body during times of starvation

creatine kinase

• catalyzes a reversible phosphoryl transfer reaction with ADP and phosphocreatine that generates ATP and creatine when a more sustained level of muscle activity is needed

• resynthesizes phosphocreatine from ATP and creatine when ATP pools return to normal

phosphocreatine shuttle

• two creatine kinase isozymes

• mito CK moves phosphate from the mitochondrial matrix to the cytosol through phosphocreatine

• phosphate is transferred to ADP in the cytosol to generate ATP for muscle contraction through cyto CK

• cyto CK also phosphorylates creatine to generate phosphocreatine

cardiac muscle

• uses mostly fatty acids and ketone bodies to continuously sustain a steady heart beat for an entire lifetime

• primary mode of energy conversion is aerobic respiration using acetyl-CoA provided by fatty acid oxidation and ketone bodies

adipose tissue

• secretes peptide hormones (adipokines) to regulate metabolic homeostasis

• makes up 15-25% of an individual’s mass

two basic types of adipose tissue

• subcutaneous: just underneath the skin in the thighs, buttocks, arms, and face

• visceral: located deep within the abdominal cavity and secretes adipokines

elevated levels of certain types of adipokines in the blood have been associated with

increased risk of cardiovascular disease

brain

• control center of our bodies

• 20% of the oxygen consumed by the body is used for oxidative phosphorylation

• depends mostly on glucose— 60% of the body’s glucose is required by the brain

astrocytes

glial cells that make multiple contacts with endothelial cells of microcapillaries to transport glucose metabolites to surrounding neurons for use in energy conversion reactions that generate ATP

kidneys

• located on either side of the abdominal cavity

• only other major organ that uses gluconeogenesis to export glucose to other tissues

• remove concentrated levels of urea, ammonium, ketone bodies, and other soluble metabolites from the blood

hemodialysis

procedure used by patients with kidney disease to remove waste products from the blood using high diffusion rates across a semi-permeable membrane

metabolic homeostasis

the process of maintaining optimal metabolite concentrations and managing chemical energy reserves within an organism

under normal homeostatic conditions the liver is the

control center and plays a crucial role in regulating metabolite flux among tissues and organs

the six primary functions required to maintain homeostatic under normal conditions

• liver exports glucose, ketone bodies, and triacylglycerols to the peripheral tissues for use as metabolic fuel

• brain requires constant input of glucose

• cardiac muscle uses fatty acids and ketone bodies for most energy needs but also uses small amounts of glucose

• triacylglycerol cycle maintains circulation of high-energy fatty acids between liver and adipose tissue

• skeletal muscle uses glucose and fatty acids from both the liver and dietary sources for ATP synthesis and also exports lactate back to the liver to complete the Cori cycle during prolonged physical exertion

• amino acids glutamine and alanine transport excess nitrogen obtained from protein degradation in the muscle to the liver nd kidneys for excretion as urea

triacylglycerol cycle

an interorgan process that continually circulates fatty acids and triacylglycerols between adipose tissue and the liver to maintain circulation of energy-rich fatty acids that can be used by the peripheral tissues

the two components of the triacylglycerol cycle

• systemic component cycles fatty acids between adipose tissue and the liver in the form of fatty acids bound to albumin and TAGs contained in lipoprotein particles

• intracellular component in adipocytes cycles fatty acids in the form of cytosolic free fatty acids and TAGs stored in lipid droplets

• dependent on sufficient level of glycerol-3-phosphate

glyceroneogenesis

functions in adipocytes and hepatocytes to synthesize dihydroxyacetone phosphate when blood glucose levels are low (no glycolysis)

• uses many gluconeogenic enzymes

• does not make glucose

insulin

• released by pancreatic beta cells when blood glucose levels are high

• stimulates glucose uptake in the liver, skeletal muscle, and adipose tissue

• activates glycogen synthesis and fatty acid synthesis

glucagon

• released by pancreatic alpha cells

• stimulates gluconeogenesis, glycogen degradation, and fatty acid export from adipose tissue when food is not available

glucose uptake in the liver cells is primarily due to (insulin signaling)

increased metabolic flux through glycolytic, glycogen synthesis, and triacylglycerol synthesis pathways

in skeletal muscle insulin stimulates glucose uptake by

increasing the level of GLUT4 protein on the cell surface and also by increasing the flux through glycolytic and glycogen synthesis pathways

in adipose tissue insulin stimulates glucose uptake by

increasing GLUT4, leading to increased fatty acid and glycerol synthesis; and by activating fatty acid uptake from lipoprotein particles to promote TAG storage

in the brain insulin signaling stimulates

neuronal signaling in the hypothalamus that leads to decreased eating and increased energy expenditure (anorexigenic neurons)

glucagon signaling in the liver tissue stimulates

glucose export as a result of increased rates of gluconeogenesis and glycogen degradation

in adipose tissue glucagon activates

TAG hydrolysis and fatty acid export

skeletal muscle and brain cells lack enough levels of

glucagon receptors (glucagon insensitive)

primary responses of insulin in liver (regulation of enzymes)

• elevated expression of glucokinase to trap glucose into glycolysis or glycogen synthesis

• activation of protein phosphatase 1 to dephosphorylate PFK-2/FBP-2 and activate PFK-1 through increased levels of fructose-2,6-bisphophate which inhibits fructose-1,6-bisphosphatase and gluconeogenesis

• protein phosphatase 1 also stimulates glycogen synthase and inhibits phosphorylase kinase and glycogen phosphorylase

• pyruvate dehydrogenase complex is activated to create more acetyl-CoA for fatty acid synthesis

• protein phosphatase 2A is stimulated to activate acetyl-CoA carboxylase to synthesis malonyl-CoA from acetyl-CoA

primary responses of insulin in skeletal muscle (regulation of enzymes)

• activation of protein phosphatase 1 to dephosphorylate PFK-2/FBP-2 and activate PFK-1 through increased levels of fructose-2,6-bisphophate which inhibits fructose-1,6-bisphosphatase and gluconeogenesis

• protein phosphatase 1 also stimulates glycogen synthase and inhibits phosphorylase kinase and glycogen phosphorylase

• pyruvate dehydrogenase complex is activated (no fatty acid synthesis)

• all glucose is used for metabolic fuel within the tissue; it cannot be exported or converted to fatty acids

primary response of insulin signaling in adipose tissue

• lipoprotein lipase is stimulated to hydrolyze fatty acids from chylomicrons and VLDL particles to promote lipid uptake

• hormone-sensitive lipase is inhibited to decrease fatty acid release from adipocytes

the glucagon receptor is a G-protein coupled receptor that stimulates

adenylate cyclase activity and production of cyclic AMP which activates PKA

primary response of glucagon signaling in the liver

• PKA activates phosphorylase kinase to induce glycogen degradation (inactivates glycogen synthase and protein phosphatase 1)

• PKA phosphorylates PFK-2/FBPase-2 which leads to decreased fructose-2,6-BP levels and increased flux through gluconeogenesis

primary response of glucagon signaling in adipose tissue

PKA phosphorylates perilipin and hormone-sensitive lipase to hydrolyze TAGs, they bind to serum albumin and and transported to tissues for use in energy conversion reactions; glycerol is metabolized by liver in glycolytic and gluconeogenic pathways

with the onset of starvation, blood glucose levels are initially maintained by

degradation of liver glycogen in response to glucagon signaling

during starvation metabolic flux is altered in two ways

• gluconeogenesis is stimulated in the liver and kidneys to generate glucose for brain cells and erythrocytes

• fatty acids are used as the primary metabolic fuel in almost all tissues

flux of metabolites between major tissues and organs during starvation

• once glycogen stores are depleted, adipose and skeletal muscle are the primary sources of metabolic fuel during starvation

• fatty acids released from TAG hydrolysis in adipose tissue are transported to skeletal muscle and the heart by serum album protein

• fatty acids are used to generate acetyl-CoA for the citrate cycle and OXPHOS

• acetyl-CoA produced from fatty acids in the liver is used for the production of ketone bodies, which are an important energy source for the heart and the brain during starvation

• amino acids derived from protein degradation in skeletal muscle provide necessary carbon to make pyruvate or alpha-ketoglutarate (catabolism of skeletal muscle is delayed as long as possible)

• alpha-ketoglutarate is used in the citrate cycle to make oxaloacetate which is then used in gluconeogenesis to make glucose

metabolic energy balance

calories consumed/ day (input) = calories expended/ day (output)

• caloric input > output = positive energy imbalance

• caloric input < output = negative energy imbalance

a balanced input/ output occurs at about ~1500-2000 calories/ day

metabolic syndrome

lifestyle of prolonged positive energy imbalance

• abdominal obesity

• insulin resistance

• hypertension (high blood pressure)

• hyperlipidemia (high LDL)

• high risk for cardiovascular disease

type I diabetes

• juvenile

• insulin dependent

• insufficient insulin production by pancreatic beta cells

type II diabetes

• adult onset

• insulin resistance

• coupled to positive energy imbalance (weight gain)

• desensitization of insulin receptor signaling

inhibition of insulin signaling by free fatty acids (insulin resistance)

• increased levels of free fatty acids lead to the production of diacylglycerol (DAG) in the plasma membrane which stimulates protein kinase C

• PKC phosphorylates insulin receptor substrate 1 (IRS-1) on serine residues, which inhibits the normal phosphorylation of IRS-1 tyrosine residues by the insulin receptor

• results in lack of insulin signaling leading to high glucose levels in blood

tumor necrosis factor alpha is an

inflammatory cytokine that is produced at higher levels in adipocytes when lipid stores are high

autocrine signaling by TNF-alpha in adipocytes leads to

down regulation of genes involved in the uptake and storage of fatty acids which leads to increased levels of fatty acids in serum and interferes with insulin signaling in muscle

drugs that treat diabetes

• alpha-glucosidase inhibitors (miglitol)

• sulfonylurea drugs (glipizide), inhibit ATP-dependent K⁺ channel

• drugs that stimulate AMPK (metformin)

• ligand agonists of the nuclear receptor PPARgamma (thiazolidinediones)

metformin mechanism

• guanidine analog that improves sensitivity in multiple tissues by elevating AMP levels, which activates AMP-activated protein kinase (AMPK) signaling

• increased levels of AMP in skeletal muscle leads to increased rates of fatty oxidation, glucose uptake, and mitochondrial biogenesis to raise ATP levels

• in the heart, fatty acid oxidation, glucose uptake and metabolic flux through the glycolytic pathway is increased

• inhibits metabolic flux through the gluconeogenic, fatty acid synthesis, and cholesterol synthesis pathways in the liver

• inhibits the rates of fatty acid synthesis and TAG hydrolysis in adipocytes

the insulin sensitizing activity of thiazolidinediones is due to

PPARgamma-mediated regulation of adipocyte gene expression which affects glucose and lipid metabolism in liver and muscle tissues

PPARgamma signaling

• peroxisome proliferator-activated gamma (PPARgamma) nuclear receptors

• PPARgamma induces expression of proteins (fatty acid transport protein and lipoprotein lipase) that inrcease the influx of fatty acids into adipocytes

• increases expression of enzymes (phosphoenolpyruvate carboxykinase and glycerol kinase genes) that activate TAG synthesis through elevated levels of glycerol-3-phosphate

• Thiazolidinedione-mediated activation of PPARgamma signaling in adipose tissue leads to down-regulation of inflammatory cytokines (TNF-alpha)

three primary factors influencing metabolic homeostasis

• genetic inheritance

• nutrition

• exercise

glycemic index

a numerical value indicating how fast glucose is released into the blood after eating carb containing foods relative to the rise in blood glucose levels after drinking a solution of pure glucose

• <55 healthy carbs

foods with a high glycemic index are associated with

a drop in blood glucose levels below the normal fasting state, which can leave one feeling lethargic and cause insulin spikes

running a 10 km race in an hour requires (endurance)

aerobic respiration using glucose derived from muscle glycogen and acetyl-CoA obtained from the degradation of fatty acids

a 200-meter sprint requires (short burst of activity)

phosphocreatine and anaerobic respiration of muscle glycogen as a source of ATP

ATP and phosphocreatine provide energy for muscle contraction for only

a few seconds

conversion of glucose to lactate can supply ATP for

several minutes