Fasting vs. Fed State

use of stored fuels in fasted state

*Fatty acids* (from triacylglycerols) are the major energy source. *Ketone bodies* produced from fatty acids by liver are *oxidized primarily by muscle* *Catabolism of muscle protein* provides *amino acids for gluconeogenesis*

digestion: proteins

-> amino acids

digestion: fats

-> free fatty acids + 2-monoacylglycerols

Digestion: carbs

-> simple sugars starch -> glucose sucrose -> glucose and fructose lactose -> glucose and galactose

Exercise changes fuel utilization

-increased overall metabolic rate -use of both glucose and fatty acids (more fatty acid w/ sustained exercise) -glucose derived from both muscle glycogen and blood (muscle glycogen, liver glycogen, gluconeogenesis) -increased percent use of glucose with increased intensity -very intense muscle works causes glucose to be converted to lactate

Dietary Glucose in Liver...

1) Liver oxidaized glucose to meet E needs 2) Glycogen synth and stored 3) glucose converted to fatty acids and glycoerol to produce TAGs (triacyclglycerides) 4) TAGs packaged in VLDL, transported to adipose tissue 5) VLDL also deliver fatty acids (triglycerides) to muscle for immediate oxidation if needed if glucose levels in portal vein increase, concentration may increase causing velocity of *glucokinase (GK)* to increase = high Km.....GK levels also induced by increased insulin

"Adaptation" to starvation

= decreased rate of protein catabolism at first start catabolizing proteins to supply amino acids for gluconeogenesis but than *brain starts to use mostly ketones so less glucose is required and urea excretion decreases since less gluconeogensis* urea excretion = good index of total protein catabolism (unless unusually high nitrogen losses from wounds or Gi malfunction)

Brain in fasted state

Although the brain has mitochondria, *free fatty acids do not readily cross the blood-brain barrier* The brain continues to *require glucose in the fasted state* With prolonged fasting, the brain can also utilize *ketone bodies*

Proteins during starvation

Body protein is not a primary storage form of fuel like glycogen or triacylglycerol. Proteins function as enzymes, structural proteins in muscle contraction. *Excess protein degradation would result in severely compromised cell, tissue, organ function* If starvation continues an individual dies because of severe protein loss. *Results in major organ failure, e.g. heart, kidney, etc.* *Increased ketones spare body protein*; allows individual to survive for long periods without food ingestion.

Depletion of Reserves during starvation

Carbohydrate stores are rapidly depleted during the initial fast. Fat is the major fuel during starvation. Note decrease in protein depletion with adaptation. When fat reserves aredepleted, body protein is rapidly depleted, leading to death.

Major Dietary Fuels

Carbohydrates (45-60% total calories, or more) Fats or triacylglycerols (20-30% total calories) Protein (10-30% total calories)

Overview of Dietary Fuels in Fed State

Food is digested and processed for storage. Muscle and liver oxidize glucose. Excess glucose is converted to fat. Amino acids are used for protein synthesis in both muscle and liver

transport of energy

Glucose and amino acids are soluble in the plasma. The products of fat digestion are reassembled into *triacylglycerols* and transported in large lipoproteins called *chylomicrons*. A second hydrolysis then releases free fatty acids for uptake by the tissues.

glycogen to glucose

Glycogen is converted to glucose 1-P, converted to glucose 6-P then dephosphorylated by *glucose 6-phosphatase* to glucose, enters blood.

Fuel metabolism of the major organs

Heart muscle prefers fatty acids while working at a normal rate. Glycogen reserves provide for increase cardiac output as needed.

Stimulation of lipolysis during fasting

Hormonal changes that occur during fast stimulate breakdown of *adipose triacylglycerols* Fatty acids and glycerol enter blood. *Glycerol is a gluconeogenic precursor* Fatty acids become the major fuel of body; *oxidized to CO2 and H2O* This enables tissues to decrease their utilization of glucose. *Acetyl CoA from fatty acids provides energy (TCA cycle) for gluconeogenesis*

Energy stores in the Body

Most in triacylglycerols in adipose tissue, muscle, and liver good amount as glucose/glycogen in liver good amount of glucose/glycogen in muscle, fat in muscle, and large amount of mobilizable proteins in muscle 3 biggest stores: 1. Triacylglycerols in adipose tissue 2. mobilizable proteins in muscle 3. glucose/glycogen in muscle

Amino Acid Metabolism in the Fasted State

Muscle proteins are broken down. Some of the amino acids are oxidized. Alanine and glutamine are the major amino acids exported.

glucokinase

Phosphorylation of glucose to glucose-6-phosphate (G6P) by glucokinase is the first step of both glycogen synthesis and glycolysis in the liver. when lots of glucose is available, glycogen synthesis occurs in liver until glycogen stores are re-stored

fed (post-prandial) state

the body stores excess dietary fuels; ongoing digestion

albumin

Serum albumin is the main protein of human blood plasma.[7] It binds water, cations (such as Ca2+, Na+ and K+), fatty acids, hormones, bilirubin, thyroxine (T4) and pharmaceuticals (including barbiturates) - its main function is to regulate the colloidal osmotic pressure of blood

Fuels in Starved State

Similiar to fasting state but brain uses mixture of glucose and ketones (the longer the fast, the more ketones used) as the brain uses less glucose, less gluconeogenesis is required = slower rate of degradation of muscle protein

alanine and glutamine

The carbon skeletons of alanine and glutamine are *used by the liver and kidney for gluconeogenesis* Glutamine utilization by the kidney provides *NH4+* which serves to buffer *ketoacidosis during gluconeogenesis*

Adipose Tissue

~ 15% water Fat = 9 kcal/gram 3,500 kcal per pound

Prolonged fast or starvation

Tissues use less glucose than during brief fast. Fatty acids and ketone bodies become main fuel. Large increase in ketone bodies 3-5 days into fasting. Nervous tissue then uses ketones, glucose utilization decreases from 150 g to 40 g per day. Result of less glucose utilization is that the rate of gluconeogenesis declines and production of urea declines.

ketoacidosis

a metabolic state associated with high concentrations of *ketone bodies*, formed by the breakdown of fatty acids and the deamination of amino acids. The two common ketones produced in humans are *acetoacetic acid and β-hydroxybutyrate*

gluconeogensis

about 4hrs post meal provides a source for blood glucose a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as pyruvate, lactate, glycerol, and glucogenic amino acids. It is one of the two main mechanisms used by humans and many other animals to maintain blood glucose levels, avoiding low blood glucose level (hypoglycemia). The other means of maintaining blood glucose levels is through the degradation of glycogen (glycogenolysis).[1]

Dietary Glucose in peripheral tissues

all cells oxidize glucose for E brain uses 150 g glucose/day other glucose dependent tissues use aprprox 40g/day *insulin* stimulates glucose transport into *adipose tissue* (insulin released if blood sugar high) Other tissues such as liver, brain and red cells utilize different types of glucose transport not regulated by insulin. In *muscle glucose is converted to glycogen*, stimulated by *insulin*, also glucose transport stimulated by insulin.

Blood Glucose in Fasting State

blood glucose declines, *insulin decreases* and *glucagon increases* Liver degrades glycogen and *gluconeogenesis* is stimulated.

fat

excess glucose synth (primarily) in liver to fat, then secreted as VLDL. Hydrolysis of TAG during circulation = free fatty acids adipocytes take up free fatty acids (from VLDL and chylomicrons) use glucose (for glycerol-3-phosphate backbone) to make TAG (liver is main source of fatty acid synth but adipocytes can also convert glucose to fat)

Muscle

~ 80% water Protein = 4 kcal/gram 364 kcal per pound

Fuel in fasted state

free fatty acids from triacylglycerols = major source of E for most tissues during fasting free fatty acids transported on *albumin* The liver provides glucose both from *glycogen stores* and de novo synthesis (*gluconeogenesis*) from amino acids, lactate and glycerol. Under these conditions, the liver is only able to *partially oxidize fatty acids* and releases intermediates known as *ketone bodies*

Storage

glucose -> glycogen in muscle and liver excess glucose -> converted to fat -synth of triacylglycerol (TAG) in liver -TAG exported from liver as VLDL (very low density lipoprotein) *adipocytes* store dietary fat (from *chylomicrons*) and endogenously synthesized fat (from VLDL) amino acids - used for protein synth -*insulin* stimulates protein synth in muscle -excess amino acids are catabolized for E or fat -excess N secreted as urea

metabolites in blood during starvation

glucose decreases and stabalizes free fatty acids increase then stable ketone bodies increase; brain able to use to partially replace glucose for E source

Amino Acid Metabolism: Fed State

in fed state dietary amino acids are used for protein synthesis excess amino acids = broken down -N to urea and excreted -C skeletons to fat most amino acid catabolism occurs in liver but muscle is active in oxidation of branched chain amino acids

Fuel Utilization of Skeletal Muscle

in the post-absorptive state *resting muscle* prefers fatty acids to glucose in prolonged fasting state: uses endogenous amino acids and ketones in fed state, muscle takes up glocse and primarily uses it to regenerate glycogen stores

Erythrocytes in fasted state

lack mitochondria and are completely dependent on glucose as an energy source. (mitochondria enables fatty acid oxidation - if can't use fatty acids than need glucose)

Fasting Blood samples

measure *basal glucose levels* levels of serum cholesterol

Ketone bodies

produced during fasting small molecules produced by partial oxidation of fatty acids synthesized in the liver when gluconeogensis depletes TCA cycle intermediates plasma ketone levels increase by 18-24hr of fasting

glucagon

stimulates breakdown of glycogen into glucose, pancreatic alpha cells elevates cAMP, activates PKA, phosphorylates phosphorylase kinase, activates phosphorylase.

insulin

stimulates uptake of glucose by cells, pancreatic beta cells

fasted (post-absorptive) state

the body must rely on stored energy - after meal has been completely absorbed (3-5hrs post eating)