INTEGRATION OF METABOLISM(Metabolisme energi otot & organ penting)

Abdul Salam M. Sofro

Faculty of Medicine

YARSI University Jakarta

Learning objectives

• By the end of the lecture, students :– will realize that human body is an integrated

system of organs, each with its own requirements for nourishment & energy utilization

– will understand the use of fuels under different metabolic conditions

Metabolism of major foodstuffs

Food Molecules

Simpler Molecules

Amphibolic Pathways

Digestion Absorption

Anabolic pathw

ays

Catabolic pathways

CO2 + H2O

O2

Proteins, Carbohydrates.Lipids,Nucleic acids etc.

2H

~ P

Metabolic pathways: (i)Anabolic pathways(ii)Catabolic pathways(iii)Amphibolic pathways

• Products of digestion:– Carbohydrate : glucose– Lipid : fatty acid & glycerol acetyl-CoA– Protein : amino acid

In Ruminants:Cellulose is digested by symbiotic

microorganisms to lower fatty acids (acetic, propionic, butyric) acetyl-CoA

Carbohydrate FatProtein

Simple sugars(mainly glucose) Amino acids

Fatty acids +glycerol

Digestion and absorption------------------------------ ----------------------------

catabolism ---------------------------------------------------------------------------

Acetyl-CoA

Citric acid cycle

2 CO2

2H ATP

• Many of the major foodstuffs are inconvertible :

– carbohydrate (glucose) is converted to FA via pyruvate dehydrogenase reaction which is essentially irreversible, so the opposite process can not take place

– No net conversion of acetyl-CoA to glucose via Cyclic acid cycle (CA cycle)

• Many carbon skeletons of non-essential amino acids can be produced from carbohydrate via CA cycle & transamination

• Reversal of this process allows glucogenic amino acids to enter the pathway of gluconeogenesis

• During starvation, FFA & ketone bodies are oxidized in preference to glucose which is spares for tissues such as brain & erythrocyte that require glucose at all times

• Ketosis is a metabolic adaptation to starvation and it is exacerbated in pathologic conditions such as DM & ruminant ketosis

Overview of Metabolism

Some important points can be made about this summary diagram

• These pathways are integrated - they do not operate in isolation. Early parts of the pathways are reversible

• this is important for the storage and mobilization of fuels within the body as dietary supply and the body's need for fuel changes

• ATP is produced from the catabolic pathways - fuels are oxidized to products ATP is consumed in anabolic pathways - synthesis of storage forms of fuels

• Acetyl CoA is a central focus of metabolism

• it is formed from all three groups of fuel molecules and acts as a carrier of acetyl groups into the TCA cycle for their final oxidation to carbon dioxide

• it is also the starting point for important syntheses – it is the starting point for fatty acids synthesis – it can be converted to ketone bodies (not

shown on this diagram) when required

Notes:

• Under positive caloric balance, a significant proportion of the total energy intake is stored as either glycogen or fat

• If the diet is mainly carbohydrate, glucose will be the principal fuel of the tissue. However, in some tissues (even under fed conditions) fatty acid (FA) are oxidized in preference to glucose, but particularly under conditions of caloric deficit or starvation

The economics of carbohydrate & lipid metabolism

• Glucose is a metabolic necessity for the brain & erythrocytes in all nutritional states gluconeogenesis is particularly important

• A minimal supply of glucose is probably necessary in extrahepatic tissues to maintain oxaloacetate concentrations & the integrity of the CA cycle

• Glucose is also the main source of glycerol-3-P in tissues devoid of glicerol kinase such as adipose tissue

minimal & obligatory rate of glucose utilization under all conditions

Large quantities of glucose are also necessity for fetal nutrition & the synthesis of lactose in milk

• Preferencial utilization of ketone bodies & FFA spares glucose for its essential functions by:– Impairing its entry into cell– Its phosphorylation by hexokinase &

phosphofructokinase– Its oxidative decarboxylation to pyruvate

Turning Metabolism Off and On.Insulin Affects both Glucose and Lipid

Metabolism.

http://www.medbio.info/Horn/IntMet/integration_of_metabolism%20v2.htm

• Notes:

– Muscle tissue & liver not just take up glucose but they have glycogen reserves will be filled up when glucose is taken up

– Skeletal muscle which makes up more than 50% of the body will use glucose as a substrate for “aerobic glycolysis”

• Increased glucose levels stimulate pancreatic secretion of insulin the immediate effects :

– Increased skeletal muscle glucose uptake

– Inhibition of hepatic gluconeogenesis & glycogenolysis and stimulation of glucose uptake in the liver (not shown)

– Inhibition of lipolysis in fat tissue

The rates of flux through the various metabolic pathways are finely controlled in

the healthy individual.

• There are a number of strategies used by the organism to achieve this regulation. These methods include:– Organ Specialisation– Compartmentalisation of metabolic pathways – Allosteric control of enzymes – Covalent modification of enzymes – Levels of Enzymes

Use of Fuels Under Different Metabolic Conditions

• Different tissues are highly inter-dependent for appropriate supply of metabolic fuels under differing metabolic conditions.

• The diagrams below illustrate the use of fuels under four distinct metabolic scenarios : – the fed state at rest – the fasting state between meals – starvation of several days duration – sustained heavy exercise

http://www.unisanet.unisa.edu.au/10921/metab.htm

THE FED STATE

• Ingested food is digested to its monomeric units and absorbed from the gut. At rest most metabolic activity is directed towards storage -

– carbohydrate as glycogen

– fatty acids as triglyceride

– amino acids as protein

• Some energy (ATP) must be synthesized to power these anabolic reactions so relatively small amounts of amino acids and fatty acids are used in this way. Brain, kidney and involuntary muscle have a continuous need for ATP synthesis and all rely on glucose supplied readily in the diet in the fed

FASTING

• During a period of fasting such as occurs between meals metabolic pathways are reversed and activity is now directed to maintaining fuels supplies for catabolic pathways to those tissues with higher needs.

• glycogen stored in the liver is mobilised (glucagon stimulates) to supply brain and muscle

• glycogen stored in muscle is mobilized (adrenaline stimulates) and is used ONLY within the muscle (remember : muscle lacks glucose 6-phosphatase)

• amino acids are used by the liver for gluconeogenesis to maintain adequate circulating blood glucose particularly for the brain

• a small amount of mobilization of triglycerides occurs and the released fatty acids can be used directly by muscle and liver for catabolism while a small amount is converted to ketone bodies for use by muscle

STARVATION

• During extended starvation the metabolic pathways utilized change again. Glycogen reserves have been exhausted quickly - a short a period as 36h will significantly deplete glycogen stores. The body then relies primarily on stored triglycerides (in adipose tissue) to supply the fuel requirements of muscle and other tissues.

• The brain uses glucose produced by gluconeogenesis in the liver, but ultimately will switch to using the polar ketone bodies which can cross the blood-brain barrier. Ketone body production by the liver increases significantly with longer periods of starvation.

HEAVY EXERCISE

• During extended exercise the aim of these metabolic pathways is to supply muscle with sufficient fuel for sustained muscle contraction.

• Glycogen stores in the liver are mobilized as are triglycerides from adipose tissue. The former supplies glucose and the latter supplies fatty acids, either directly or as ketone bodies (after they are synthesized from fatty acids in the liver).

• Muscle uses its own glycogen reserves, primarily via glycolysis and then aerobic oxidation of pyruvate via the TCA cycle.

• Muscle has the capacity to rely solely on glycolysis in the absence of oxygen for a short period. Anaerobic glycolysis can be regarded as an emergency pathway and is only capable of supplying sufficient ATP for 1 - 2 minutes.

Ketosis• Is a metabolic adaptation to starvation & fat

feeding is relatively mild compared with the condition encountered in uncontrolled Diabetes Mellitus

• Arises as a result of a deficiency in available carbohydrate (glucose) & causes an imbalance between esterification & lipolysis in adipose tissue as a result of lower insulin levels release of FFA into the circulation (metabolic or endocrine factor affect the release of FFA from adipose tissue)

• Ketone bodies are utilized by extrahepatic tissues in proportion to their concentration in blood

http://www.medbio.info/Horn/Time 3-4/homeostasis_2.htm#Tissue distribution of glucose after a meal