L1: Responses to fasting

What is metabolism

• chemical procosses required to sustain life

Unit of ernegy

• calories

• heat energy required to raise the temperature of 1 gram of water from 14.5-15.5

One calorie is how many joules

• 4.186 joules

• 1 Calorie (capitalized)= one kilocalorie

Aim of the lecture

• see how long you could last without eating by considering

1. Rate of energy expenditure of the body

2. measure our fat reserves

3. How hormones guide fasting metabolism

4. Consequences of long-term malnutrition

1. Metabolic rate

• rate at which energy is consumed by the body

Average requirement of energy used

• 8500 kJ day-1

• rising to 30,000 kJ day-1 with very hard labour

What is metabolic rate affected by

1. Sleep→ 10% decrease

2. Fasting (up to 40% decrease, due to lower thyroid hormone level)

3. Post-prandial thermogenesis→ up to 40% increase

   • after eating

   • when food is processed in the liver

   • Nitrogen metabolism→ heat

4. Temperature

   • Thermoregulation demands energy

   • body temp itself directly affects rate of metabolic reactions

5. Muscle: fat ratio

   • Differs in men and women

   • muscle uses more energy

6. Exercise

   • metabolic rate can typically be increased to x10 BMR or up to 20x in trained athletes

7. Growth, gestation and lactation

Pathologies

8. Hormone imbalances

   • variations in levels of thyroid hormone

   • can alter BMR from 40-200% of normal

   • Growth hormone and testosterone have similar effects

   • hypothydroi→ ½
     hyper→ x2

How to compare metabolic rates: Basal metabolic rate BMR

Energy consumptin in the resting , post absoprtive state

• 12-14 hours after last meal

• thermoneurtral environment

  • no shiver or sweat

What is the average BMR

• 80W in a 70kg man

What is BMR due to

• activities including

  • ionic pumping

  • necessary muscle function

  • protein metabolism

  • basal secretion of glands

How is BMR assessed

• Indirect calorimetry

  1. Measure rate of oxygen consumption in STP

  2. estimate energy production as 20.2 kJ litre -1 O2 consumed

  3. assumes that metabolism is based on 40% carb and 60% fat (RQ=0.82)

Note on respiratory questions

• Normal→ 0.82

• never really fully one fuel used or the other

• metabolism is like dials→ not an on and off switch

• RQ= Rate of CO2 production/ rate of O2 consumption

Respiratory question: average diet

• 45% carbs→ 17 kJg-1

• 40% from fats→ 37kJ g-1

• 15% from proteins→ 17kK g-1

• given losses from incomplete metabolism

When may RQ exceeed 1

• when rate of fat synthesis from glucose is unsually high

Next thing to measure: Energy stores→ fat: different types of fat

1. Essential fat→ cannot be used/broken down→ 2kg in 70kg man

   • CNS (myelin sheath)

   • Lipid membranes

2. Storage fat→ 8.5 kg in 70 kg man

   • can be used for energy

Average fat % in man vs women

Man: 15% body mass

• Essential→ 2 kg

• Storage→ 8.5 kg

Woman: 27% body mass

• Essential→ 7 kg

• Storage→ 8.5 kg

What is Visceral fat

• found in the abdominal cavity

Why is this fat assoicated with great risk of disease

1. Broken down

2. goes to the liver

3. changes metabolism

4. great predisposition to metabolic disease:

   • Type II diabetes

   • hypertension

   • atheroscleosis

comapres to subcutaneous fat

Android vs gynoid districubtuion of subcutaneous fat

Android→ ‘manlike’

• around abdomen

• apple shaped

• more dangerous

Gynoid→ ‘woman like’

• hips and thighs

• Pear shaped

Ways to measure body fat

1. Body mass index

2. Underwater weighing

3. Skin-fold thickness

4. Bioelectrical impedance analysis

5. Others

1. Body Mass index (BMI)

BMI= Mass in kg/ Height²

• Crude measure of ‘fatness’

• Forms different risk categories of diseases

• these categories are different for different populations

Problems with BMI

1. Cannot distinguish between muscle and fat (or odema)

2. risk categories differ between populations

2. Underwater weighing

One of the most accurate wats to assess body fat percentage

2. How does this work?

1. Note that different body tissues have different densities

   1. Fatty tissue: 0.9 gcm-3

   2. non-fatty→ 1.1 gcm-3 (desnser than water)

2. Weight underwater is equal to normal g force - buyoant force F upwards

3. F= the weight of water displaced by the body

4. correction must be made for residual lung volume

5. must be in 4 degree water (for desnsity of water to be 1 gcm-3) but can just use different density for different temp

Calculating body fat % from this data

2. Skin fold thickness

• skin fold thickness measured with callipers

• at different places

3. Bioelectrical impedance analysis

Uses V=IR

• sends a current through the body

• measure the voltage

• calculate the resistance

• more fat→ high the resistance

4. Dual energy X-ray Absoprtiometry (DEXA)

Two xrays at different energy

1. One absorbed through bone

2. one absorbed through soft tissue

Computer analysis:

• puts them together to estimate body composition

note: still less accurate than underwater weighing

Now that we have measured the energy consumption rate and stores, what else if needed to understand what is happening in fasting?

Endrocrine response to fasting

• no point in havng the energy stores if they cannot be regulated properly to be used for survival of fasting

Endocrine response to fasting: what is fasting defined as

• absence of food intake

  • strictly from 24 hours after the last meal

What is starvation?

• the effects of this on the body

What directly affects metabolic pathways

• the relative changes in glucose and FFA availability

This control mechanism being referred to as the RANDLE cycle

These loacl effects are regulated in a whole bdy context by what

Hrormonal Milieu

What hormones affect blood sugar levels

Decrease

• Insulin

Increase

1. Glucagon

2. Cortisol

3. growth hormone

4. Adrenaline (fight-or-flight; exercise)

Why only one hormone to decrease it but many to increase it?

May be more reason/ different types of input needed to increase blood sugar

• only need one way to decrease it because it is just about lowering it in the blood????

Which of these are short and long term

Short term→ minute to minute

• Insulin

• Glucagon

• adrenaline

Long term→ adaptive rather than reactive

• cortisol

• GH

note: adrenline is more for exercise and fight or flight tahn fasting

FDF21 when released

• by the liver

• during longer-term fasting in humnas

What does FGF21 do

1. glucagon-like effects in promoting gluconeogenesis from proteins

2. ketogenesis by the liver

3. promote resistance to the growth-driving effects of growth hormone

What is glucagon

• 29 amino acid peptide

Where is glucagon released

• alpha cells of Islets of Langerhans

Helps to maintain blood sugar levels between meals

What is glucagon release stimualted and augmented by

Stimulation

1. lower glucose: hypoglycaemia

2. lower insulin

Agumentated

• ANS

• high Amino acids

Effects of glucagon

Opposite effects to insulin

1. Glycogenolysis increases

2. Gluconeogenesis increase

3. blood sugar increase

4. Fat oxidation increase

5. Keogenesis increase

How does it do this effect

1. binds to plasma membrane recetpor

2. stimulates glycogenolsysis

3. amino acid uptake and gluconegogenesis

4. hepatic glucose output is increased

5. stimualtes fat oxidation and ketogenesis

Half life of Glucagon

• degraded by liver and kidney

• has a short half life in the blood→ 3-4 mins

Metabolism following a meal

1. Postprandial period

2. Post-absorptive period

1. Postprandial period

• 5 hours of a meal

• cabrs are oxidised for exergy

• RQ approaches 1 (but does not reach it)

• Glycogen and fat are syntehsized and stores

• amino acids are made into proteins

INSULIN dominates

although note this isn’t really what hormones do

2. Post absoprtive

Within 24 hours of a meal

• Insulin drops

• Glucagon levels rise

  • note the ratio

• Glucose for fuel drops

• Hepatic output of glucose many initially by 75% from glycogenolysis

  • 25% from gluconeogenesis during the period

  • proportion arising from glycogen falling as supplies are diminished

• Free fatty acids and amino acids are mobilized

2. What hormone change is most responsible?

• Aruged that it is more to do with the drop in sinuslin than the rsie in glucagon

• glucagon being more important in extending fasting

Metbaolism during fasting

1. Phase I

2. Phase II

3. Phase III

1. Phase I: within days of a meal

Lasts for a weak

1. Plasma glucose levels drop from 5-3mM after about 3 days

2. Further drops being prevented by enhanced gluconeogeneesisfrom protein (in both liver and kidney)

3. Glucose uptake by peripheral tissues is inhibited→ sparing it for the brain

4. Fat metabolism and ketogenesiincrease

5. Metabolic rate starts to drop (lower T3)

Hormone changes

• Glucagon high, insulin low

• GH rises;

• Cortisol increase only a little

• T3 Drops

2. Fasting phase II (after a week or so)

Can last for weeks or months

1. Initially high rate of protein usage as gluconeogenic source slows down

   • note: NOT TO ZERO

2. gluconeogenesis declines

3. Metabolism moves further towards the use of fats→ reaching something approaching a stead-state

4. Liver glucogen levels are low

   • but small labile pool remaining

5. Brain account for 70-80% of total glucose use

   • the rest= RBC

6. After a few weeks→ brain can derive up to 75% of its energy from ketone bodies

RQ= 0.7

2. Hormonal controls in phase II

1. Insuline low

2. Glucagon return to normal

3. Growth hormone??

   • maybe: but levels are difficult to measure because it pulsates throughout the day

   • different literature suggest it might increase or decrease

4. FGF21 from the liver

   • released in fasting

   • helps move GH into metabolism mode

3. Phase III

Lasts a few days before death

1. fat reserves nearly exhausted

2. protein catabolism must increase to meet glucose demands

3. RQ risees from 0.7 to around 0.8

4. Death: when protein levels about ½ of the body’s protein

3. Hormone control at this stage

Cortisol finally start to rise significantly

What eventually kills you?

• last of muscle strength in the respiratory muscles

• can still breath

• cannot cough

• build up of debris in the lungs

• infections

• pneumonia kills you

Three phases of fasting graph

note:

• the protein metabolism never fully levels off in phase II

• the phases are not strict phase→ gradually moves from one phase to another

Why should you not flash diet?

• yes you may still have more fat to lose but the continual loss of proteins will continue

• the body has no way to sense the amount of protein left

• so may still have fat but not enough protein

• you will die

Calculating how long you would last

Protein-energy malnutrition: malnutrition contributes to how many deaths a year

3 million child death per year

• but very poorly understood

Two examples of protein-energy malnutrition

1. Kwashiorkor (the sickness that the older one gets when the next baby is born)

   • After weaning→ from protein rich to low protein diet

   • peripheral oedma

2. Marasmus

   • no oedma

Why does kwashiorkor cause oedema

1. not getting enough protein

2. low plasma albumin

3. low pi c

4. lots of tissue fluid out

Kwashiorkor characterised by waht

• peripheral oedema

• hypopigmented

• loose hair

• flaky paoint dermatitis

Wyh does it happen

• Protein deficieny

• despire sufficient calorie intake

Alternative cause of this disease?

Oxidative stress

• imbalance between free radical generation and disposal

• perhps as a result of cysteine deficiency?

Evidence of this in the USA

• using plant milk for vegan babies

• not enough protein

now more reserching going in because of interest in the west

2. Marasums features

• ‘wasting away’

• less dangerous

• due to calorie deficiency alone

Why are these not completely understood?

• children on identical diets can develop either of these diseases

v

2. some studies of why get marasmus in some instead of kwashiorkor

• children with natrually lower rate of endogenous protein catabolsim

• can be sustained at the same low level even when malnourished

Exams questions

1. Discuss the endocrine response to fasting.

2. Discuss why there is only one hypoglycaemic hormone (insulin) but several hyperglycaemic mechanisms.

3. What methods can be used to assess whether or not you are overweight, and what are the advantages and shortcomings of each method?