Outline for today

• Mad cow disease • Energy Metabolism and Weight Control

– Ketosis– Fasting

• Set Point Theory• Obesity

Introduction to energy metabolism Role of Vitamins and Minerals in Metabolism Glycolysis TCA cycle

Recap of last lecture

SYMPTOMS OF VCJD

Over a few months period one of your friends starts having insomnia, then depression, confusion, personality and behavioral changes, strange physical sensations, and problems with memory, coordination and sight. As the disease advances, the patient experiences a rapidly, progressive dementia (loss of memory and mental function) and in most cases, involuntary and irregular jerking movements known as myoclonus. Problems with language, sight, muscular weakness, and coordination worsen. The patient may appear startled and become rigid. In the final stage of the disease, the patient loses all mental and physical functions. The patient may lapse into a coma and usually dies from an infection like pneumonia precipitated by the bedridden, unconscious state.

Year Sporadic

Iatrogenic Familial GSS vCJD Total Deaths

1990 28 5 0 0 - 33

1991 32 1 3 0 - 36

1992 45 2 5 1 - 53

1993 37 4 3 2 - 46

1994 53 1 4 3 - 61

1995 35 4 2 3 3 47

1996 40 4 2 4 10 60

1997 60 6 4 1 10 81

1998 63 3 4 1 18 89

1999 62 6 2 0 15 85

2000 50 1 2 1 28 82

2001 57 4 3 2 20 86

2002 72 0 4 1 17 94

2003 69 5 3 2 18 97

2004* 10 0 0 1 1 12

Total Deaths 713 46 41 22 140 962

CJD• GENETIC (Familial) CJD (GSS, FFI)• Genetic CJD is a very rare illness.  In this form, CJD is caused by an inherited abnormal

gene.  In most cases, the illness is known within the family because of the family history.  There are only a few deaths due to genetic CJD in a year.

•  •  IATROGENIC CJD• Iatrogenic CJD is also very rare.  This is CJD which has been accidentally transmitted during

the course of medical or surgical procedures.  The most important example of this relates to CJD transmitted via Human Growth Hormone treatment in childhood. 

•  •  SPORADIC CJD• Sporadic CJD is numerically the most common form of CJD.  It has been found in every

country in the world where it has been looked for.  In general, it affects about one person per million of the population.  The cause of sporadic CJD remains uncertain.  However, the most favored current theory suggests that the normal prion protein in the brain undergoes a spontaneous change to the abnormal form, thereby resulting in disease. 

•  •  VARIANT CJD• Variant CJD was first reported in 1996.    Aside from 6 cases in France, one case in Ireland,

one case in Italy and one case in the USA, variant CJD has been confined to the United Kingdom.  The current view on variant CJD is that it has resulted from transmission of infection from BSE in cattle to humans via infectivity in food.

•  •  

vCJD– An early age of onset or death (average 27.6, range 18-41)

– A prolonged duration of illness (average 13.1 months, range 7.5 - 24)

– A predominantly psychiatric presentation including anxiety, depression withdrawal and behavioural change which progresses. Nearly all these patients were referred to a psychiatrist early in the clinical course.The first evidence of neurological involvement in 4 patients was dysaestheesiae in the limbs and/or face. After a period of weeks or months the development of a cerebellar syndrome with gait and limb ataxia.

– Forgetfulness and memory disturbance develop, often late in the clinical course but progress with the development of sever cognitive impairment and a state of akinetic mutism in the majority of cases.

– Myoclonus develops in the majority of patients and in some is preceded by choreiform movements, but typical EEG appearances of CJD are absent.

– Neuropathologically there is spongiform change, neuronal loss and astrocytic gliosis most evident in the basal ganglia and thalamus. The most striking and consistent neuropathological feature is amyloid plaque formation extensively distributed throughout the cerebrum and cerebellum.

TCA Cycle Overview

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

1CoA–

(Acetyl-CoA)

4-carbon molecule(Starting material) 6-carbon

molecule

2

6-carbon molecule

4-carbonmolecule

5-carbonmolecule

NADH

NADH

CO2

ATP

CO2

3

NADH

FADH2

4-carbon molecule(Starting material)

4-carbon molecule

TCA Cycle Overview

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

1CoA–

(Acetyl-CoA)

4-carbon molecule(Starting material) 6-carbon

molecule

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

1CoA–

(Acetyl-CoA)

4-carbon molecule(Starting material) 6-carbon

molecule

2

6-carbon molecule

4-carbonmolecule

5-carbonmolecule

NADH

NADH

CO2

ATP

CO2

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

1CoA–

(Acetyl-CoA)

4-carbon molecule(Starting material) 6-carbon

molecule

2

6-carbon molecule

4-carbonmolecule

5-carbonmolecule

NADH

NADH

CO2

ATP

CO2

3

NADH

FADH2

4-carbon molecule(Starting material)

4-carbon molecule

2 ATP

Pyruvate

Glucose

GlycolysisATP2

Where the ATP comes from

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

4 ATP2 NADH

Total net ATP yield = 36 ATP

18 ATP6 NADH

4 ATP2 NADH

2 ATP

Krebscycle

6 ATP2 NADH

Acetyl-CoA

Where does energy metabolism occur?

The liver – a chemistry factory

Fig. 4.3Mitochondria – make most of the ATP

Ketosis

• Ketosis is the presence in the blood of abnormally high levels of acidic substances called ketones. The normal body fuel is glucose. Ketones are produced when there isn’t enough glucose in the bloodstream, and fats have to be used. The real danger in ketosis is that ketones are acidic, and high levels of ketones make the blood abnormally acid.

• Normally the blood ketone levels are low, but in starvation, untreated diabetes and when the diet is very high in fats and low in carbohydrates, the levels rise. Ironically, in diabetes, the blood contains large quantities of sugar, but because of the shortage of insulin, this glucose can’t be used as fuel.

Ketosis

• What will happen if someone has a very low intake of carbohydrate (<130 g/day)?

(e. g. from low carbohydrate diet, fasting, starvation)

• There will be little pyruvate present. Recall that oxaloacetate, the metabolite which acetyl-CoA reacts with at the start of the TCA cycle, is formed from pyruvate.

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Citric Acid Cycle

Acetyl-CoA (2 C)

Oxaloacetate (4 C) Citrate (6 C)

NADH

CO2

NADH

CO2

FADH2

GTP

NADH

Propionyl-CoA

Pyruvate

Ketosis cont’d• Consequently if there is little pyruvate there will be little

oxaloacetate. This means that there will be a bottle-neck at the entrance to the TCA cycle. As a result acetyl-CoA will accumulate to higher than normal levels.

• This leads to formation of the ketones. The situation is compounded by the fact that the lack of glucose will force the body to use TG's as the source of energy which will mean a lot of acetyl-CoA.

• Another factor is that when a person fasts their insulin production decreases which results in the conversion of stored fats into acetyl-CoA (as a source of energy).

Acetone – the simplest ketone

CH3-C-CH3

O

Ketogenesis

• Ketones are products of incomplete fatty acid oxidation

• Usually a result of insufficient glucose

Low CHO intake,

insufficient insulin

Fatty acids flood the liver

Acetyl-CoA

Ketone Citric Acid

Bodies Cycle

Acetyl-CoA

Ketogenesis in Diabetes

• Not enough insulin produced

• CHO metabolism is limited

• Oxaloacetate is needed to produce glucose

• Citric Acid Cycle is limited

• More ketones produced; ketones spill into urine

• Blood becomes acidic

Insufficient insulin

Fatty acids flood the liver

Acetyl-CoA

Ketones, ketones Citric Acid

Cycle

Many Acetyl-CoA Limited Acetyl-CoA

Urine

Ketosis cont’d• Symptoms

• Ketones give the breath a sickly, fruity odour like nail-varnish remover or pear-drops.

• A ketogenic diet may also cause short-term side effects.  These might include fatigue and insufficient energy to perform normal activities, nausea and hypotension.  

• (High levels of ketones with acidity in the blood is called ketoacidosis. Ketoacidosis causes nausea, vomiting, abdominal pain, confusion, and, if not rapidly treated, coma and death.)

 

Ketosis cont’d

• In diets containing fewer than 130 grams of carbohydrates, ketosis occurs and your body starts breaking down muscle and lean tissue to provide glucose for brain and nerve fuel.

• Dietary ketosis is a natural adjustment to the body's reduced intake of carbohydrates as the body shifts its primary source of energy from carbohydrates to stored fat. 

Ketosis cont’d

• As we will see, the brain can use ketones though mental processing seems to become a bit sluggish on this fuel as it prefers glucose.

• The current accepted practice in medical nutrition therapy is to not recommend ketogenic or fasting diets. There are other factors at work with ketogenic diets i.e. the loss of lean tissue mass, which decreases metabolic rate, but because catabolism of lean tissue yields glucose, the blood sugar is maintained in a safe range.

Fasting

• The only difference between a true fast and starvation is that one is voluntary, the other not. What most of you consider fasting, i.e. the "juice fast" is not really a true fast because you are in fact taking in considerable amounts of nutrients, including a significant amount of energy (typical juice fasts involve about 1000 kcals).

*

Fasting• There is no nutritional value to fasting and the risk is dependent on many factors

(age, health status, outside temperature, physical exercise and length of the fast). If you are a healthy adult without diabetes, there is probably little associated risk to fast for one day as long as you include water to prevent dehydration.

• Fruit juice contains fructose (fruit sugar) which can be used as caloric fuel for the body during a fast. Eight ounces of fruit juice only contains 30 grams of carbohydrate and about 120 calories. You would have to drink 12 1/2 eight ounce glasses of juice to spare blood glucose or glycogen (stored glucose) from being used as fuel.

• During a fast, your body still burns calories, usually as blood glucose or glycogen stored in muscles. Once that 1500-calorie supply is exhausted, the body has to burn protein stores. Unfortunately, body fat is not easily moved out of storage and burned as a calorie source during a fast.

• Various fad diets have advocated periodic fasting to supposedly shock the metabolism or rid the body of waste products. Neither has been substantiated by research.

Fasting – body’s response

• There are no incoming nutrients; therefore the body begins to break itself down to supply energy, especially for the brain, liver and kidneys. The energy comes from stored fat and from breakdown of proteins. The brain requires glucose. This is obtained from some of the amino acids and from glycerol from the breakdown of TG's. The absence of incoming sugars leads to a relative decrease in the amount of pyruvate and oxaloacetate relative to acetyl-CoA and this leads to ketosis. Prolonged lack of food intake causes the body to undergo major metabolic changes.

FastingEnergy "reserves"

Consider the following table for a normal and obese male. Assume BMR (basic metabolic rate) is 1800 kcal/day:

No. of gms Normal Obese (70kg)(154 lb.) (135 kg) (300 lb.)

Adipose tissue (fat) 15,000 141,000 kcals 752,000 kcals Protein (mostly muscle) 6,000 24,000 32,000 Glycogen (muscle + liver) 120 + 70 900 920 Circulating glucose + fat 20 100 110 Total 166,000 785,000 kcalsEstimated survival time 2-3 months 8 months

Fasting

• The major changes during fasting are a change to using fat and protein as energy sources.

• Typically the body takes about 4 weeks to adapt to a lack of food. During this time the blood sugar level remains relatively constant around the normal value of 80 mg/dl. However the blood levels of free fatty acids and ketones increases significantly, as does the excretion of N in urea in urine, due to amino acid breakdown and conversion to glucose to "feed" the brain. The brain requires about 20% of the energy consumed at rest, in the form of 140 g glucose/day. Low blood sugar leads to impaired mental and nerve functioning. After the glycogen stores are used up the main source of glucose is amino acids from the breakdown of protein and a small amount from glycerol from TG breakdown. The aa's are deaminated, the N excreted as urea, and the C skeleton yields 57g glucose per 100g body protein.

Fasting

Blood concentrations (mM)

Glucose FFA's Ketones amino acids

Normal 4.5 - 4.8 0.5 0.02 4.5

Fasting 3.8 1.5 5.0 4.5

1 wk

Fasting 3.6 2.0 7.8 3.1

5 wks

Fasting- Order of loss of body protein

1. Digestive enzymes • 2. Liver enzymes processing incoming nutrients • 3. Muscle protein • For the first week protein is lost at the rate of 100g/day (obviously

couldn't go on for long at this rate). After 4-6 weeks it’s down to 12-15g/day. In addition after this period the brain has made a major adaptation and has begun to use ketones as an energy source. Once all the fat is used up the person will die rapidly. Since children normally have rather limited stores of fat they cannot survive too long.

• The body's first priority is to get glucose for the brain. The second is to conserve protein by having the liver and muscles use fatty acids and ketones as energy sources.

Cont’d

• During fasting the BMR decreases and the body decreases its physical activity to conserve energy. Naturally fasting or starvation is accompanied by weight loss:

• The initial weight loss is due mostly to water, due to the excretion of electrolytes (minerals) such as Na, K, Ca, Mg and urea.

• It has been shown that if a pregnant woman fasts, especially during the first trimester, it has very severe effects on the fetus.

How fast can you lose weight due to fat?

• Seen those ads for losing 25 lbs in one week - sound to be too good to be true? 25 lbs of adipose fat corresponds to 87,500 kcals, or 12,500 kcals per day. To burn that many calories the person would have to ride the equivalent of a tough Tour de France bike race for most of the 24 hours each day!!

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Low carb diets

• The arguments of people that favor quick weight loss diets (Scarsdale, Stillman, Atkins, Ski Team, Air Force, Drinking Man's, Calories Don't Count, Mayo or grapefruit diets) is that if you eat enough protein, you will spare your own body protein from being broken down and instead will break down your body's stored fat. This is incorrect and not how your body uses protein or fat.

Do our bodies control our weight?

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Do our bodies control our weight?

• Yes• We normally keep our body weight constant

1% over periods of many years, in spite of fluctuating food intake and physical activity. It is believed that total fat mass is sensed in the feedback system (the lipostat theory). The hypothalamus is the main control center: damage leads to obesity and stimulation leads to increased energy expenditure and reduced eating.

Set Point Theory

• Weight is closely regulated by the body• Genetically predetermined body weight• Body resists weight change• Leptin and thyroid hormone assist in weight

regulation• Weight returns after weight loss• Reduction in energy intake results in lower metabolic

rate• Ability to shift the set point weight

Set-point theory

• This is the best available theory at present. It postulates that each individual has some particular body weight, which the body maintains by regulation and control of a number of things. The key feature, however, is that the body can alter its metabolism to make it more or less efficient, e. g. by converting more or less energy into heat. By converting more energy into heat, rather than fat, the body weight can be controlled. Obesity then results either from a high set-point, or a malfunction in the control system.

• There is growing evidence to support the idea that the body regulates its weight in the same manner that it regulates its temperature, but with one difference: the controlled body weight differs substantially from one person to the next: however, for that person the body will try to maintain that particular weight (now usually called the set-point). It is apparent that if, for some reason, a person becomes obese, the set-point is often reset to a much higher value.

Set-point theory

• A telling argument in favor of some kind of regulatory system is the following: normally our daily caloric input varies significantly. On average we tend to err on the side of taking in more than we need. Thus, if we took in an extra 500 kcals a week, at the end of a decade this would mean we should weigh 10 x 500 x 52 /3500 = 75 lbs more.

• There are a number of observations which strongly support the set-point theory. For example, it has long been known that animals seem to have their own stable weights. If they are force-fed they will become fatter, but as soon as the force feeding is stopped they revert to their earlier levels. If they are semi-starved they lose weight, but on returning to a normal diet their weight returns to its earlier level.

Set-point theory

• In an interesting study with a small set (12) of identical twins forced to eat an extra 1000 kcals a day for 100 days it was found that some gained only 9 lbs, whereas others gained 29 lbs (also each twin in a pair gained about the same amount!). (From 3500 kcals equivalent to 1 lb. fat one would have expected 28.6 lb. gain.) This is only one of several studies which indicate that different individuals respond to excess calories in different ways.

Set-point theory• Both rats and humans, if forced to eat more than

they want, put on weight, but after being allowed to eat what they want, lose the excess. If a substantial mass of fat is removed, it is followed by excess eating and an increase in the remaining fat stores! If an obese mouse (due to the ob gene mutation) is surgically joined to a normal mouse the former will lose weight, presumably due to transfer of the hormone from the normal mouse to the blood of the obese one.

Cont’d

• One well-documented metabolic change on weight-loss through dieting is a substantial decrease in the resting metabolic rate - this may be decreased by as much as 50% - and is thought to reflect the body's going into "starvation" mode. As a result weight loss drops off dramatically since the body is using many fewer calories - this is a very strong argument against using very low calorie diets!

Set-point theory cont’d• The set point theory also explains the observation that some people eat

relatively little and become overweight, whereas others can eat almost unlimited amounts and not become obese. The former have very efficient metabolism, the latter inefficient, that is they convert a lot of energy into heat, rather than storing it as fat. The thyroid is one of the factors that controls the rate of metabolism. However, things appear to be considerably more complicated.

• For example, some types of adipose tissue are known as brown fat, due to its color. The color is imparted by cells which are very rich in mitochondria. Its main function seems to be to produce heat. Hibernating animals, e.g. have large amounts. In studies with rats, overfeeding leads to increased amounts of brown fat and increased heat production. For example rats fed 80% excess kcals over controls put on only 27% more weight, but increased their energy production by a factor of two as measured by oxygen consumption. Obese rats don't adjust.

Is this you?

• Much of our eating and drinking is determined by social settings and customs, e. g. the stereotype of sitting down to watch TV with a bag of chips and a bottle of beer (lots of calories - 5 kcals per chip, 150 kcals for the beer (180 for a typical slice of pizza)).

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Weight loss

• The maximum amount of weight (fat or muscle) a person can lose in a day is 1/2 pound. Any additional weight lost is water. Since the body is about 60% water and 1 gallon of water weighs 8 pounds, a person can see weight losses greater than 1/2 pound on a scale simply by losing body water. However, when your body replaces the water lost, weight gain will re-occur. So you are right back to where you started at an unhealthy weight.

• Research has proven that quick weight loss is quickly regained. Studies have shown that gradual weight loss, a lower calorie / fat diet, exercise and analyzing everything you eat is more likely to result in permanent weight loss. Weight loss of 1 to 2 pounds per week is slow enough. A goal of losing 10% of your current weight has been shown to improve your health risk and may be a more reasonable, attainable goal. So figure 10% of your weight as a weight loss goal, then divide by 1 or 2 to determine how many weeks it will take you assuming you follow this advice.

Estimation of Body Fat

• Underwater weighing Most accurate– Fat is less dense than

lean tissue

– Fat floats

Body Fat DistributionUpper-body (android) obesity• Associated with more heart disease, HTN, Type II

Diabetes• Abdominal fat is released right into the liver• Fat affects liver’s ability to clear insulin and lipoprotein• Encouraged by testosterone and excessive alcohol

intake• Defined as waist measurement of >40” in men and

>35” in women

Body Fat Distribution

Body Fat Distribution

Lower-body (gynecoid) obesity

• Encouraged by estrogen and progesterone

• After menopause, upper-body obesity appears

• Less health risk than upper-body obesity

Juvenile-Onset Obesity

• Develops in infancy or childhood

• Increase in the number of adipose cells

• Adipose cells have long life span and need to store fat

• Makes it difficult to loose the fat (weight loss)

Adult-Onset Obesity

• Develops in adulthood

• Fewer (number of) adipose cells

• These adipose cells are larger (stores excess amount of fat)

• If weight gain continues, the number of adipose cells can increase

Overweight and Obesity

• Underweight = BMI < 18.5

• Healthy weight = BMI 18.5-24.9

• Overweight = BMI 25-29.9

• Obese = BMI 30-39.9

• Severely obese = BMI >40

Causes of Obesity

Genetic factors• Identical twins raised apart have similar weights• Genetics account for ~40%-70% of weight

differences• Genes affect metabolic rate, fuel use, brain

chemistry, body shape• Thrifty metabolism gene allows for more fat

storage to protect against famine

Causes of Obesity

Environmental factors

• Learned eating habits

• Activity factor (or lack of)

• Poverty and obesity

• Female obesity is rooted in childhood obesity

• Male obesity appears after age 30

Why Diets Don’t Work

• Obesity is a chronic disease– Treatment requires long-term lifestyle changes

• Dieters are misdirected– More concerned about weight loss than healthy

lifestyle– Unrealistic weight expectations

High protein diets

• A high protein diet can cause the body to lose calcium, which can lead to development of osteoporosis. Osteoporosis can result in broken bones. After a few days on a low carbohydrate diet of less than 130 grams per day, a person develops ketosis.