Human nutrition  Metabolisable energy (ME) = DE minus energy

lost in urine
Overview of topic - Availability of energy is more important than
absolute amount
- Lecture 1 and 2 – Nutrients and foods
- Lecture 3 – Digestion Carbohydrates
- Lecture 4 – Energy and metabolism - Chemical classification
- Lecture 5 – Obesity and appetite  Monosaccharides
- Lecture 6 – Genetics of obesity » Simple sugars – mostly hexoses (6-carbon)
» Glucose, galactose and fructose
Lectures 1 – Nutrients and foods  Disaccharides
» Two monosaccharides linked together by a
Key points: glycosidic bond
- How does nutritional research inform public health? » Lactose (milk sugar): glucose + galactose
 Recent changes in nutrient recommendations » Sucrose (table sugar): glucose + fructose
- Review the major groups of food nutrients » Maltose: glucose + glucose
 Specifics of carbohydrates and fats  Polysaccharides
» Glycaemic index » Long chains of monosaccharides – most
» Types and carriage of fats in the body abundant dietary carbohydrates
» Starch (several forms) – major plant glucose
Nutrition and public health storage
» Cellulose (fibre) – major part of plant cell wall
- Large improvements in nutrition in the last 100 years » Glycogen – major animal glucose storage
- Simple messages (e.g., eat adequate protein, vitamins - Body breaks down carbohydrates (except for fibre)
and minerals) into monosaccharides during digestion
- Major deficiencies rarely seen in developed nations
 Converted to glucose in liver
Nutritional deficiencies
What effect does eating carbohydrates have on our
- Iodine deficiency – enlargement of thyroid
blood glucose concentration?
- Protein deficiency – swelling, water retention
- Different types of carbohydrates and different food
affect blood glucose differently
Nutritional messaging
- Glycaemic index
- Huge amount of nutritional research
- Manufacturers take advantage of confusion
What is the Glycaemic index?
- Healthy eating pyramid – Australian main messaging
- A ranking of foods (0-100) based on the immediate
- Nutrition information panel on backs of foods
effect of 50g carbohydrate on the concentration of
glucose in the blood
Nutrients
- High GI foods
 Fast carbohydrate breakdown
What are nutrients?
- Nutrients are food in a form that can be used by the  Blood glucose response fast and high
body - Factors affecting GI
- Macronutrients – serve as fuel or are essential in  Type of sugar (fructose vs. glucose)
synthesis of cellular products  Nature of starch (amylose vs. amylopectin)
 Carbohydrates  Processing and particle size (wholemeal vs. rye)
 Proteins  Cooking methods (carrots raw vs. cooked)
 Fats  Fat – large amounts may reduce GI
- Micronutrients – required in small amounts, such as - Why is the glucose response relevant?
vitamins and minerals  Managing diabetes
» Prevent hyperglycaemia
What is energy in food?  Reduce risk of type 2 diabetes (insulin resistance)
- Energy in food is transferred to bonds of ATP, which  Prevention of coronary heart disease
is used by the cell  Satiety, appetite control, weight reduction
- Different components yield different amounts
 Fat = 37kJ/g Fructose – a cause for concern?
 Carbohydrates = 16kJ/g - Many claims but major one is that fructose initiates
 Protein = 17kJ/g lipogenesis in liver
 Alcohol = 29kJ/g - Amount consumed is critical
- Distinguish between:  Large doses can cause problems in humans
 Gross energy (E) = total energy  Amounts consumed by the vast majority of
 Digestible energy (DE) = E minus energy lost in Australians do not lead to these issues
faeces
 Fats - Liver synthesises fats and cholesterol from
chylomicron residues
Important types of fats
- Fatty acids ‘Good’ and ‘bad’ cholesterol
 Long chains of carbon molecules linked together 1. Chylomicrons release triglycerides and cholesterol in
and flanked by hydrogen and oxygen liver  repackaged as very low-density lipoproteins
» Saturated (no C=C bonds) (VLDL) which carry fat to cells
» Unsaturated – either one or multiple C=C 2. LDL (low-density lipoproteins) carry cholesterol to
bonds cells – when oxidised, LDL can initiate plaque
 “alpha’ and ‘omega’ ends formation in the walls of the arteries which cause
 Differences in melting point due to shape of atherosclerosis (‘bad’ cholesterol)
saturated vs. unsaturated fatty acids 3. HDL (high-density lipoproteins) are synthesised in
 Some fatty acids are essential in the diet (e.g., the liver  carry fat and cholesterol back to the liver
linoleic acid) – others can be synthesised in the for excretion (‘good’ cholesterol)
body (non-essential)
Lecture 2: Food and nutrients (continued)
 Trans fats – promoters of heart disease
» Cis fatty acids – hydrogens next to the double
Key points for this lecture:
bonds are on the same side of the carbon chain
- Proteins = amino acids
» Trans fatty acids – hydrogens are on opposite
- Macronutrient balancing – protein prioritisation
sides of the double bonds. This is a result of - Micronutrients
hydrogenation (natural microbiological or
 Vitamins – fat or water soluble
industrial)
 Deficiencies and excesses
 Trans fats banned in many countries, but not
 Minerals
Australia
- Phytochemicals/nutraceuticals
» Australia chooses to “work with food
- Prebiotics and probiotics
manufacturers” to reduce or eliminate trans
fats from products
Proteins
» No legal requirement to label trans fats in
Australia - Proteins are polymers of amino acids linked together
» WHO recommends trans fats make up <1% of by peptide bonds
total energy intake… - No large body stores of protein
» Average Australian intake = 0.6% - Generally, proteins must be reduced to single amino
- Triglycerides acids before they can be absorbed
 Most fats in food and body present as - Enzymes that hydrolyse peptide bonds and reduce
triglycerides (glycerol + 3 fatty acids) proteins or peptides to amino acids are called
 In the body, triglycerides: proteases or peptidases
» Provide energy
» Store energy Digestion of protein involves breaking peptide bonds
» Insulate and protect body
» Transport fat soluble vitamins
- Sterols (especially cholesterol)
 Cholesterol
» Part of important hormones (testosterone,
oestrogen, corticosteroids)
» Precursor of bile acids
» Essential structural component of cell
membranes
» Part of particles that transport lipids in blood
» We consume ~300mg cholesterol per day, and
make 1,000mg in body Amino acids
» Dietary cholesterol intake has little effect on - There are 21 dietary amino acids
blood cholesterol - Protein turnover
» Saturated fat intake increases blood  Constant synthesis and breakdown
cholesterol - Some amino acids can be made in the body, but some
are essential (cannot be synthesised)
Carrying fats in the bloodstream  Which ones are essential depends on species…
- After absorption, fatty acids are mostly re-packaged  Humans: histidine, isoleucine, leucine, lysine,
as triglycerides methionine, phenylalanine, threonine, tryptophan,
- Transported in blood in protein shells as valine
chylomicrons (lipoproteins) - Meat, eggs and milk – contain all in balance
- Deliver some fatty acids to peripheral tissues - Plant food often lack some essential amino acids
  A varied diet of plant foods will usually supply all Vitamins and minerals
essential amino acid requirements
Vitamins
Protein deficiency or excess - Many act as co-enzymes
- Protein deficiency (Kwashiorkor) - Not synthesised by the body (must be obtained from
- Protein excess the diet)
 Acid load - Water soluble – B, C
 Calcium loss  Enter blood directly after absorption
- How much is too much?  Excesses excreted in urine
 Protein normally 10-25% of daily energy intake - Fat soluble – A, D, E, K
 Enter lymph first, require protein carriers in blood
Macronutrient balance  Excesses stored in fat

Water soluble vitamins

- Eight B vitamins
 Differ chemically
 Roles in cell metabolism
 Highest in meats, eggs and dairy products
- Vitamin C – ascorbic acid
 Many functions (e.g., tissue repair, immune
function, iron absorption)
 Highest in fruits and vegetables
- Deficiencies
 Not stored in the body – excreted in urine
» No long-term effects of overdose
» Temporary side effect
 Scurvy (Vitamin C)
» Uncommon nowadays
 Pregnant women and people with digestive
conditions (e.g., coeliac) or alcohol addition most
Protein is prioritised at risk of B vitamin deficiencies
- People ate 14% more when they were restricted to » Beriberi (Vit B1)
low-protein food  Folate (B9)
- People eating diets high in ultra-processed foods » Symptoms of deficiency include fatigue,
overeat carbs and fats to meet protein requirements
irritability, headaches, anaemia
- Humans overeat carbs and fats to meet protein
» Folate deficiency in pregnant women causes
requirements
neural tube defects (e.g., spina bifida)
 Tend to eat less overall on a high protein diet
» Mandatory to fortify bread with folate in
 BUT studies suggest that animals on low protein
Australia
diets are healthier and live longer
 Australian Dietary Guidelines recommend:
Fat soluble vitamins
» 15-25% protein, 45-64% carbohydrate, 20-
- Vitamin A
35% fat  Many functions (e.g., immune system, vision)
 Found in animal food sources (retinol) or some
Gluten
plant foods (specific carotenes)
- Proteins found in some grains (e.g., wheat, barley,
- Vitamin D
rye)
 Increase absorption of some minerals (e.g.,
 Two main proteins – glutenin and gliadin
calcium)
- Forms a network of fine stretchy strands when wet
 Few food sources (fatty fish), but manufactured in
- Widespread perceptions of gluten sensitivity
body through reaction with sunlight
 No evidence for widespread gluten sensitivity
- Vitamin E
 Perhaps something else responsible for the
 Incorporated into cell membranes, antioxidant
symptoms
 Found in whole grains, green leafy vegetables,
 FODMAPs possible (fermentable
nuts, seeds
oligosaccharides, disaccharides,
- Vitamin K
monosaccharides, and polyols)
 Involved in blood clotting
» Bypass small intestine and fermented in large
 Found in green leafy vegetables, but also
intestine by bacteria
synthesised by some bacteria in the large intestine
- Deficiencies
 Vitamin A – leading cause of preventable
blindness
  Vitamin K – uncontrolled bleeding - Layers of the digestive system
 Vitamin D – bone deformities - Stomach processes
- Excesses  Zymogens
 Fat soluble vitamins can accumulate in body - Digestion is a regulated process
tissue, causing toxicity - Digestion and absorption along the gut
 Kidney and liver damage  What is digested and absorbed where?

Vitamin bioavailability
- Determining bioavailability is complex
- Influenced by:
 Amount in food
 Amount absorbed
» Previous nutrient intake
» Other food consumed concurrently
» Method of preparation (e.g., cooked vs raw)
» Source (e.g., naturally occurring vs. fortified)

Minerals
Terminology
- Only specific appetite is for sodium
All digestion is ultimately enzymatic
- Concentration may not reflect availability
- Traditional to distinguish between digestion by
 Fibre-mineral interactions (e.g., phytic and oxalic
enzymes…
acid)
 That are produced by our own digestive system
 Mineral-mineral interactions (e.g., zinc and iron
 enzymatic digestion
block copper absorption)
 That are produced by symbiotic microorganisms
- Deficiencies
in the gut  fermentative digestion
 Iron, calcium and iodine common
- Excesses
The hollow tube
 Sodium (hypertension)
- The gut is an open tube that runs through us
Phytochemicals and nutraceuticals - Nothing is ‘in’ until it crosses the exterior wall (even
- Constituents that either naturally occur in plant foods if that ‘exterior’ wall is deep inside us)
(phytochemicals), or are added to foods - The lining of the gut is HIGHLY selective about
(nutraceutical) what is absorbed where
Phytochemicals Mucosa (inside of tube)
- Colour and flavour - Highly convoluted
 Sulphur compounds (garlic) - High surface area
 Capsaicin (chillies) - Exocrine cells
 Lycopene (tomatoes)  Acid, enzymes, etc. to gut
- Potential health effects - Endocrine cells
 Antioxidants (chocolate, tea, wine, fruits)  Hormones to blood
 Caffeine (coffee, tea)  Sensitive to the composition of digesta
 Salicin (aspirin)
Nutraceuticals
- E.g., sterols (margarine)

Prebiotics and probiotics

Prebiotics
- Substrate which stimulates the growth and/or activity
of one or a limited number of beneficial bacteria in
the colon

Probiotics
- Food or supplement that contains live micro-
organisms which benefit the host by improving ‘the
balance of intestinal microbes’

Lecture 3: The digestive system - Digestion tightly regulated

 Muscles, nerves, hormones, enzymes
Key points:
The second brain - There is a co-ordinated, sequential breakdown of
- Gut can work with little input from the CNS large molecules by enzymes secreted along the length
 Can sever connections with CNS and gut of the gut
continues to operate  Both hormonal and nervous control
- Gut is the only organ that has its own intrinsic
nervous system
- Contains a rich array of neurotransmitters

Mouth

- Saliva
 Buffering and lubrication
 Secretion is under nervous control – Pavlov
 Enzymatic digestion – amylase (starches)
 Toxin binding
- Physical digestion
 Teeth in mammals
 Exposure of cell contents and larger surface area
allows more rapid and complete digestion

Oesophagus

- Carries food from mouth to stomach

Stomach

- Short-term storage reservoir

- Vigorous contractions of smooth muscle mix and
grind foodstuffs with gastric secretions, resulting in
liquefaction
- Liquid food slowly released into small intestine

Small intestine
Digestion in stomach
- Chemical and enzymatic digestion initiated, - Primary site of digestion and absorption in the GI
particularly of proteins tract
- Some fat digestion by lipase (but most lipase in small - Extends from the stomach to the large intestine
intestine) - Comprised of
- Little to no absorption in stomach (ethanol/aspirin –  Duodenum
major irritants)  Jejunum
- E.g.,  Ileum
 Substrate – protein - Surface area of small intestine is large for maximal
 Gastric enzyme process absorption
 Product – peptides
 Not absorbed Digestion in small intestine
- E.g., - Major site for enzymatic digestion of proteins,
 Substrate – fat carbohydrates (sugars and starches) and fats
 Gastric enzymes process - Good correspondence between digestive enzymes
 Product – fatty acids and natural diet (e.g., amylase, sucrase, galactosidase
 Not absorbed in vegetarians)

Why doesn’t the stomach digest itself?

- Many digestive enzymes produced in an inactive
form
 Zymogens
 Activated by pH or another enzyme (e.g.,
pepsinogen to pepsin)
- Stomach protected by a surfactant – ulcers happen if
surfactant is breached

Control of gastric digestion

Incomplete digestion in small intestine
- Food components (FODMAPS – oligosaccharides - Distinction between white and brown fat
beans)
- Genetic – lactose intolerance Energy for the body
- Drug-induced (e.g., Xenical)
 Inhibits pancreatic lipase - Food contains chemical energy in the bonds of
 Stops fat from being digested carbohydrate, fat, protein, and alcohol
 Unpleasant side effects if too much fat eaten - Following digestion, the products (e.g., glucose, fatty
acids) can be used as fuel for cells)
Large intestine - Cells break down these fuels further and some of the
released energy is stored in ATP
Human large intestine bacteria - These reactions occur in a part of the cell called
- More than 50% of the cells in our bodies are mitochondria
intestinal bacterial cells - Conversion of fuels to energy in ATP requires
- We carry around 2kg of bacteria in our large intestine oxygen, and generates heat
- Major modulators of health and immune function
- Potential roles in obesity, diabetes, mental health Units of measurement
- Correct unit = Joule (J) = 0.24 cal
Digestion in large intestine - Calorie (cal) = 4.2J
- All enzymes produced from micro-organisms - Kilojoule (kJ) = 1,000J
- Material that resists enzymatic digestion is available - Kilocalorie (kcal) = 1,000 cal
for microbial digestion (e.g., dietary fibre)  Often just called “Calorie”
- Products of digestion are short-chain fatty acids
(SCFA) (acetic, propionic, butyric) What fuel is the body using?
- Gases – hydrogen, methane, and hydrogen sulphide, - Metabolic rate or heat production can be determined
CO2 by indirect calorimetry:
- Significant water absorption  How much oxygen (O2) is consumed
 How much carbon dioxide (CO2) is exhaled?
- Different fuels need different amounts of O2
 Ratio of CO2 produced to O2 consumed
» Respiratory quotient (RQ) OR
» Respiratory exchange ratio (RER)
- Fixed relationship between amount of fuel burnt
(oxidised), oxygen consumed, and heat liberated
- Same relationship if fuel is oxidised in a test tube, or
in the cell of a human or animal

Respiratory quotient (RQ)

Inflammatory bowel disease (IBD)
- Carbohydrate as fuel = 1.0
- Crohn’s disease – chronic inflammation of GIT
- Fat as fuel = 0.7
 Terminal ileum and colon
 Probable autoimmune disease Fuel use depends on duration and intensity of exercise
- Ulcerative colitis – ulcerative inflammation of colon - Fasting – fat
 Partly autoimmune and other factors - Rest and low intensity exercise – mixture of
carbohydrate and fa
New treatment for IBD - High intensity exercise – exclusively carbohydrate
- Crohn’s virtually unknown in Africa where intestinal
parasites are common Components of daily energy metabolism
- Infection of humans with pig whipworms leads to - Resting (RMR) or basal metabolic rate (BMR)
relief of symptoms - Thermic effect of food
 Worms survive but don’t reproduce - Physical activity
 Alter microbiome composition  Exercise
 Non-exercise activity thermogenesis (NEAT)
Lecture 4: Energetics and metabolism
Basal metabolic rate
Key points in lecture
- Link between energy in food and energy in cells - Sum total of energy needed to keep body going
- Which fuels are being used?  At rest
 Respiratory quotient  Fasting (digesting food requires energy)
- Major components of energy expenditure
 Thermal neutral zone (no energy for warming up
 Basal metabolic rate (BMR) or cooling down)
 Thermic effect of food  Adult (children are growing – energy demanding
 Activity
- Importance of fat-free mass for BMR
- Less restrictive conditions for measuring resting » Large cytoplasm
metabolic rate (e.g., measured while at rest any time » Multiple lipid drops
during the day and fasting not required) » Nuclei round, central
- 50-60% of total daily energy expenditure » Lots of mitochondria
- Most of BMR used by small organs » Contains uncoupling protein (UCP 1) in
mitochondrial membranes
Factors important for BMR » Respiratory chain “uncoupled” – heat
- Fat free mass (higher FFM = higher BMR) produced instead of ATP
 Obese people have bigger hearts, kidneys, livers,  Allows ingested energy to be “wasted”
skeletal muscle, etc. » BAT activity is stimulated by cold, some
 Age (FFM reduces with age) drugs, and high fat diets
 Gender (females have lower FFM)
2, 4-dinitrophenol (DNP)
Basal metabolism and thermoregulation - Causes protons to leak across mitochondrial
- The transfer of energy from one form to another membrane and thus bypass ATP synthesis
(e.g., breakdown of fuels or transfer to ATP) is not - Produces large amounts of heat
perfect - Used extensively in dieting pills in the 1930s
 Some of the energy is released as heat - Many fatalities due to overheating
- This heat can be used for thermoregulation - Other serious side effects (e.g., vomiting, headaches,
 Optimal cellular function cataracts)

Thermic effect of food Can white fat turn into brown fat?
- Brown and white fat cells develop from different
- Metabolic rate increases when you eat (energy for precursors
digestion, absorption, transport, storage) - But beige adipocytes are found within some white fat
- ~10-15% of daily energy expenditure deposits
 No difference in obese vs lean individuals  Characteristics of white fat before stimulation
- Protein-rich meals tend to be more thermogenic  Thermogenic action after stimulation
- Caffiene leads to higher MR – sone lipolysis - Not clear whether white cells become beige cells, or
- Hot and spicy foods have a very minor effect whether beige cell precursors occur in conjunction
with white adipose tissues
Physical activity
Lecture 5: Obesity and appetite
Exercise
- Deliberate activity to maintain or improve health or Key points:
fitness - Body composition – why the focus on fat?
- Metabolic rate increases during exercise, but most - Understanding of fat balance vs. energy balance
people do little exercise - Understanding the efficiency of fat deposition
- Exercise contributes relatively little to overall daily - Appetite
energy expenditure for most people  Importance of hypothalamus
 Factors that influence long and short-term
Non-exercise activity thermogenesis (NEAT) regulation
- Fidgeting, moving around, changing posture, walking
to lectures, housework, etc. Obesity and human health
- NEAT originally thought to contribute little to
energy balance - Commonest nutritional disorder
 People overfed and activity limited  measured - > 65% Australians overweight (30% obese)
oxygen consumption and body composition - Health issues
» “Easy gainers” and “hard gainers”  Type II diabetes
 Hypertension
Human body fat (adipose tissue)
 Hyperlipidaemia
» Heart disease
- Specialised connective issue that is the major storage
» Stroke
site for fat (in the form of triglycerides)
- Mammals have two forms:
Energy balance – the physics model
 White adipose tissue – heat insulation,
- Energy balance = E intake – E expenditure
cushioning, energy reserve
» Little cytoplasm  Simple and common approach
» Single lipid droplet  BUT perhaps too simple
» Eccentric nucleus
Body composition – “overfatness” not overweight
 Brown adipose tissue (BAT) – thermogenic - Bodies are made of:
(makes heat)
 Protein
  Fat - Protein
 Water  Some stimulation of insulin – inhibition of fat
 “Ash” (minerals) oxidation
 Small amount of carbohydrate (glycogen in  High protein diets increase protein oxidation
muscles and liver)
- All except fat are largely constant Ethanol
- Metabolised by liver in preference to other nutrients
Energy intake > energy expenditure - Products from alcohol metabolism inhibit glycolysis
- Energy density of tissues varies (glucose breakdown), gluconeogenesis (glucose
 More energy stored in less fat generation), and fatty acid oxidation
 Same amount of energy stored in different tissues  Fatty acids accumulate in the liver
leads to different changes in mass  Long term damage with excessive alcohol
» 1,000kJ as fat = 27g consumption
» 1,000kJ as glycogen = 59g
- Efficiency of conversion to fat differs between Important of maintaining fat balance
nutrients - Excess fat intake and low fat oxidation both
 5% of energy in fat used to store fat as fat – fat influence obesity
can readily be deposited as fat in the body - Not all fat in your body is the same – some fat is
 25% of carbohydrate used to store carbohydrate more easily mobilised
as fat - Steady states are reached between rate of fat
» Significant metabolic cost – not favoured in deposition and fat oxidation
the body
Body mass index
» Carbohydrate is not converted to fat except in
cases of massive overfeeding of carbohydrate
BMI = [weight(kg)/height(m)2]
- Need to consider both energy and nutrient balance
- Developed by a Belgian mathematician in 1830s
- A study in 1972 determined BMI to be ‘at least as
What determines fat deposition and fat removal
good as any other relative weight index’
(oxidation)?
- WHO 1980s – standardised measure for recording
- Dietary carbohydrate stimulates insulin
obesity statistics?
- Net result of insulin (in whole body)
- Adopted by life insurance industry – risk of dying
 Increase in % of energy derived from greater for people who are overweight or obese
carbohydrate oxidation
 Decrease in % energy derived from fat BMI-related health risks
- The logic behind the ‘low carb’ diets
 Claims: Hypertension, heart disease, type II diabetes, sleep
» Avoid cards because they promote fat storage apnoea, osteoarthritis, infertility
» You will burn fat if you don’t eat carbs
 Facts: Category Risk +other factors
» Carbs only promote fat storage if energy <25 Low Low
intake exceeds energy expenditure 25-27 Low Moderate
» Long-term health outcomes are better for 27-30 Moderate High
people who eat carbohydrates 30-35 High Very high
» Weight loss is due to loss of water, glycogen 35-40 Very high Extreme
and muscle, and to restriction of energy intake >40 Extreme Extreme
rather than the absence of carbohydrates
- Ketones Limitations of the BMI
 In the absence of glucose, incomplete breakdown - Easy to calculate and understand, but…
of fat for energy produces ketone bodies  Does not take into account location of body fat
» Ketones can be used as an alternative fuel for  Some (e.g., frail and elderly and bodybuilders)
cells that normally require glucose (e.g., brain) can’t be classified
» During ketosis, metabolism slows to conserve  Does not distinguish between body fat and learn
energy body mass
» Symptoms of headache, nausea, fatigue as  Makes little allowance for age/body types
body adjusts to ketones as fuel
 Long term effects poorly understood Fat deposition

Fat and protein - Many different fat deposits

- Diet fat stimulates fat storage, but not fat oxidation  Visceral
 Very high fat meals induce a weak increase in flat  Subcutaneous
oxidation - Different deposits have different properties
 Most fat stored in adipose tissue
  Abdominal fat – major risk for heart disease and - Normal vs. lesions
diabetes  Lateral hypothalamic lesions  anorexia
- Fat deposition patterns differ between men and  Normal
women  Ventromedial hypothalamic lesions  obesity
 Women tend to have more subcutaneous fat - Short-term hypothalamic inputs
- Android (apple) vs. gynoid (pear) obesity  Physical – stretch receptors in stomach
 Apple – high risk of CHD  Physiological – enormous number of feedback
 Pear – low risk of CHD loops that act on the appetite centre in the brain
- Intra-abdominal (visceral) fat: the dangerous inner fat » Insulin and blood glucose – signals meal
 More visceral fat = higher risk of health issues » Cholecystokinin (CCK) – hormone released in
 Males have lower subcutaneous fat, and greater gut during digestion
visceral fat » Serotonin (5-HT) – many diet/eating disorder
 Females have high subcutaneous fat, and lower drugs target this pathway
visceral fat » Endocannabinoids
» Ghrelin (recently recognised – major
Appetite influence) – produced by cells in the GI tract
 Ghrelin low and leptin high = hunger
- Brain regulates appetite and satiety  Ghrelin high and leptin low = satiety
- Appetite control centre (hypothalamus) - Long-term hypothalamic inputs
 Changes eating behaviour  Leptin – hormone made by adipose cells
 Changes metabolism
 Changes physical activity Marijuana and the munchies
- Experiments with mice critical in demonstrating role - Brain contains natural cannabinoids and cannabinoid
of the hypothalamus receptors (hypothalamus + others)
- Cannabinoids stimulate appetite
1958 – Body mass is regulated through hypothalamic - Knockout mice (-) cannabinoid receptor eat less
interaction - In humans – drug that block cannabinoid receptors
- Mouse had a lesion in the hypothalamus  Weight loss
- After surgery, mouse kept eating and eating and  BUT also depression, suicide, nausea, anxiety
eating until it was fat and continued to have the - May also stimulate release of ghrelin
lesion
- Joined the circulation of the fat mouse with the lesion Integrating short-term impacts on appetite
to that of a normal mouse (parabiosis) - The physiological feedback signals probably all
 Fat mouse stayed fat with lesion operate via neuropeptides in the brain
 Normal mouse became really skinny  Neuropeptide Y (NPY) – potent appetite
» Was getting signals from the fat mouse telling stimulant
it that it was too fat and needed to stop eating
 Conclusion: something in the blood circulates and Environmental effects on appetite
controls appetite hormones - There are also significant environmental impacts on
how much we eat
What controls how much we eat?  Snacking (increases caloric intake)
- Ultimate control is in the hypothalamus  Breakfast (missing = reduces intake)
 Hunger centre and satiety centre  Variety of foods (greater = increased intake)
 Short-term and long-term regulation  Portion size (large = increases intake)
- Lesions and disturbances of hypothalamic function  Number of people with whom you eat (increases
can have major impacts intake)
 Prader-Willi syndrome (hypothalamic Lecture 6: Weight regulation and genetics
dysfunction) – overwhelming and obsessive
eating, and low energy expenditure Key points:
- Long term regulation of intake/body weight
Hypothalamic centres - A genetic basis for body weight?
- Satiety centre (ventromedial hypothalamus) - “Adipostatic” body weight regulation
 Destroyed – rise in plasma insulin, inhibition of - Properties of an ideal adipostatic signal
lipid oxidation, overeating - Leptin – the hormone produced by the Ob gene
 Stimulation – inhibits pancreatic insulin release - Leptin as part of a negative feedback loop
- Hunger centre (lateral hypothalamus) - Concept of obesity as a polygenic disease
 Receives olfactory, gustatory and visual inputs
 Senses change in glucose concentration Long-term regulation of feeding
 Inhibited by glucose, insulin, gut hormones
(CCK) - Studies on adopted children show:
 Destroyed – refuse to eat  Little relationship between body weight and
 Stimulated – overeat adoptive parents
  Close correlation with biological parents Set-point hypothesis
- Twin studies - Your body defends a particular amount of fat
 Monozygotic twins raised together were closer in - Animals fed an ad libitum diet return to their basal
weight than dizygotic twins raised together weight after both
 Monozygotic twins raised apart were closer in  Forced weight gain (overfeeding)
weight than dizygotic twins raised apart  Forced weight loss (starvation)
- Identical twins – shared genes and environment
- Fraternal twins – shared environment - Body fat matches target – no change in energy
intake or expenditure
Genes vs. environment - Body fat higher than target – decrease energy
- Your body mass index is significantly heritable intake and/or increase expenditure
 Twin studies - Body fat lower than target – increase energy intake
 Family studies and/or decrease expenditure
 Adoption studies
» All three 50-70% of variation in BMI Feedback signal – ideal properties
- Obesity (genes) - Hormone secreted from fat cells
 Monogenic syndromes - Amount secreted varies proportionately with quantity
of fat stores
 Susceptibility genes
- Can be transported into brain
- Obesity (environmental factors)
- Receptors for hormone located within brain,
 Metabolic rate
particularly the hypothalamus
 Exercise - External administration of hormone will change
 Food intake usual weight
 Culture
Feedback loops
Case study – Pima - Feedback circuits very common control mechanisms
- Tribe split ~700 years ago in physiology, especially endocrine system
- Pima in Arizona live a modern lifestyle - Negative feedback is much more common
- Pima in Northern Mexico live traditionally  Negative feedback occurs when the output of a
- Arizona Pima now one of the most obese populations pathway inhibits inputs to the pathway
in the world  E.g., central heating systems switch of when they
reach the set temperature
Arizona Northern Mexico
- 90kg - 64kg Mice and obesity
- BMI = 33 - BMI = 25 - db/db make abundant negative feedback signal
- T2 diabetes in: - T2 diabetes in related to body fat but can’t respond to it
 54% of males  6% of males - Opposite for ob/ob – can’t make signal but can
 37% of females  11% of females respond
- Diet dominated by - Diet high in complex - Ob gene encodes for a negative feedback hormone
highly processed carbohydrates and
foods (high in fat and low in animal fat Expectations
refined sugar) - High energy - Ob gene should be expressed in adipocytes
- Low energy expenditure - Ob protein should circulate in plasma
expenditure - Plasma levels of ob protein should increase in obese
animals and decrease with weight loss
“Thrifty” phenotype - Ob protein should reduce body fat when injected into
- Genetic pre-disposition to converse energy ob and wild mild, but not db mice
 Efficient metabolism of fuels - Inconclusive for 22 years – much effort but nothing
 Reduced energy expenditure discovered
- Advantage in times of food shortage
- Disadvantage in modern Western culture 1995 – Ob gene
- Increased susceptibility to obesity under specific - Ob gene is expressed only in adipose tissue – fat is
environmental conditions not a metabolically inactive tissue
- Ob gene encodes a hormone called leptin which is
secreted into blood proportionally to body fat

Appetite centre
- Remember – appetite centre regulates
 Food intake
 Energy expenditure
 Physical activity
- Leptin reduces feeding and weight – what effect does
it have on energy expenditure
What is the brain target of Leptin?
- Most likely target is hypothalamic pathway
containing Neuropeptide Y (NPY)
 NPY is a potent stimulant of food intake and
suppressor of energy expenditure
 Administration of NPY to hypothalamus in rats
leads to rapid obesity
 Leptin decreases action of NPY

Why do we still have obese people?

- Most people are not leptin deficient
- Other possible explanations
 Obese people are leptin resistant
 Obesity may result from the defective delivery of
leptin through the BBB
 Leptin receptors are defective
 Defective signalling of leptin distal to leptin
receptors in the hypothalamus
 Non-linear relationship between ratio of leptin in
serum to cerebrospinal fluid
» Suggests leptin does not enter CSF in
proportion to its release from fat cells

What causes leptin resistance?

- Main issue seems to be entry of leptin into CNS
- Leptin levels in CNS in obese humans tend to plateau
when plasma leptin is high
 New set point?
- May be other reasons for leptin resistance
downstream of the leptin receptor in the
hypothalamus

Relevance to human physiology

- Weight loss by dieting results in a decrease in plasma
leptin – low leptin conc are a potent stimulus to
weight gain
 Diets often fail
- Human mutations in ob gene rare – few individuals
known
- Many other genes involved in a predisposition to
obesity have been identified