Lecture 20 - Eating Behavior

Question 1

Energy balance and weight maintenance

Answer 1

Homeostasis: maintenance of a steady state of an organism by physiological or behavioural feedback control mechanisms

Feeding behaviour is governed by homeostasis
body’s need to maintain an optimal energy “set point”

Signals from the gastrointestinal tract and adipose tissue responsible for this process

There are also hedonic pathways which have a role

The interoceptive system sends inputs via parasympathetic relays to the CNS

These inputs contain information about thermal, chemical, metabolic and hormonal changes (from skin, muscle, joints, etc.)

Important part: the enteroendocrine system

Question 2

Energy balance is regulated by a complex system

Answer 2

Orexigenic peptides: increase motivation to eat
e.g. ghrelin, NPY, AgRP, MCH, Orexin A, Orexin B, galanin

Anorexigenic peptides: decrease motivation to eat
e.g. leptin, insulin, alpha-MSH, CRH, TRH, CART, POMC, GL-P1

Question 3

Ghrelin

Answer 3

Discovered in 1996: still new-ish by the standards of science

A peptide hormone produced by the stomach cells; it is thought to increase feelings of hunger.

Also an orexigenic hormone (stimulating appetite)

May have evolved as a response to the feast or famine conditions of early humans.

Not as relevant in situations when food is abundant

It is inhibited when the stomach is stretched and designed for situations of feast/famine

Question 4

Ghrelin System

Answer 4

Secreted from empty stomach

• Stimulates food intake
• Release stopped when -stomach stretched

Produced in the arcuate nucleus of hypothalamus

• Acts in dopaminergic centers to increase reward behaviour
• GH will take energy from good and build the body with it
• Stimulates secretion of growth hormone

Activates mesolimbic dopamine
Increases drive to consume food

Question 5

Ghrelin and feeding behaviour

Answer 5

Systematic injections of ghrelin stimulate food intake and increase body mass in rats.

Increased hyperphagia, weight gain and adiposity occur after continuous systematic ghrelin administration at low doses

Ghrelin important in food intake

Higher levels linked to increased consumption

Blood concentrations of ghrelin peak around the time of meal onset

In humans increase nearly twofold immediately before each meal

Fall within one hour after eating

Ghrelin levels show a diurnal rhythm that is exactly in opposite phase with that of leptin – rising and falling at the opposite times during the day

This rise and fall supports the hypothesis that ghrelin plays an important role in meal initiation in humans.

Question 6

Prader Willi Syndrome

Answer 6

Genetic disorder with mild growth retardation

Hyperphagia and obesity common, even if only bland food is available they will still eat

Elevated levels of plasma ghrelin typically observed

Missing methylation on ghrelin promoter region - excess ghrelin

Dysregulation of many hormone systems
-Insufficient growth hormone - low muscle, high fat
Incomplete sexual development
-Hypocortisolemia (underactive adrenal cortex)

Inactivity in many hormonal systems

Question 7

Leptin

Answer 7

Leptos: “thin”

Adipokine Hormone - produced by adipose tissue

Adipocytes not just storehouses, endocrine glands too!

Levels are higher in obese people and after meals

Lower in thinner people and during fasting periods

Question 8

Actions of leptin

Answer 8

Leptin levels are proportional to body fat and fluctuate in opposition to Ghrelin

Active transport mechanism brings leptin across BBB
NB - Ghrelin is produced in the arcuate nucleus, leptin must actively cross the BBB to get into the brain and exert an effect

Binds to receptors in hypothalamus to inhibit eating and send satiety signals

High while fat is being stored, fall when fat metabolized

High levels of leptin cause long-term satiety

Question 9

Rodent Studies

Answer 9

• Mutations in mice in genes coding for leptin (“ob”) or leptin receptors “db”
• Leptin treatment of ob/ob mice caused significant weight loss
• Leptin critical for reducing excessive weight

Leptin was found by looking at obese mice and seeing how they differed from normal ones

ob gene = obese gene

If you have no receptor for leptin, you have the same issue

Question 10

Leptin treatment can rectify obesity

Answer 10

Mutation of both leptin and leptin receptor genes found in humans, though very rare
Heterozygous means moderate obesity

The ob(lep) gene is found on chromosome 7

Can be treated with daily leptin injections

People with this mutation get thinner. They are still fat but not in the top 1% anymore

Question 11

Pancreatic Hormones Regulate Glucose

Answer 11

Insulin is released immediately following a meal.

Glucose moves from the blood to other tissues.

Excess glucose is stored as glycogen, then as fat
As blood glucose levels drop, glucagon converts glycogen back into glucose

Insulin and Leptin linked: satiety hormones

(1) Insulin stores fat
(2) Leptin says we have enough nutrients stored

Fat storage vs. reducing fat stores

Opposite effect to achieve same ends

Question 12

Energy balance is regulated by a complex system

Answer 12

Orexigenic peptides: increase motivation to eat
e.g. ghrelin, NPY, AgRP, MCH, Orexin A, Orexin B, galanin

Anorexigenic peptides: decrease motivation to eat
e.g. leptin, insulin, alpha-MSH, CRH TRH, CART, POMC, GL-P1

IDEAL WORLD ENERGY HOMEOSTASIS

When you eat ghrelin decreases and insulin increases

• Reduced hunger and absorption of sugar to maintain blood glucose
• Leptin increases with storage, reducing overall appetite, causing body to use stores

THIS DOES NOT HAPPEN!

Question 13

Hedonic foods: throwing off a fine balance

Answer 13

Signals from outside the body (availability of food options) can alter hormonal processes

Hedonic foods are high in fat and sugar

High caloric density

Intrinsically motivating - act on the dopamine pathway of the brain to increase their incentive salience (drive to get and consume)

Question 14

What’s gone wrong with our energy homeostasis

Answer 14

How do current eating patterns dysregulate this process?

Highly palatable food readily available
Often fastest and cheapest options
Obese people greater responsivity to food cues

Ghrelin – reduced in obesity
Reduced growth hormone so increased adipose storage….
Stomach size

Leptin does not readily cross blood brain barrier
Heightened levels of blood leptin are not absorbed into the CNS
Aging may also contribute to leptin resistance

Resistance to satiety hormones

CHRONIC HIGH LEVELS CAN DECRESE THE EFFECTIVNESS OF INSULIN AND LEPTIN

Question 15

Insulin resistance

Answer 15

How do current eating patterns dysregulate this process?

Hedonistic driven eating = chronically high blood glucose

Insulin released in response to eating/blood sugar

Chronic high insulin reduces receptors

Insulin resistance means no effect of this satiety hormone

Major factor in type 2 diabetes

Insulin resistance closely linked to leptin resistance

Satiety hormones both have little effect

Question 16

Experiment in overfeeding rats

Answer 16

Rats: can control all food intake and limit activity
-Eliminate all confounding variables

Compare rats getting healthy and high fat food

Add pair-fed to assess role of control over food consumption
(Healthy food by in the same number of kcals as non-healthy food)

Administer insulin + glucose and leptin
Assess blood glucose and gluconeogenesis

How does short term overfeeding affect response to satiety hormones?

Overfeeding:

Reduced glucose uptake in response to insulin

Decreased inhibition of glucose production in response to insulin

Leptin did not increase glucose production from fat stores

No decrease in food consumption either

Overeating reduces sensitivity to satiety hormones

Question 17

What’s gone wrong with our energy homeostasis

Answer 17

Ghrelin – reduced but still there in obesity

Leptin resistance
Fat not turned into glucose for use
BBB (max out leptin transporter)? Aging?

Insulin resistance
Cannot store glucose as well, and do not maintain glycogen

Still some orexigenic signal but not satiety signals
Combo with palatable food = obeisity

Question 18

The selfish brain (brain pull) hypothesis

Answer 18

Background

World-wide surge in obesity and diabetes threatening longevity

Link between chronic stress and obesity

Pathophysiology of obesity has to do with a number of hormonal mechanisms
Ghrelin
Leptin
Insulin

Interaction between HPA hormones and feeding behavior?

CNS has 2% of body mass but accounts for 50% of total body glucose usage
100g of glucose per day
Will not use fatty acids or amino acids unless desperate, NEEDS glucose

Neuroglycopenia
Increased heart rate, light headed, irritable, confusion, emotionality, focal seizures
GABA inhibition of neurons throughout brain to reduce energy requirements
KETO FOG!!!

Glucose is hard to store…
How can the brain guarantee supply?

Question 19

Glucose in the CNS

Answer 19

Cellular mechanism via glutamate
Glutamate uptake by astrocytes in synaptic cleft

One molecule of glutamate = one molecule of glucose via GLUT1 transporter

Glucose in circulation is limited
Circulating glucose can be as low as 5g

Two main mechanisms for brain to ensure glucose availability:

(1) Prevent glucose loss to peripheral tissues (glycolysis) and
(2) stimulate glucose production in liver (gluconeogenesis)

Endocrine and CNS input control glycolysis and gluconeogenesis

Eating behaviour: regulated by paraventricular hypothalamus (where HPA originates)

-Input from hippocampus: memory allows us to prepare for energy demands (using our past experience to estimate the amount needed)

GR receptors in PVN and hippocampus – stress interacts with feeding
PVN: Cross-link to HPA, SNS

ACTH, cortisol and adrenaline:
suppress insulin secretion, induce insulin resistance, and stimulate gluconeogenesis (‘cerebral insulin suppression’)
Energy on request (‘brain-pull’ system)

We will pull for sugar based on the stress in the environment

Question 20

Push and Pull of the Brain

Answer 20

If (perception of) insufficient glucose neuroglucopenia commences

Activation of hypothalamus (lateral)

This simulates food intake behaviour

Release of other feeding hormones stimulate appetite and eating
‘body pull’

Stress should specifically increases carbohydrate consumption

Fast access to glucose to meet brain need

Can be tested!

Question 21

Psychological stress and brain pull

Answer 21

These days most of our stressors are psychological

The brain and the body do not need energy to deal with them but they hijack the system

The result is excess carb eating which increases blood sugar

Is not actually needed

So comfort eating makes us fat

Question 22

Brain pull comfort eating study

Answer 22

Use a within participate study (the same people in the stress/no stress conditions)

G1: Rich buffet
G2: Salad
G3: Dextrose infusion
G4: Lactate infusion

DV1: Measure of SNS activity

Increased in stressor groups with TSST but not non stressed groups

DV2: Keto fog

(1) Stress in all four groups caused increase in neuroglycopenic symptoms
(2) Evidence for brain pull in response to psychological stressors
(3) Alleviated following meal in all groups except meagre salad
All bar salad had fast-available brain energy substrates. Stress fog was only brought back to baseline by sugaror other brain energy substrate.

DV3: Blood Glucose

Blood glucose goes up after a stressor even if you did not eat because the stressor causes release of glucose from stores to blood because of brain pull

Evidence for brain pull in response to stress

DV4: What food did the buffet group eat?

No difference in protein, fat or energy consumed between the stressed and non stressed buffet groups. Sig difference in carbs, the stressed group chose to eat more carbs.

DV5: Depressed mood

Depressed mood is a symptom observed in all groups following stressor

Improves when blood sugar up, artificially or with food

DV6: Perception of Stress

Eating is better than artificial sucrose augmentation for stress

You get lower subjective stress among those who ate vs sugar infusions alone

Eating food reduces perception of stress

Question 23

Conclusions from our selfish brain

Answer 23

When stress systems activated brain pull mechanisms exceed levels the body can meet

Brain activated feeding behaviour so blood stream has glucose to meet potential demand

High levels of energy available but not needed for psychological stressor

When no physically demanding stressor stored as fat

Once start overeating feel better

• Classical conditioning as well as brain pull leads to excess eating
• Repeated overeating + stress means insulin and leptin resistance

All add to make a fatty a fatty