Control of food intake

Learning objectives
By the end of this lecture you should be able
to:

•Explain how energy intake and energy

expenditure are controlled, the brain regions
involved and the main hormones.

•Understand the mechanism of action of the

drugs used to treat obesity.
Energy balance is mainly regulated through control of food
intake affected by:
– Hunger
(desire/need for food)
– Appetite
(psychological desire to eat certain food)

– Satiation
(feeling of fullness that terminates meal)
– Satiety
(feeling of repletion that inhibits further meals)
 Control of food intake
Rats fed ad libitum on laboratory chow maintain
weight (hunger and satiety)

Rats given palatable foods gain weight

(appetite more powerful than hunger)

Hypothalamus controls
food intake
Control of Appetite

Evolutionary pressure- drive to eat as much as

possible when food is available?

Hypothalamus- arcuate nucleus (ARC)- role in

integration of appetite signals

- region of the brain not protected by

BBB- allows gut hormones to pass into
brain
 NPY POMC
AgRP CART ARC

- -

Orexigenic Anorexigenic
neurons neurons PVN

+
Reward
-
circuits Food Intake
POMC- proopiomelanocortin; CART- cocaine and amphetamine regulated transcript
PVN- paraventricular nucleus
POMC
undergoes posttranslational modification to generate:

Melanocortins

Act at melanocortin receptors

•AgRP- endogenous antagonist of the melanocortin-4

receptor
 Brain

ARC NPY/ POMC/

AgRP CART

Ghrelin
Insulin
PYY Vagus
CCK
Leptin
Pancreas
Adipose
tissue GIT
Gut peptides involved in regulation of food intake:

Gastric distension leads to release of a number of

hormones from the enteroendocrine cells:

cholecystokinin (CCK)

glucagon-like peptide-1 (GLP-1)

Oxyntomodulin
Inhibit food
peptide YY (PYY3–36) intake

apolipoprotein A-IV

enterostatin
Leptin (Greek: thin)

•Peptide hormone secreted from adipose tissue

• food intake leptin levels

-Reversed by refeeding or insulin

•Production of leptin correlates with amount of

adipose tissue- ie energy stores

•Mutations causing absence of leptin leads to severe

obesity
•Leptin is transported into the brain
- inhibits NPY AgRP release
-activates the POMC/CART neurons
-switch from appetite stimulation to appetite
suppression.

•Leptin deficiency is a rare genetic mutation- does

not explain increase in obesity
Insulin

Plasma increase at times of positive energy balance

and decrease at times of negative energy balance

Crosses BBB through receptor-mediated process

Decreases intake and body weight- actions on ARC

Ghrelin

•Produced from GIT.

•Secreted on anticipation of food

•Acts centrally at ARC or brain stem to stimulate

food intake through NPY and AgRP

•Hunger at certain times of day- Ghrelin

B L D

Ghrelin

Insulin

Leptin

Cummings et al., 2001

•Ghrelin levels peak before meal.

•Stimulates hunger in humans.

•If obese try to lose weight- ghrelin levels

increase

•Ghrelin may be involved in reward: causes

increase in risk taking.

•Ghrelin antagonists in development for treatment

of obesity.

•Cause weight loss

PYY

•PYY- secreted from distal GIT dependent on nutrient

intake (eg protein> fat or CHO).

• Also stimulated by CCK, gastric acid, bile

•PYY1-36 cleaved to PYY3-36- acts at NPY Y2 receptor

•Inhibits food intake. Possibly through vagal inputs

•PYY levels stay elevated for 12 hours post meal.

•Decreases food intake in lean and obese (no

resistance)
PYY

Y2
Inhibits
NPY

NPY
Y1 Y5

Neuron
CCK (cholecystokinin)

•Released from duodenum and jejunum in response

to FAs.
• Acts on receptors on vagal nerve
•And possibly crosses BBB
•Inhibits food intake
Leptin Grehlin
Leptin
PYY - +
Insulin +

NPY - POMC ARC

AgRP CART

+ -

Food Intake
Reward Centres also involved

Appetite linked to reward processes in the brain.

eg opioid receptors (endorphins)

Cannabinoid receptors
Dopamine

Reinforcement of motivation to find and consume

foods of high incentive/energy content?
Dopamine & Reward

•Feeding is associated with dopamine release in the

dorsal striatum.

•Degree of pleasure correlates with the amount of

dopamine released.

•Bupropion- dopamine reuptake inhibitor

weight loss
Inhibition of Neurotransmitter Re-Uptake
eg Bupropion- dopamine reuptake inhibitor

DA

DA
D-R
DA

DA
D-R
Inhibition of this reuptake leads to an increase in the
amount of dopamine in the synapse, leading to a
prolonged activation of the dopamine receptor

Bupropion
DA

DA DA
D-R
Cannabinoid Receptors

-Food reward depends upon CB1 receptor activation.

-May regulate dopaminergic system

-Rimonabant- CB1 receptor antagonist

Current Prescription Only Medicines

Orlistat

Liraglutide - 2017

Sibutramine- Suspended Jan 2010

Rimonabant- marketing authorisation suspended

Oct. 23rd 2008.

Dexfenfluramine, fenfluramine and phentermine

associated with valvular heart disease and
pulmonary hypertension.
No longer recommended.
Orlistat

- Inhibits Gastric and Pancreatic lipase

- minimal absorption

- Needs to be taken before each main meal

- ~ 30% inhibition of lipases at normal

therapeutic doses (lose 200kcal per day)

-Needs to be combined with a low fat diet –

reinforces the need to restrict fat intake
Side effects

Steatorrhea- fatty, foul smelling faeces

- may actually help to reduce fat intake

Reduced absorption of fat therefore need to monitor

fat soluble vitamin status- supplements?
Meta Analysis of Clinical Trials
(Rucker et al BMJ Online &
Padwal et al Cochrane Database, 2003)

16 clinical trials (10,631 subjects)

Orlistat for 1 year reduced weight by 2.9kg more than

placebo.

With calorie-reduced diet.

BUT – Controlled trials are not always mirrored in

Clinical Practice.
Prescribing guidelines

To be combined with reduced calorie diet.

BMI > 30 kg/m2 or

BMI > 28 kg/m2 if other risk factors eg type 2
diabetes, hypercholesterolaemia, hypertension

Should only be continued after 12 weeks if weight

loss exceeds 5%

Treatment > 12 months should only be done after

discussion potential benefits and risks with patient.
Dose

120 mg taken immediately before, during or 1 hr after

each main meal

Max. 360 mg daily

Miss dose if meal contains no fat-low chance tbh

OTC Orlistat (Alli)

•Reduced dose- 60mg tds

•Max 6 months

•Combined with reduced fat diet

•BMI > 28

•Review after 12 weeks

•Dietary approaches and physical activity should be

tried before Orlisat
http://www.rpsgb.org/pdfs/otcorlistatguid.pdf
 Saxenda- GLP1 agonist- Approved 2017

Liraglutide is a glucagon-like peptide-1 (GLP-1)

receptor agonist

s.c. injection

• Appetite suppression- increased secretion of

POMC/ CART- anorexigenic neurons

• GLP-1 can also reduce high fat food intake by

suppressing dopamine signalling- effect on
reward pathways.

30 day cost £196

Orlistat £18
Treatment Guidelines similar to orlistat

ie BMI> 30 or lower if concurrent disease

NB care with type 2 diabetes- is patient already

on a GLP-1 agonist?

Monitor after 12 weeks- stop if less than 5%

weight loss
Mysimba

Combination of naltrexone (opioid receptor

antagonist) & bupropion I (dopamine reuptake
inhibitor)

Effects on reward pathway.

Similar efficacy as orlistat.

Not recommended by NICE- cost effectiveness not

clear
Sibutramine

•Combined NA and 5HT uptake inhibitor.

• cf antidepressants.

•Appetite suppressant.

•No longer used- increase bp and hr.

Rimonabant (Acomplia)

-CB1 receptor antagonist

-Licensed for use in EU July 2006

-NICE guidelines issued June 2008

-European Medicines Agency suspended marketing

authorisation Oct. 23rd 2008.
-Review found that benefits do not outweigh the
risks.
Phentermine- US

Not licensed in UK.

Increases catecholamine levels in brain.

Also peripheral effects- increase hr, bp, palpitations.

Qsymia - phentermine + topiramate

42% > 10% weight loss

Approved by FDA

Refused by EMEA October 2012

 Summary
• Appetite/ satiety controlled by complex
mechanism

• Some current treatments interfere with these

pathways

• Understanding these mechanism may produce

novel therapies for obesity.