medical-notes/content/Fysiologi/Canvas/Del III/Block 13 - Hormoner, tillväxt och kroppsviktreglering/Body weight Homeostasis SD (1).md

# Body weight Homeostasis SD (1).pdf

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## Page 1

2025-05-05
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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
BODY WEIGHT HOMEOSTASIS
PROFESSOR SUZANNE L DICKSON
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
1
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Measuring obesity and obesity 
statistics
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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## Page 2

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
DEFINITIONS
Overweight and obesity are 
defined as abnormal or 
excessive fat accumulation 
that presents a risk to 
health. 
ADULTS: A body mass index 
(BMI) over 25 is considered 
overweight and over 30 is 
obese.
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
>18.5
18.5-24.9   
25.0-29.9
30.0-34.9
>35.0          
BODY MASS INDEX (kg/m2)
3
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Body mass index (BMI) = weight/height2 (kg/m2)
Weight (kg)
Height 
(m)
BMI
Normal
20-25
Overweight
>25
Obese
>30
Morbidly Obese
>40
BMI for adults
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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## Page 3

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Weight (kg)
Height 
(m)
BMI
Normal
20-25
Overweight
>25
Obese
>30
Morbidly Obese
>40
Weight: 110 Kg
Height: 1.8 m
à BMI: 34
A cautionary note …..
This calculation does not predict obesity for body 
builders (muscle) or for those that are very tall
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
5
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Age 5-19: 
Use BMI-for-age
Overweight : >1 standard 
deviation above the growth 
reference mean
Obesity: >2 standard deviations 
above the growth reference 
mean
Age
5
19 yrs
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
BMI-for-Age GIRLS
obese
overweight
BMI (Kg/m2)
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## Page 4

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Age <5
Use Weight-for-age
Overweight: >2 standard 
deviations above the growth 
reference mean
Obesity: >3 standard deviations 
above the growth reference 
mean
Age
Birth
5 yrs
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Weight (kg)
Weight-for-Age GIRLS
7
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Direct methods for assessing fat mass
Underwater 
weighing
Accurate. Was gold 
standard before more 
advanced methods. 
Fat vs non-fat tissue 
have different 
densities.
Whole-Body (ADP)
Air Displacement 
Plethysmography 
Like underwater weighing –
displace air instead of water. 
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Total body water (TBW). Drink 
deuterated (or tritiated) water à ends 
up in the fat-free compartment à
sampling gives TBW.  From this, fat mass 
can be calculated (since body weight is 
known). 
2H2O
H2O
2H2O
H2O
+
5 hours
e.g. 
1 liter
e.g. 
80 liters
Dilution: 
1:80
Sample (eg saliva)
(known)
(unknown)
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## Page 5

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Direct methods for assessing fat mass
Dual X-Ray absorptiometry (DEXA)
X-rays of two different 
energies. One absorbed 
more strongly by fat.  
Subtract one image from 
the other à amount of 
fat relative to other 
tissues at each point. 
Measures total fat and 
gives distribution. €€€. 
Involves exposure to 
(low level) radiation. 
OFTEN USED IN 
RESEARCH.
Computerized tomography
Cross-sectional radiographs of 
abdomen à computerized 
measurement of total fat area and 
regional fat determination (e.g. 
subcutaneous versus visceral fat). €€€. 
Radiation (like many x-rays).
Bioelectrical impedance
Resistance between 2 electrodes is 
higher in obese individuals. 
Resistance high for fat & low for 
water. Not accurate.
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
9
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Indirect methods for assessing fat mass
ØSkinfold measurements – subcutaneous fat 
measured using calipers. Use conversion tables 
to estimate body fat % to about 3-5% accuracy. 
More useful than BMI in athletes. 
ØWaist:hip ratio – cut-offs are ≥ 0.90 cm in 
men and ≥ 0.85 cm in women 
ØBMI - based on weight and height (kg/m2)
Most obesity 
statistics are 
based on 
BMI data
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Source: hereandnowwellness.com
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## Page 6

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
2020: % US adults with an obese BMI (>30)
11
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
1992
2000
2010
Sweden –
Prevalence of 
Overweight (%)
% BMI>25 kg/m2
<18 
>18-25
>25-35
>35
And in 2022 
Adults – 35% overweight, 16% 
obese
Children – 20% overweight.
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
DOI:10.1177/1403494815579478
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## Page 7

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Health consequences of obesity
OBESITY
CARDIOVASCULAR 
DISEASE
TYPE 2 DIABETES
Increased risk:
Breast cancer
Bowel cancer
Osteoporosis
Lung disease
Strokes
Heart attacks
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Metabolic Syndrome
A cluster of conditions that occur 
together, increasing risk of heart 
disease, stroke and type 2 
diabetes. 
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
About two-thirds of people 
suffering from obesity develop 
metabolic syndrome.
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## Page 8

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Metabolic Syndrome Diagnosis (WHO 1998)
Type 2 diabetes plus 2 out of 3 of the other 
components:
Type 2 diabetes:
­ Fasting glucose (> 6.5 
mmol/L)
¯ Glucose tolerance or 
­ Insulin resistance
High Blood Pressure
Visceral Obesity
Blood fat disturbance:
­ Triglycerides
¯ HDL (good) 
cholesterol
­ LDL (bad cholesterol)
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
15
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Debate regarding metabolic syndrome
We say that “it 
is just a 
constellation 
of symptoms 
or sub-
diseases”
We disagree. 
Surely there is 
a causal 
relation 
between 
symptoms –
perhaps even 
a common 
cause?
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Depositphotos
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## Page 9

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Below
waist
Above 
waist
Increased risk of metabolic disturbances
­ Visceral fat   à ­ Free Fatty Acid (FFA) release , e.g. to the liver (bad)
à ­ release of adipokines* (exception is adiponectin, 
whose secretion is decreased).
*Adipokines are fat-derived cytokines such as leptin and resistin and also
immune-stimulating hormones  e.g. interleukin-6 (IL-6), TNFa
§ Android
§ Central
§ Abdominal
§ Truncal
§ Upper body
§ Gynoid
§ Peripheral
§ Gluteo-femoral
§ Lower body
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
17
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
How does obesity cause insulin resistance?
1. Free fatty acid ”overflow hypothesis”
2. Adipokines, immune stimulating hormones from white 
adipose tissue (↑ TNFa, ↑ resistin, ↓adiponectin)
Both can be 
true!
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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## Page 10

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Glucose
Glucose
Glucose
Glucose
Health
Disease
1. Fat overflow hypothesis. Fat outside fat tissue is 
dangerous for metabolic health
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
19
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
2. “Adipokine” hypothesis
Immune stimulating 
hormones (adipokines) 
from adipocytes and 
macrophages in fat à
inflammationà diabetes 
in liver, muscle and 
pancreas
Adipocyte
Macrophage
Blood vessel
Glucose
Glucose
Healthy 
Metabolic syndrome 
adipokines
Insulin 
Insulin 
IL-1β 
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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## Page 11

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
The relation between obesity, adipokines and their 
impact on insulin resistance
↑ TNFα 
↑ resistin
↓ adiponectin
↑ leptin 
INSULIN
RESISTANCE
+
_
Leptin resistance
Adipokines
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
21
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Adipokines in metabolic syndrome
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Adiponectin – Levels reduced in 
metabolic syndrome. In normal weight 
individuals, it has beneficial effects 
(increases insulin sensitivity, anti-
inflammatory, anti-artherosclerosis). 
1. modify insulin sensitivity e.g. 
acylation stimulating protein, tumor
necrosis factor α (TNF-α), IL-6, 
resistin, visfatin, apelin, omentin, 
chemerin, leptin and adiponectin.
TNFa & IL6 - Levels increased in 
metabolic syndrome. 
Proinflammatory. Produced by 
adipocytes and macrophages. Cause 
insulin resistance and increase 
circulating free fatty acids.
Adipokines include proteins that:
3. impact on vascularity e.g. 
angiotensinogen, plasminogen 
inhibitor protein, PAI-1) among 
others.
2. ↓ insulin release (e.g. IL-1β)
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## Page 12

2025-05-05
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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Adipokines in metabolic syndrome
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Role in many metabolic processes:
Energy expenditure, neuroendocrine function, immune function, 
vascular remodelling, angiogenesis, fatty acid oxidation, 
lipogenesis, gluconeogenesis, glucose uptake, insulin 
signalling, and energy expenditure in metabolically active 
tissues such as the liver, skeletal muscle and the brain. 
Site of action:
Can act locally, through autocrine/paracrine mechanisms, or 
systemically, through endocrine effects
I’m not expecting 
you to memorize this 
list but to realise 
they have many & 
diverse functions
23
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
↔Cortisol (despite signs of ↑ cortisol 
activity - looks like Cushings syndrome!)
↑ androgens in women (polycystic 
ovarian syndrome, PCOS)
↓ androgens in men
↓ growth hormone
Additional endocrine changes in metabolic syndrome
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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## Page 13

2025-05-05
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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Body weight homeostasis
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
- Powerful physiological processes aim to keep body weight constant
25
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Energy Expenditure: 
- Basal Metabolism
- Physical activity
- Adaptive thermogenesis**
Food intake & energy expenditure balanced à body weight maintained at a “set point”. 
1. Genetic 
predisposition*
2. Long term changes 
in body weight
3. Obesogenic 
environment
*Predisposition= tendency to suffer from
**Occurs in brown adipose tissue.
Factors influencing 
the “set point”
Ø Target weight maintained with an extraordinary degree of control.
Ø “Set point” controller = brain (especially hypothalamus) 
“Set point” hypothesis of body weight regulation
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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## Page 14

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
In obesity, there is a defense of an elevated body weight, rather 
than the absence of regulation.
Evidence that we defend our body weight at a set point?
ØBody weight defended despite diet attempts (­ hunger & ¯
metabolism).
ØDiet and lifestyle changes ineffective.  
ØReturn to “set point” (normal weight) after dieting or illness and 
after voluntary overfeeding.
ØThe 0.5 kg gained per year during ageing (average) = 
surprisingly little
“Set point” is a hypothesis to explain obesity!!!
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Age: 20
50
+ 30 kg
27
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Weight gain as we age
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Age 20
Age 50
+ 15 kg
Powerful Physiological Systems 
Control Energy Balance & Body Weight.
1 g fat = 9 kcal
15 kg fat = 130,000 kcal 
13,000 kcal in 30 years
= 86 kcal/week
8 minutes 
running
or
Per week 
imbalance:
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## Page 15

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Change in weight (kg)
Overfeeding 
(6736 kcal/day)
months
Body weight
Fast mass
Pasquet P, Apfelbaum, M. Am J of Clin Nut 1994;60:861-3
“Guru Walla" fattening session 
in the Massas ethnic group in 
Northern Cameroon
"The fattening session resulted in a mean 
extra energy intake of 955 MJ and an 
increase of 17kg in body weight...Over 
the whole overfeeding session, we noted 
a 43.5% mean increase of resting 
metabolic rate, which is much higher 
than previously reported”
Evidence for set point: Return to normal weight after a 
period of voluntary over-feeding
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
29
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Does energy expenditure adjust if we over- or under-eat 
enough calories to alter our body weight?
Over-eat à gain 10% body weight
Diet à Lose 10% or 20% body weight
Measure
Energy 
Expenditure
Predict
Energy 
Expenditure
Difference??
Leibel RL et al. N Engl J Med 1995;332:621-628.
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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## Page 16

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Does energy expenditure adjust if we over- or under-eat 
enough calories to alter our body weight?
Leibel RL et al. N Engl J Med 1995;332:621-628.
Over-eating  (à weight gain) 
à ­ Energy expenditure (> 500 kcal above 
that predicted)
Food restriction (à weight loss) 
à ¯ Energy expenditure (¯ was > 300 kcal 
more than predicted)
Observed minus
predicted 
total energy 
expenditure 
(kcal)
Dieter’s 
curse
People go up in energy 
expenditure when they gain 
weight & down in energy 
expenditure when they lose 
it – more than expected!
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
31
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Body weight
Set
point
Free 
choice
Free 
choice
Free 
choice
Under
Feed
Over
feed
¯ energy expenditure
­ appetite
­ energy expenditure
¯ appetite (less effective)
Both under- and over-nutrition can lead to weight gain 
over time
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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## Page 17

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Food available
EAT!!!!
STORE ENERGY 
(TO PREPARE FOR 
FUTURE FAMINE)
­­ HUNGER à search for 
food
¯ METABOLISM à save 
energy
survival
LEAN 
ENVIRONMENT
Food scarce (famine)
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
THEN….. In our evolution, there was genetic pressure to 
increase body weight
33
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
EAT!!!!
STORE ENERGY 
(TO PREPARE FOR 
FUTURE FAMINE)
OBESOGENIC  
ENVIRONMENT
­­ HUNGER à search for 
food
¯ METABOLISM à save 
energy
Food available 24/7
Dieting (attempts to limit weight gain) 
Obesity
Same 
genetic 
pressures as 
our 
ancestors
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
NOW: Food is more available  … but our genetics have 
evolved to increase our body weight
EssayPlant.com
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## Page 18

2025-05-05
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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Energy expenditure
Basal 
Metabolism
Physical 
activity
Adaptive 
thermogenesis
Metabolism
Energy
Storage
(fat)
Total energy 
expenditure 
(= Heat+work 
done on
environment)*
*When at rest, all energy 
expenditure is equal to heat 
produced (ie thermogenesis)
•Variable (at most 10% in modern life)
•Regulated by brain
•Responds to temperature & food intake
•Occurs in brown adipocyte mitochondria, 
skeletal muscle & other sites
•Variable (~25%)
(~65%)
For performance of cellular & organ 
functions:
•synthetic processes
•electrical work
•membrane transport
•detoxification
•degredation
Energy intake (Food)
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
35
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Energy dissipated (wasted) in the form of heat in response to environmental 
changes, essentially cold exposure and food intake. It helps protect against 
weight gain by causing a compensatory increase in energy expenditure 
when we eat.  
Adaptive thermogenesis
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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## Page 19

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Function = energy expenditure 
(not storage).
Present in interscapular area.  
Present in human infants but 
declines with age.
Sympathetic nervous system 
(SNS) increases BAT activity in 
response to cold or increased 
food ingestion. Adaptive 
thermogenesis.
Heat generated in mitochondria 
via “uncoupling”.
Electron 
transport 
chain
MITOCHONDRIA
Fatty
acids &
glucose H+
ATP
synthase
H+
ADP
ATP
(Energy storage)
UCP1
H+
H+
UCP1=uncoupling protein 1
It is present in BAT but not in 
other cells. It is increased by over-
eating and decreases with fasting
HEAT
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Brown Adipose Tissue (BAT)
37
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
PET scan after intravenous 
injection of 18F-
fluorodeoxyglucose (18F-FDG) à
BAT visualized
New information on BAT:
Present in human adults.
Women have more than men.
More in younger adults
More BAT in lean subjects? 
Therapeutic interest? 
Stimulation of BAT à energy 
expenditure & weight loss
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
2010: BAT also discovered to be present in human adults
DOI:10.1038/ijo.2010.241
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## Page 20

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
2. Thyroid hormones  (TRβ on BAT) - chronic
­ UCP-1 expression in BAT
(BUT NOTE: THEY ARE ALSO THE PRIMARY CONTROLLER OF THE BASAL METABOLIC RATE; 
ACTING ON MOST BODY CELLS (NOT BRAIN) TO ­ ­ ENEGY EXPENDITURE)
1. Noradrenaline (β3 AR on BAT) – acute
Caused by sympathetic nervous system  (SNS) activation. Contribute to heat 
produced when emotionally stressed.
­ Metabolism of brown adipose tissue (BAT).
­ UCP1 activation and hence energy expenditure
3. Glucocorticoids (via glucocorticoid receptor on BAT)
Inhibitory effect on BAT.
Suppresses noradrenaline-induced UCP1 activation
4. Leptin (via ObRB in hypothalamus that stimulate SNS)
­ UCP-1 expression in BAT
Hormones important for BAT activation
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
39
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
BMI
Energy 
expenditure
Obese
Ex-obese 
(↓ diet-induced 
thermogenesis, 
eg ↓ T3)
Lean
A formerly obese individual 
will require ~300–400 fewer 
calories per day to maintain 
the same body weight and 
physical activity level as a 
never-obese individual of 
the same body weight.
Reduced energy expenditure in the post-obese state
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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## Page 21

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Body weight Homeostasis - the 
control systems
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
41
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Effector systems
Sensors
Altered Internal 
Environment
Principles of homeostasis – keeping (body weight) 
constant
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Controller
Homeostasis
- maintaining a 
steady state.
- involved feedback 
systems.
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## Page 22

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Food intake
Energy expenditure
Adaptive thermogenesis
Sensors
???
Energy deficit/excess
Key questions:
1. What are the control 
systems in the brain that 
alter food intake & energy 
expenditure?
2. What are the sensors?
3. Why do these fail in ways 
that result in body weight 
gain & obesity?
Hunger/full etc
Longterm
Short term
Principles of homeostasis – keeping (body weight) 
constant
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
43
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Locke et al Nature. 2015 Feb 12;518(7538):197-206
Genes linked to 
BMI are mostly 
found in brain, and 
notably in the 
hypothalamus
Energy homeostasis control system is in brain
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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## Page 23

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Brain areas involved in energy balance regulation
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Hypothalamic and brainstem autonomic 
circuitry (orange) includes the arcuate nucleus 
(ARC), the dorsomedial hypothalamus (DMH), 
the dorsal-vagal complex (DVC), the lateral 
hypothalamus (LH), the pontine parabrachial 
nucleus (PBN), the preoptic area (POA), the 
paraventricular hypothalamus (PVH), the raphe 
pallidus (RPa), and the ventromedial 
hypothalamus (VMH). Structures of the brain 
executive system (green) include the anterior 
cingulate cortex (ACC), the insula (Ins.), and 
the prefrontal cortex (PFC). Structures of the 
brain reward system (blue) include the 
amygdala (Amy.), hippocampus (Hipp.), Ins., 
LH, nucleus accumbens (NAc), striatum (Stri.), 
and ventral tegmental area (VTA).
DOI:10.1111/nyas.13263
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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
§Nearly all hypothalamic nuclei 
engaged.
§Especially - Mediobasal 
hypothalamus (MBH) - includes 
arcuate nucleus (Arc) and 
ventromedial nucleus (VMN) – energy 
intake and adaptive thermogenesis.
§Arc cells project to many other 
hypothalamic (and extra-
hypothalamic) areas to regulate 
energy balance.
§Lateral hypothalamus – feeding 
center. 
Autonomic control of energy balance: Hypothalamus
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
VMH, LH, 
DMH, POA 
Arc
PVH
Appetitice & 
Consummatory 
Behaviours
Adaptive 
thermogenesis
Autonomic & 
neuroendocrine 
control of food intake 
& energy 
expenditure 
Hypothalamic areas regulating energy balance.
+ VMN
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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
1. Lesions of key hypothalamic areas cause animals to lose 
control of their set point for body weight. 
Ventromedial nucleus (VMN) lesion à obesity.  
Role = satiety center
Lateral Hypothalamus (LH) lesion à appetite loss. 
Role= hunger center
2. Arcuate nucleus (Arc): Contains orexigenic AgRP/NPY 
neurones and anorexigenic POMC neurones.
3. Leptin Fat-derived hormone that suppresses food intake. 
Activates POMC & inhibits AgRP/NPY neurones.  Informs 
brain on fat stores. Leptin resistance in obesity.
4. Leptin and leptin receptor gene mutations – extremely 
rare monogenic cause of obesity.
Johan’s hypothalamic lecture – some key points
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Adapted from M.W. Schwartz
49
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
1. Dorsal vagal complex (DVC)
§
nucleus of the solitary tract (NTS), 
§
area postrema (AP)
§
dorsal motor nucleus of the vagus
nerve (DMV)
Integrate homeostatic signals about 
nutritional and energy reserve status.
Involved in appetite suppression, malaise, 
response to infections, gut-brain signals, 
gastric distension, swallowing etc.
Important target for the anorexigenic 
peptide, GLP-1 (see later)
Autonomic control of energy balance: Brainstem
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
DOI:10.1111/nyas.13263
50


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## Page 25

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
2.Parabrachial nucleus (an anorexic 
hub)
•
Relays sensory information to forebrain.
•
CGRP neurons relay aversive signals (e.g., 
food poisoning, pain, itch etc) to the 
amygdala (CeA), the bed nucleus of the stria 
terminalis (BNST) and other brain regions.
•
Chronic activation of CGRP neurons can 
lead to severe anorexia and starvation.
•
When activated, CGRP neurones block 
incoming orexigenic information from AgRP
neurones in Arc.
•
Other PBN neurons transmit taste, 
temperature, respiratory, satiety, thirst, salt-
appetite, or glucose counter-regulatory 
signals.
Autonomic control of energy balance: Brainstem
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
CGRP = 
calcitonin gene-
related peptide
Anorexigenic
https://doi.org/10.1016/j.tins.2018.03.007
51
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
3. Others
The Raphe Pallidus (RPA) receives 
thermoregulatory information from 
the hypothalamus and projects to 
the intermediolateral nucleus (IML) 
of the spinal cord, from which 
originate the preganglionic neurons 
of the sympathetic nervous system 
(SNS) outflow to BAT.
Autonomic control of energy balance: Brainstem
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
POA (Preoptic area), DMH (Dorsomedial hypothalamus)
DOI:10.1111/nyas.13263
52


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## Page 26

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Role of the reward system
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Motivation for food, including palatable 
foods.
Pleasure from food and food choice
Important when hungry (to help restore 
energy balance) but also to ensure we eat 
in excess of metabolic requirement (to help 
prepare for a future famine).
Golocalprov.com
53
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
• Sustaining energy – eat when available, ­ energy store 
for future need
• Nutrition – variety
• Food selection/preference  – sweet, salty, umami >> 
sour, bitter (edible >> poisonous)
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Food reward – eating for survival (adaptation)
54


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## Page 27

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Food reward – eating against survival (maladaptation)
Vitagazette.com
News.bbc.co.cuk
55
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
u They promote eating in the absence of hunger or 
energy need (= hedonic, non-homeostatic feeding) 
u Certain foods make us want to eat more 
(=reinforcement)
“Appetite comes with eating; the more 
one has, the more one would have”. 
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Food reward – eating for survival
56


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## Page 28

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
“Hunger is the best spice”
Swedish
Reward value also reflects: 
Palatability, taste, orosensory experience, 
reward expectation/prediction, genetics
“A good meal ought to begin 
with hunger”.
French
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Hunger increases the reward value of foods
57
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Goldstone et al., 2009, EJN
à Brains pathways involved in 
(visual) food reward processing 
are regulated by metabolic 
signals 
FED
FASTED
vs
ACC
amygdala
insula
ventral
striatum
lateral
OFC
medial
OFC
Brain reward areas:
- Activated by pictures of 
rewarding foods. 
- Linked to food reward!
- Regulated by nutritional 
state.
Δ
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Brain areas linked to reward are more activated by 
photos of palatable foods when hungry than when fed
58


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## Page 29

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
OFC & Amygdala à reward 
value of food
Insula à taste & hedonic 
evaluation
NAcc, VTA  & dorsal striatum 
à Motivational and incentive 
properties of rewards
Lateral hypothalamus à
regulates rewarding response 
to palatable food and drives 
reward-seeking behaviours
Adapted from Kenny PJ, 2010 Neuron 69: 664
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Brain Areas Activated in Response to Palatable Food 
or Food Associated Cues
59
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Wanting/motivation
Liking/hedonics
DOPAMINE (VTA à NAcc)
OPIOIDS
ENDOCANNABINOIDS
Muscle
BAT
MBH – mediobasal hypothalamus
DVC – dorsovagal complex
PFC – Prefrontal cortex
DVC – Anterior Cinglate Gyrus
Dopamine and “friends”
DOI:10.1111/nyas.13263
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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Ventral Tegmental 
Area (VTA)
Nucleus 
Accumbens (NAc)
dopamine
The midbrain dopamine neurones signalling reward
VTA
é Cell firing
NAc
é dopamine release 
Natural and artificial rewards
+
sex
food
gambling
drugs
alcohol
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Theguardian.com
Rodin
Picasso
Cezanne
Jean Kieffer
Adriaen Brouwer
61
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
dopamine
Ventral Tegmental 
Area (VTA)
Nucleus 
Accumbens (NAcc)
What does accumbal dopamine actually signal?
u Pleasure of eating 
(Small et al, Neuroimage 2003)
u Novel (unexpected) rewards
(Norgren et al, Physiol Behan, 2006) 
u Reward anticipation (cue-
induced eg smell)
(Epstein et al, Psychol Rev, 2009)
u Motivational/incentive value
(Volkow et al, Synapse, 2002) 
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Increases “wanting” and approach behaviour for food
Picturequotes.com
Golocalprov.com
62


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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Food Reward
Generation
Food 
Intake
“Gluttony” Hypothesis
Reward
“Reward deficiency” Hypothesis
Reward
http://commons.wikimedia.org
/wikiCategory:Animations_from
_Anatomography
Evidence favours a reward deficiency hypothesis
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Obesity is associated with an altered reward function
Rubens
63
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
↓ Striatal dopamine D2 
receptor availability in obese 
subjects.
(Similar to drug-addicted 
subjects). 
lean
morbidly obese
… supports the reward deficiency hypothesis in obesity
Volkow et al. 2008, Phil. 
Trans. R. Soc. B 
363:3191
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Obesity is associated with an altered reward function
64


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## Page 32

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Potential “reward” contributors to obesity:
1. Genetic and other pre-existing 
differences in reward function
3. Intake of palatable food as an 
escalating, addictive process
2. Changes in reward function that are 
secondary effects of the obese state.
Could some obese patients be food addicted? 
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Obesity is associated with an altered reward function
Rubens
65
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Probably not a chemical-like addiction. 
In man, there is no solid evidence that any food, 
ingredient, combination of ingredients or 
additive (exception = caffeine) causes us to 
become addicted to it!
More likely a behavioural addiction. 
Certain obese individuals appear to 
express addiction-like behaviour to food 
eg binge eating disorder
http://www.neurofast.eu/consensus/
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Could food be addictive?
66


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## Page 33

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
See Ziauddeen H et al., 2012, Nat Rev Neurosci
Tolerance
Dependence
Withdrawal
Failed 
abstinence
Preoccupation
Continued use 
despite known 
consequences
Many addiction criteria are difficult 
to apply to food and require severity 
or impairment thresholds
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
67
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
 
Food addiction score
Food receipt: Activation in medial OFC
Gearhardt AN et al., 2011,  Arch Gen Psychiatry 
Questionnaire à Food addiction score
fMRI brain imaging à Areas activated by anticipation & receipt of 
palatable food.
Correlations and comparisons
“Food addicted” subjects - differing brain activity response – both 
for food anticipation and receipt. 
fMRI
response
in OFC
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
People that score high on the Yale Food Addiction Scale 
have a different brain response to food
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## Page 34

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
The cortical executive system and the decision to eat.
PFC circuits (incl. ACC) are close to and 
influenced by the adjacent olfactory, gustatory, 
and somatosensory cortices, which compose 
the insula. 
Receive sensory information from the oral 
cavity and digestive tract.
Play a decisive role in the eating; the ultimate 
decision of eating is conscious and voluntary.
This can over-ride homeostatic drives, for 
example.
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Pre-frontal cortex
Anterior cingulate cortex 
Insula
DOI:10.1111/nyas.13263
69
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Homeostatic metabolic/hormone 
signals important
What kinds of 
information 
are signalled 
to the brain?
DOPAMINE (VTA à NAcc)
OPIOIDS
ENDOCANNABINOIDS
DOI:10.1111/nyas.13263
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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Δ Feeding behaviour
Δ Energy expenditure
Δ Adaptive thermogenesis
Energy deficit/excess
Energy Homeostasis: filling in the gaps
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Executive control systems
Reward systems
Hypothalamus
Brainstem
Hunger/satiation
/satiety
Longterm
Short term
GUT
Pancreas
Leptin
Other adipokines?
Hormones
Gastric 
distension
Insulin
Others?
Fat
71
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Δ Feeding behaviour
Δ Energy expenditure
Δ Adaptive thermogenesis
Energy deficit/excess
Energy Homeostasis: filling in the gaps
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Executive control systems
Reward systems
Hypothalamus
Brainstem
Hunger/satiation
/satiety
Longterm
Short term
GUT
Pancreas
Leptin
Other adipokines?
Hormones
Gastric 
distension
Insulin
Others?
Fat
Leptin resistance 
in obesity
72


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## Page 36

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Anti-starvation signal
Weight (fat) 
loss
¯ LEPTIN
­ food intake
¯ energy expenditure
¯ food intake
­ energy expenditure
BRAIN
BRAIN
Ineffective signal due 
to leptin resistance
LEPTIN
RESISTANCE
Weight (fat)
gain
­ ­ LEPTIN
Leptin resistance in obesity – the brain no longer “hears” the signal 
73
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Eating – for energy requirements & to have reserves
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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## Page 37

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
The Brain’s Energy Balance Systems: survival
… when food is scarce
Reduce metabolism
Food searching & consumption
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
75
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Daily 
energy intake: 
2000 kcal
Energy stored in fat: 140.000 kcal
Impact of a meal 
on reducing 
appetite
(important)
Impact of energy stores (and 
hence, leptin) on reducing 
appetite – cannot be the meal-
to-meal determining factor on 
how much we eat.
Who drives eating – your fat or your gut?
Signals & 
mechanisms
?
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
GUT
DOI: 10.1016/j.physbeh.2016.03.038
76


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## Page 38

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
The meal cycle: hunger, satiety 
and satiation
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
I’m full (= satiated)
I’m not hungry (=satiety)
77
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Hunger, Satiety & Satiation
Meal
Stimulatory
signals
Inhibitory
signals
Satiation = 
meal termination
Satiety = absence of 
appetite/hunger until the next meal
Eating time
Intensity
I’m 
getting 
hungry
I’m 
full
I need 
to eat
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
NOTE: People commonly confuse satiety & satiation
Image: 
https://www.madlab.ca/are-your-
hunger-and- fullness-cues-out-of-
whack.html
78


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## Page 39

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
VAGUS
Ghrelin
PYY
Leptin
Others?
Insulin
Others?
CCK
CNS
peptides
Marx J, Science. 2003 299:846-9.
Murphy K, Bloom SR. Nature 444, 854-859
Anorexigenic (i.e. eat less)
A. Increase satiety, 
B. Increase satiation,
C. Cause nausea or aversion,
D. For some hormones, their 
anorexigenic mechanism is unclear 
(ie. A,B and/or C)
Orexigenic (i.e. eat more)
E. Increase hunger
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Anorexigenic and orexigenic hormones
79
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
GUT
Behavioral
Responses
Autonomic
Responses
Endocrine
Responses
ENERGY BALANCE
PANCREAS
ADIPOSE TISSUE
LIVER
NUTRIENTS
LEPTIN
ADIPOKINES
PP
AMYLIN
GLUCAGON
INSULIN
GHRELIN
CCK
PYY (3-36)
GLP-1
OXM
NPY
AgRP
POMC
CART
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
80


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## Page 40

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Important gut hormones for energy 
balance
Ghrelin
Gastrin
GLP-1
GLP-2
Oxyntomodulin
PYY(3-36)
FGF19
CCK
Secretin
GIP
Motilin
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
GLP-1 and GLP-2 (Glucagon-like peptides), CCK (cholecystokinin), GIP (Gastric 
inhibitory peptide), Peptide YY 3-36 (PYY3-36), Fibroblast growth factor 19 (FGF19)
81
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Distribution of enteroendocrine cells in gut
Ghrelin
CCK
GLP-1
PYY(3-36)
stomach
Small
intestine
bowel
Steinert et al., Physiol Rev 2017; 97:411
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Cell 
type
Highest density
Peptide released
G-cells
Stomach
Gastrin
X-cells
Stomach
Ghrelin
ECL-
cells
Stomach
Histamine
???
Stomach & duodenum
Gastrin-releasing peptide 
(GRP)
S-cells
Duodenum and jegunum
Secretin
I-cells
Duodenum and jegunum
Cholecystokinin (CCK)
K-cells
Duodenum and jegunum
Glucose-dependent 
insulinotropic peptide (GIP).
N-cells
Ileum
Neurotensin
L-cells
Ileum and Colon
Glucagon-like peptide (GLP-1)
L-cells
Ileum and Colon
PYY3-36
D-cells
Entire GI tract
Somatostatin
EC-cells Entire GI tract
Serotonin
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
83
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Gut peptides influencing energy balance
1. PYY (3-36):
Ø Anorexigenic. Produced esp. by the ileum, colon and 
rectum (L cells) in response to feeding/meals.
Ø Signals satiety (long inhibition of eating).
Ø It is an agonist at the Y2 receptor (ie NPY receptor 
subtype 2), a presynaptic NPY receptor. (Note: other 
NPY receptors are post-synaptic). C.f. NPY acting at 
Y1 post-synaptic receptors that is orexigenic)
Ø Target systems: Arc very important for anorexigenic 
effect. Y2 receptors also located in DVC and 
amygdala.
Ø Obesity does not appear to be associated with 
reduced PYY3-36 levels although there are promising 
effects to reduce meal size.
Y2
(autoreceptor)
Y1
NPY
Food intake
PYY(3-36)
-ve
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Batterham et al., Nature 450, 106-109 
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
In healthy subjects, PYY(3-36) reduces caloric intake in 
a buffet meal
85
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Gut peptides influencing energy balance
2. GLP-1 (and oxyntomodulin)
Ø Mostly produced in the ileum, in the L cells (that also produce PYY3-36)
Ø Proglucagon (precursor for GLP-1, glucagon, glucagon-like peptide-2 (GLP-2) and 
oxyntomodulin).
Ø Circulating levels increase after meals. 
Ø Exendin 4: GLP-1 receptor agonist (first isolated from saliva of Gila monster lizard). 
Ø GLP-1 receptors in CNS: especially brainstem (DVC) and hypothalamus (Arc) but 
also reward system. Acts as a satiety signal.
Ø Oxyntomodulin also binds to the GLP-1R 
Ø GLP-1 and oxytomodulin à↓food intake and ↓food reward. ↓gastric motility.
Ø Long-acting GLP-1 agonists now used clinically (e.g., Liraglutide, Semaglutide) 
Ø Improved glucose homeostasis (via its incretin effects – see glucose lecture 
from me).
Ø Weight loss
Gila 
monster 
lizard
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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## Page 43

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Ozempic (Semaglutide) – anti-obesity drug
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Long acting 
GLP-1 analogue
87
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Gut peptides influencing energy balance
3. Cholecystokinin (CCK)
Ø Produced by I cells in the GI tract (eg duodenum and jejunum)
Ø Release increased especially by fat or protein in duodenum
Ø Causes meal termination (satiation signal)
Ø Also suppresses gastric emptying
Ø Two CCK receptors exist (CCK1 and CCK2) and can be found 
on vagal afferents as well as in relevant brain areas, especially 
brainstem (NTS, AP, Dra, the dorsal raphe) but also in reward 
areas. 
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
88


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## Page 44

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
•
Insulin and amylin. release from beta cells regulated by 
gut hormones (especially GLP-1 and GIP).
•
Glucagon. Increases FGF21 release from the liver.
•
Pancreatic polypeptide (PP)
Glucagon
Insulin
Amylin
FGF21
PP
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Pancreatic hormones
FGF21 
-
a hormone secreted by the 
liver
-
regulates sugar intake and 
preferences for sweet foods 
via signaling through FGF21 
receptors in the PVN 
(hypothalamus)
89
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Pancreatic hormones and energy balance
1. Insulin
ØReleased in association with meals.
ØInsulin receptors - hypothalamus (NPY, POMC) and brain 
stem (nucleus tractus solitarius).
ØDirect brain action: Reduces food intake (and increases 
energy expenditure).
ØMay act as a satiety signal.  Also provides a marker of fat 
mass (obese individuals have high levels).
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
90


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## Page 45

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Pancreatic hormones and energy balance
2. Amylin – a satiation signal?
Ø Produced by pancreatic beta cells
Ø Eating triggers release in proportion to 
caloric load
Ø When administered with leptin, a 
synergistic effect for weight loss was 
observed.
Ø Role: slows appearance of nutrients in 
blood after meals by (i) ↓food intake 
(decreased meal size), (ii) slowing gastric 
emptying, (iii) inhibiting digestive 
secretions [gastric acid, pancreatic 
enzymes, and bile ejection]. 
Ø Centrally acting eg area postrema of the 
brain stem.
Maintenance of body weight loss 
induced by sustained infusion of 
amylin + leptin combination 
requires the presence of both 
amylin and leptin in diet-induced 
obese rats.
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
doi-
org.ezproxy.ub.gu.se/
10.1038/oby.2009.187
91
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Pancreatic hormones and energy balance
3. Pancreatic polypeptide
ØReleased after a meal (and in proportion to 
caloric load) and reduces food intake acutely.
ØSatiation signal?
ØChronic administration reduces body weight in 
genetically obese mice (ob/ob).
ØBinds to neuropeptide Y4 and Y5 receptors.
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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## Page 46

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Ghrelin 
Food searching & intake
¯ Fat utilization (RQ)
­ Body weight
200
0600
0800
1000
1200
1400
1600
1800
2000
2200
2400
0200
0400
300
400
700
800
Ghrelin (pg/ml)
500
600
Time of day
breakfast
lunch
dinner
Empty 
stomach
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Gut peptides influencing energy balance
4. Ghrelin (hunger signal)
Cummings DE et al., 2001; Diabetes 50:1714-9
Hunger
GHS-R1A 
(receptor)
GHS-R1A = growth hormone secretagogue receptor 1A
Tschöp et, al, 2000, Nature
Oxyntic 
glands
93
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Cummings et al, 
Am J Physiol
Endocrinol Metab
Ghrelin: the hormone that decides when you eat?
Hunger
Score 
(mm)
Ghrelin
% 
baseline
Time (% inter-meal interval)
Meal 1
Meal 2
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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## Page 47

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Ghrelin targets both homeostatic and reward 
systems to increase food intake and motivation 
Ghrelin 
­ METABOLIC FEEDING
­Food intake
­REWARD 
BEHAVIOUR
­Food reward
­Food motivation
­Food intake
­Food anticipation
Δ Food preference
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Main targets:
Hypothalamus 
(especially Arc).
Many brainstem areas
Reward system
95
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Lever pressing for sucrose
How much work (number of lever presses) is a rat is willing to expend to obtain 
a sugar reward à an objective measure of reward value 
Ghrelin à Increased motivation to work for a food reward
FR1 à FR3 à FR5 à PR
Fixed Ratio
Progressive 
Ratio
à
5 min
120 min
30 min
Number 
rewards
(sucrose
pellets)
**
**
**
0
2
4
6
8
10
saline
Ghrelin 0.3 mg/kg
Ghrelin 
FOOD REWARD & 
MOTIVATION
WORK TO      
RECEIVE SUGAR
FULL/SATIATED RAT
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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## Page 48

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Ghrelin:
Ø Circulating stomach-derived hormone
Ø Produced by the X/A-like cells in the oxyntic glands
Ø The enzyme ghrelin-O-acetyltransferase (GOAT), present in these cells, is 
responsible for acylating ghrelin on serene 3 (makes it active).
Ø Increases food intake and food seeking. 
Ø Ghrelin receptor (GHS-R1A) located in brain areas controlling
energy balance (eg hypothalamus, brain stem), 
reward (eg tegmental areas such as the VTA)
also amygdala, hippocampus
Ø Physiological role: meal initiation, hunger, reward-seeking (eg for food).
Ø Obesity is not associated with hyperghrelinaemia. 
Ø May be relevant for eating disorders, including those that lead to obesity.
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
97
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
AgRP neurones (a target for ghrelin) signal the 
unpleasantness of hunger.
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Method: Optogenetic activation if AgRP neurones when mice are in the left 
(Blue) chamber. Result. With each of 7 (15 min) sessions they increasingly 
avoid the chamber in which their AgRP neurones were activated. 
Conclusion:
Mice dislike having 
their AgRP 
neurones activated.
Likely they are 
experiencing the 
unpleasantness of 
hunger.
doi: 10.1038/nature14416
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## Page 49

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
hunger
satiation 
satiety
Meal
time
plasma level
Ghrelin
CCK/Amylin
PYY3-36/GLP-1/ 
oxyntomodulin/insulin
Appetite-regulating hormones signal hunger, satiation and satiety
99
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Hedonic feeding behavior
Hunger/satiety
satiation
Meal
time
plasma level
Ghrelin
CCK/Amylin
PYY/GLP-1/oxyntomodulin/ insulin
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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## Page 50

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Nature Reviews Gastroenterology & Hepatology 1010, 729–740(2013)
Endocrine intestinal cells sense nutrients and signal directly to the 
nervous system
Nutrient 
sensing
Gut 
hormones
Brain
DOI:10.1038/nn.3211
101
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Several neural circuits respond directly to hormones from intestine, fat, and 
pancreas
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
•DOI:10.1038/nn.3211
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## Page 51

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So, what causes obesity and 
what can we do about it?
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
103
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Arguing for a genetics component:
§
People in same environment don’t 
necessarily have same body weight 
§
The remarkable increase in obesity 
trends over last few decades cannot be 
only due to genetics.
§
Some ethnic groups are more likely to 
develop obesity)
§
There have always been some people 
predisposed to weight gain
§
Data from twin and adoption studies
§
Heritability of body weight is 70% 
(almost as much as that of height 85%)
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
How much obesity is genetics and how much 
is environmental?
EndocrineWebPro
104


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## Page 52

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Dizygotic 
Twins
Monozygotic 
Twins
Wardle J et al Am Clin Nutr 2008 Heritability of childhood BMI in UK – 75% 
Heritability estimates 
#0.6-0.8 
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Genetics of obesity: twin studies
105
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Genetic factors contribute 40-70% to excess 
body fat. 
Pima Indians – nomads - scarce conditions 
but develop obesity when food is available. 
“Thrifty genotype” hypothesis. Certain genes 
in humans have evolved to maximize 
metabolic efficiency and fat storage.  In times 
of plenty, these genes predispose their 
carriers to obesity and diabetes.
Environment gives genetics (Darwin)
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Genetics of obesity- interaction with environment
Ravussin E et al., Diabetes Care 1994
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## Page 53

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
§
Few obesity genes known yet (less than 5% of genetically determined 
obesity). 
§
Monogenic causes (eg gene deletions) rare
§
POMC/MC4-R deletions - MC4-R; heterozygotes have “middle” phenotype.
§
Leptin/leptin receptor dysfunction
§
>300 SNPs linked to obesity traits, emerging from GWAS. Most still of 
unclear biological significance (eg FTO). The association of the FTO
region to obesity explains ~1% of BMI heritability, such that adults 
homozygous for the risk allele, have a 2–3 kg higher weight compared 
to non-risk allele homozygous (Frayling TM et al., 2007)
FTO = FaT mass and Obesity-
associated protein
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Genetics of obesity: known genes that contribute
107
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Manhatten plot
•
Subtle changes in individual genes impact on body weight. 
•
The more risk alleles you have the more likely you will have a high BMI
•
Many risk alleles are hypothalamic.
108


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## Page 54

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Source: Giles Yeo
Note, semaglutide is a recently approved drug for obesity that is caused by 
gene defects upstream of MC4R
Disruption of melanocortin signalling causes severe 
obesity
109
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
ØEpigenetics - the study of heritable changes which affect gene 
function without modifying the DNA sequence.
ØEpigenetic markers are tissue specific and include DNA 
methylation and histone modifications which mediate biological 
processes such as imprinting. (Note FTO codes for a DNA 
methylase that turns off genes)
ØHypothesis: early environmental influences induce epigenetic 
variation, thereby permanently affecting metabolism and chronic 
disease risk. 
ØEg Epigenetic factors may explain why under or over-nutrition in 
utero (environment) à ­ risk of metabolic disease in later life.  
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Epigenetics factors and Obesity
110


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## Page 55

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
• The human gut has a diverse microbial ecosystem (>2000 different                  
species, high inter-individual variability). 
• Hypothesis: Gut microbiota contribute to the development of obesity and the 
metabolic syndrome.
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Gut microbiota and obesity
Evidence: Transplantation of gut 
microbiota from obese mice to 
non-obese, germ-free mice 
resulted in transfer of metabolic 
syndrome-associated features 
from the donor to the recipient. 
111
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
• The human gut has a diverse microbial ecosystem (>2000 different                  
species, high inter-individual variability). 
• Hypothesis: Gut microbiota contribute to the development of obesity and the 
metabolic syndrome.
• Evidence: Transplantation of gut microbiota from obese mice to non-obese, 
germ-free mice resulted in transfer of metabolic syndrome-associated features 
from the donor to the recipient. 
• Mechanism currently being researched
§ provision of additional energy by the conversion of dietary fiber to short-chain 
fatty acids?
§ effects on gut-hormone production? 
§ ­ intestinal permeability à systemic levels of lipopolysaccharides (LPS à low-
grade inflammation (as seen in obesity/metabolic syndrome)?
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Gut microbiota and obesity
112


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## Page 56

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
• We have evolved to over-eat available foods to prepare for 
a future famine.
• People with genetic obesity are fighting their biology.  Prone to 
make unhealthy decisions around food, for example. 
• Obesogenic caloric foods are energy-dense and it is easy to 
overconsume them, even when full.
• All diets that reduce caloric intake or decrease energy 
expenditure work – if we keep to them. Why do they fail?
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
But what about dietary control? 
Dessert when full
The happyfoodie.co.uk
113
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
• Decreased leptin is important when dieting – turns on the 
starvation response: over-eating, ↑ reward value of food, 
save energy for brain, switch off costly energy functions 
(e.g. reproduction, immune system). 
• The threshold to respond to a dieting-induced fall in 
circulating leptin may be higher in obese individuals, 
making it hard for them to reduce food intake. 
• When hungry (or dieting) food cues are increasingly 
attractive and it becomes hard to resist food.
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Why don’t diets work?
114


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## Page 57

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_
_
Intense hunger
Food craving
(Neuro)biological 
adaptations
Dietary failure
Weight gain
Caloric Restriction
Dieting
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
https://www.upmcmyhealthmatters.com/the-5-ds-of-dieting/
115
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
!
"!!
#!!
$!!
%!!
&!!!
'()*+',
-.*/
)0+1
Caloric intake per day
Caloric intake
sugar
fat
chow
normal
diet
normal diet 
extra fat
normal diet 
extra fat
and sugar
hedonic feeding
| INST NEUROSCIENCE &
Study in rodents given choice diets.
Adan RA & LaFleur SE
The more to choose, the more calories are eaten
116


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## Page 58

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
!
"#
#!
$#
%!!
!
#
%!
%#
"!
"#
&!
&#
'(F*H,-./01
23-/H4*(5S'H5.(7H,51
8S34
9:9;
!
"!
#!!
#"!
A!!
#%&''(
"%&''(F
*%H,H-%.*%/0%12/&%34/5ST
12/&
898W
*
*
*
*
| INST NEUROSCIENCE &
Animals on a high fat-high sugar (HFHS) diet gain weight
117
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
!
"!
#!!
#"!
A!!
%C'
C()*
+,%-./M.NO.P4NR6
*
*
| INST NEUROSCIENCE &
Animals on a high fat-high sugar (HFHS) diet become 
leptin resistant & have a “hungry” neuropeptide profile
Effect of leptin injection 
on food intake
HFHS-choice diet: insensitive to leptin 
– it doesn’t suppress food intake 
HFHS
Control diet
HFHS-choice diet: hypothalamic gene 
changes similar to hunger à eat more!
118


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## Page 59

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
_
_
Intense hunger
Food craving
(Neuro)biological 
adaptations
Dietary failure
Weight gain
Caloric Restriction
Dieting
How can we break the cycle?
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
https://www.upmcmyhealthmatters.com/the-5-ds-of-dieting/
119
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Breaking the viscous cycle of weight gain: 
bariatric surgery à improved food reward control
(Neuro)biological 
adaptations
Dietary failure
_
_
_
_
Bariatric surgery
(eg gastric bypass)
Weight gain
Intense hunger
Food craving
Caloric Restriction
Dieting
We need to understand how/why bariatric surgery works
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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## Page 60

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Bariatric (weight loss) surgery
Gastric banding
Vertical banded 
gastroplasty
Gastric bypass
Only effective 
Obesity therapy
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
121
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Swedish Obese Subject study: Weight loss 
after bariatric surgeries
Change 
in 
Body 
Weight
(%)
control
banding
Ventral-banded 
gastroplasty
Gastric bypass
Sjöstöm L et al NEJM 2004 
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## Page 61

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Gastric bypass surgery à weight loss and reduced 
mortality. Life expectancy ­ by 12 years.
Swedish Obese Subject study: Mortality
123
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
The future: Novel obesity therapies that “bypass”
gastric bypass?
(Neuro)biological 
adaptations
Dietary failure
_
_
_
_
Bariatric surgery
(eg gastric bypass)
Weight gain
Intense hunger
Food craving
Caloric Restriction
Dieting
¯ Ghrelin
­ PYY
­ GLP-1
It is not yet clear that these changes in hormone levels               
are important for the weight loss after gastric bypass!!!
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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## Page 62

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UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Gastric Bypass surgery: Physiology
Food enters small gastric pouch à fullness sensed (nervous)
Discomfort & vomiting if over-eat.
When food enters small intestine à Anorexigenic hormones released 
eg CCK (duodenum), GLP-1 & PYY(3-36) (ileum) 
Mechanism
Decreased container function /restriction? Probably not – other 
restrictive procedures are less effective.
Malabsorption?  Certainly not a primary mechanism.
Increased energy expenditure (eg could involve increased bile salts 
taken up into blood).
Increased anorexigenic signals after meals and/or decreased ghrelin
before meals? Hormones likely contribute to weight loss success.
Improved food choice – brain reward system implicated.
Others? Eg microbiota, nutrient sensing by gut.
… actually … we don’t really know.
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
125
UNIVERSITY OF GOTHENBURG   |   SAHLGRENSKA ACADEMY
Anti-obesity drugs: possible mechanisms?
Ø Decrease food intake (reduce hunger, reduce reward, increase 
satiety, delay meal initiation, reduce portion size, improve 
choice)
Ø Decrease gut uptake of nutrients
Ø Increase energy expenditure (ie the use of energy by the 
body).
Longterm effects only persist if we can reduce the ”set point” 
(ie make an individual percieve their energy homeostasis to 
be set at a level lower that it is). 
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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## Page 63

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Energy Balance Fluctuations Over a Day 
Adan RA, TINS,  2013, 36: 133–140
-ve
+ve
Preventative and treatment strategies for obesity should 
target especially food intake. 
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
127


---