Stockholms Obesitasdagar, 18 april 2013

Dr. Karolina P Skibicka Assistant Professor Inst. Neuroscience & Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden

Sahlgrenska Academy

Since the 1940s: Hypothalamus as the most critical structure for regulation of appetite

Reward and homeostatic circuits likely interact FOOD ADDICTIONADDICTIONLIKE BEHAVIORS?

Berthoud HR et al 2009

Which neural circuits control craving?

Compared with homeostatic mechanisms of feeding, much less is known about how hedonic systems in brain influence food intake. Excessive consumption of palatable food can trigger neuroadaptive responses in brain reward circuitries similar to drugs of abuse.

Areas of the Human Brain Activated in Response to Palatable Food or Food-Associated Cues Adapted from Kenny PJ, Neuron, 2011

Emerging evidence suggests that obesity and drug addiction may share common hedonic mechanisms

Dopamine released in reward areas

Volkow N D et al. Phil. Trans. R. Soc. B 2008;363:3191-3200

Potential contributors to obesity: 1) genetic and other preexisting differences in reward functions 2) intake of palatable food as an escalating, addictive process 3) changes in reward functions induced by secondary effects of the obese state. state

NAc

In selectively bred lines of obesity-prone (OP) and obesity-resistant (OR) rats, basal and induced mesolimbic dopamine release is lower

Dopamine impairment in obesity prone rats was apparent at birth Is the hyperphagia compensatory? Geiger BM; FASEB J. 2008

People with a certain change in the gene encoding the mu opioid receptor (G/G genotype) reported higher preferences for sweet and fatty foods

Food preferences were also related to all overeating measures, which in turn accounted for a substantial proportion of the variance in BMI

RewardReward-associated genes can change food reward behavior Davis C; Int J Obes (Lond). 2011

Less D2 receptors and less inhibition in obese?

Obese subjects had less dopamine D2 receptors in the rewardassociated brain areas

PET scan of averaged images for DA D2 receptors in a group of (i) controls (n=10) and (ii) morbidly obese subjects (n=10).

The more dopamine D2 receptors the more active the control/inhibition areas

D2 receptor availability (measured in striatum) and brain glucose metabolism in (i (i) CG and (ii) OFC in obese subjects

Volkow N D et al. Phil. Trans. R. Soc. B 2008;363:3191-3200

Less D2 receptors and less inhibition in obese? Images of DA D2 receptors (measured with [11C]raclopride in striatum) in (i) a control and (ii) a cocaine abuser.

Cocaine abusers showed similar changes in brain dopamine D2 receptors in reward areas and in control/inhibitory areas as morbidly obese subjects

Volkow N D et al. Phil. Trans. R. Soc. B 2008;363:3191-3200

Genetic and other preexisting differences in reward functions

Model of brain circuits involved with addiction and obesity: reward/saliency motivation/drive, memory/conditioning and inhibitory control/emotional regulations.

Inhibition of behavior/con trol is diminished

Food is highly valued

There is a significant motivation to obtain it

Volkow N D et al. Phil. Trans. R. Soc. B 2008;363:3191-3200

Potential contributors to obesity: 1) genetic and other preexisting differences in reward functions 2) intake of palatable food as an escalating, addictive process 3) changes in reward functions induced by secondary effects of the obese state. state

Depressed dopamine release may lead obese animals to compensate by eating palatable "comfort" food, a stimulus that released dopamine when laboratory chow failed

Geiger BM; Neuroscience 2009

Unlimited sucrose access reduces dopamine release to sucrose changes may be responsible for the observed escalation of sucrose binging

Avena NM; 2008

In Wistar rats, exposure to a palatable cafeteria diet led to sustained hyperphagia over 40 days and lateral hypothalamic electrical selfstimulation threshold increased in parallel to body weight gain Kenny PJ, Neuron, 2011

The more of the reward you consume the harder it will be to get satisfied with the same amount next time – you will need MORE

Potential contributors to obesity: 1) genetic and other preexisting differences in reward functions 2) intake of palatable food as an escalating, addictive process 3) changes in reward functions induced by secondary effects of the obese state. state

central insulin and leptin resistance

Figlewicz DP, 2006; Physiol Behav. 2006

Figlewicz DP, 2006; Physiol Behav. 2006

5 weeks of high-fat diet In rodents after 5 weeks on fat diet hormones like leptin and insulin loose their ability to curb food reward behavior

BUT what can we do about it?

Gastric bypass is currently the most effective treatment of obesity It is expensive and carries risks associated with a surgical procedure DOES IT CHANGE FOOD REWARD BEHAVIOR? REWARD NEUROCIRCUITRY?

breakpoint (= motivation) for candy, but not vegetables, was reduced by 50% in the obese group after gastric bypass. Patients with the largest reduction in the breakpoint had the largest decrease in BMI.

Miras AD et al 2012

Postsurgical reductions in brain activation were found in key areas within the mesolimbic reward pathway, which were significantly more pronounced in response to food cues that were high (vs. low) in caloric density

VTA ventral striatum

putamen and lentiform nucleus

posterior cingulate and dmPFC

concurrent postsurgical reductions in desire to eat

Ochner CN et al, 2011

Less activation in reward areas to high- calorie foods

Classic homeostatic areas like the hypothalamus might not be needed for the beneficial effects of gastric bypass on food reward Patient with large part of the hypothalamus removed: food cravings before and after bariatric surgery

Inge TH et al. (2007) Gastric bypass surgery for treatment of hypothalamic obesity after craniopharyngioma therapy Nat Clin Pract Endocrinol Metab 3: 606–609

CCK receptor

PYY receptor

Ghrelin receptor

Source: Princeton University

Leptin receptor

GLP-1 receptor

How are these gut and fat hormones affecting the function of the reward neurocircuitry?

• hormone produced by the stomach • only circulatory hormone known to potently increases feeding − Hunger & meal initiation

Cummings et al, 2001, Diabetes

Ghrelin level increases with weight loss as part of the compensatory response to an energy deficit

Ghrelin: a gutgut-brain signal that increases appetite Reward & pleasure circuits

−

?

FOOD REWARD & MOTIVATION

Ghrelin

Overeating/obesity is often due not to hunger but to rewarding effect of food or because of − FEEDING DICTATED BY food associated ENERGY NEED environment (HOMEOSTATIC FEEDING)

- Ghrelin increases the neural response to food pictures in brain regions involved in the incentive value of food cues (Malik et al, 2008 Cell Metab)

- Ghrelin enhances the amount of money a subject is willing to pay for food but not non food rewards. rewards.

FOOD REWARD? Cho YM, 2012

FOOD MOTIVATION

EX4 0.3 µg/kg EX4 2.4 µg/kg

EXENDIN 4 REDUCES MOTIVATION FOR SUGAR

10

***

50 40 30

*

20

***

***

5

EXENDIN 4 REDUCES CHOCOLATE REWARD % CPP

VEHICLE

15

CONDITIONED PLACE PREFERENCE FOR FOOD

Food reward

10

Time (min)

µg /k g

120

3

30

0.

10

EX 4

0

IC LE

0 VE H

No. of sugar rewards earned

OPERANT BEHAVIOR FOR HIGH-CALORIE FOOD

FOOD REWARD

250

200

150 REDUCES * FOOD INTAKE 100

**

2

0

50

µg 0. 1

VE H IC LE

VE H IC LE EX 4 0. 03 µg EX 4 0. 1 µg

0

EX 4

NAc

4

Spontaneous activity

Chow (g) consumed

6

REDUCES FOOD SUCROSE REWARD

CPu

NAcC NAcS

No. of sugar rewards earned

10

VEHICLE EX4 0.03 µg

8

EX4 0.1 µg

6

**

*

*

4 2 0 10

30 60 Time (min)

120

PLOS One April 16th 2013

“Gut peptide GLPGLP-1 and its analogue, ExendinExendin-4, decrease alcohol intake and reward” Rozita H. Shirazi, Suzanne L. Dickson, Karolina P. Skibicka

GLPGLP-1 reduces alcohol intake

GLPGLP-1 reduces alcoholalcohol-reward behavior

The reduction in intake is most pronounced in highhigh-alcohol consuming rats

GLPGLP-1 and EX4 can reduce alcohol intake by targeting the dopamine producing VTA Endogenous GLPGLP-1is a key component of alcoholalcohol-intake regulation

VTA

Acknowledgements Rozita Shirazi, MSc Caroline Hansson, PhD Heike Vogel, PhD

Collaborators Sahlgrenska Academy: Prof Hans Nissbrandt Prof Suzanne Dickson

Jim Collander Maja Fenander Karin Warenius

University of Pennsylvania Prof Harvey Grill Hungrian Academy of Sciences Prof Zsolt Liposits

Funding Swedish Research Council (VR 2011-3054) Sahlgrenska Academy, GU NTNU, Trondheim Novo Nordisk Fonden Prof Duan Chen

Thank you!

Food addiction? DSM IV criteria (1)

Tolerance

(2) Withdrawal symptoms

Translation to food 1)

2)

(3) Taking in larger amounts or for a longer duration 3)

(4) Attempts to cut back (5) Excessive time spent pursuing, using, or recovering from use (6) Reduction/discontinuation of important activities because of use (7) Continued use despite consequences

4)

5)

6)

7) Food addiction: true or false?. Corsica, Joyce; Pelchat, Marcia; Current Opinion in Gastroenterology. 26(2):165-169, March 2010.

Starting out with a single cookie, gradually increasing to several or a whole box Habitually eating to relieve depression, anxiety, and other emotional states; unpleasant physical sensations when cutting back on carbohydrates Intending to eat a single serving but instead eating a whole package; binges extending several hours Frequent attempts to eat ‘correctly’ (e.g., avoid overeating or eating certain foods) that can only be maintained for a short period of time Frequent thinking about food, planning intake, preparing, and/or resting or sleeping after excessive intake Eating instead of spending time with friends; feeling too sick after overeating to do anything Overeating in spite of overweight, physical illness, and/or distress about overeating

food

drug

potency as a reinforcer

++

oral, ++ snorted, +++ smoked, injected ++++

delivery

oral

oral, snorted, smoked, injected

mechanisms reward

somatosensory (palatability) chemical (glucose)

chemical (drug)

relevance of kinetics

not investigated

the faster the stimulation the more powerful its reinforcing effects

regulation of intake

peripheral and central factors mostly central factors

adaptations

physiologic

supraphysiologic

physiological role

necessary for survival

unnecessary

learning

habits conditioned responses

habits conditioned responses

role of stress

+++

+++

. (Modified

from Volkow & Wise 2005.)

Berthoud HR et al 2011