Amy Rothberg, MD, PhD August, 2016education.endocrine.org/sites/default/files/Course Files... ·...

Homeostatic and Non-homeostatic (hedonic) control of weight regulation:

Which wins?

Amy Rothberg, MD, PhD August, 2016

International Congress of Endocrinology

Propensity to Obesity• Determined by genetics, epigenetics, and multiple

environmental influences

Energy Balance - Homeostasis

• Obesity is simply an energy balance where calories

consumed are greater than calories expended

Flegal et al. 2010

Propensity to Obesity• Determined by genetics, epigenetics, and multiple

environmental influences

There are two apparently conflicting points of view:

Why Do We Eat?

Experimental evidence

in animals and humans

suggests that body

weight is tightly

regulated – the concept

of energy homeostasis.

In contrast, population

evidence says that

average body weight is

gradually increasing.

This reflects a fundamental tension between homeostatic and

non-homeostatic controllers of food intake.

• The brain monitors the internal milieu through a

number of hormonal- and neural nutrient-sensing

mechanisms.

• It is under constant influence of both environment

and lifestyle

• through the senses

• through the cognitive and emotional brain.

Regulation of appetite and energy balance

Hypothalamus

NPY/AGRP

&

POMC/CART

Cortico-limbic

structures &

hypothalamus

Autonomic &

endocrine

systems

Orosensory

systems

(brainstem)

Hormones

Transmitters

Nutrients

Seek & procure Eat –OR- Do NOT EatAssimilate, store,

mobilize, expend

Adapted from: Huiyuan Zheng, and Hans-Rudi Berthoud Physiology

2008;23:75-83

Signaling

Pathways

http://www.google.com/url?sa=i&rct=j&q=brain&source=images&cd=&cad=rja&docid=aRpRK9R3boGDxM&tbnid=g_oS7zYemXs_cM:&ved=0CAUQjRw&url=http://www.empowernetwork.com/jlamarferren/brain-test/&ei=GX4WUvy0IMvcqQGl3ICAAQ&bvm=bv.51156542,d.b2I&psig=AFQjCNGb7XXHPNxznGIJK2yHe6Y_qPrQYQ&ust=1377292183257006

Why we eat, what we eat and the amount we eat is governed by:

• Taste perception

• Meal size (portion)

• Caloric density

• Environmental setting

• Timing of meals

• Composition

Regulation of Eating

Under most circumstances, meal initiation is not controlled by

metabolic or hormonal signals.

• The food industry uses chemistry, engineering,

psychology and mathematics to produce

formulations that optimize consumer enjoyment

16

Environmental Factors

Consumers base food choices on:


TASTE PRICE CONVENIENCE HEALTH

Others:


SUPERSIZED

PORTIONSMACRONUTRIENT

“ADDICTION”

HABIT/ PATTERN

ULTRA-

PROCESSING-

CHEAP FOOD!

Mountjoy, Kyiv 2003

Our sense of hunger and fullness are

determined by complex interactions between a

number of peptides (proteins) and hormones

from our:

• digestive system (ghrelin, CCK, PYY)

• adipose tissue (leptin)

• pancreas (insulin)

These relay signals from our gut to our brain.

Homeostatic Signals

Important Hormones/Neurotransmittors:

CCK PYY Insulin Leptin Ghrelin GLP-1

Oxynto-

modulin

amylin

Bombe-

sin

(family)

GRP

Neuro-

medin B

Apolipo

-protein

A-IV

Gluca-

gon

Polypeptide hormone produced by cells lining the fundus of the stomach and by

Ε cells of the pancreas. It is also produced in the arcuate nucleus where it

stimulates secretion of growth hormone by the anterior pituitary gland in the

central nervous system. It increases smell sensitivity and makes food taste

better. It has an orexigenic effect (stimulates food intake).

Important Hormones/Neurotransmittors: a description

Ghrelin (Q9UBU3) (ghre=growth)

•GH

•hunger


Ghrelin (Q9UBU3) (ghre=growth)

•GH

•hunger

• Patients who have lost > 15% of their body weight by diet have significantly

increased ghrelin levels and exaggerated peaks before meals compared to obese

controls

Key role in the motivation of feeding, but mechanisms still not characterized

Ghrelin

Kojima et al. Nature. 1999;402:656-60.

Ghrelin

Chambers et al., 2012 Gastroenterology

Vertical Sleeve Gastrectomy (VSG) in Ghrelin KO Mice

Peptide hormone produced in the small intestine in response to feeding. It

causes the release of digestive enzymes from the (exocrine) pancreas, bile from

the galbladder and release of H+ in parietal cells of the stomach. In the central

nervous system it acts as an anorexigen (hunger suppressant).


cholecystokinin (P06307) (chole=bile, cysto=pouch, kinin=move the bile bladder)

hunger

Peptide hormone released by adipose tissue in response to triglyceride

loading. Leptin is the key hormone in energy balance

regulation. Mice lacking the peptide or its receptor are obese. It acts as an

anorexigen (hunger suppressant). But, leptin acts on many neurons and can

gate food-related sensory input signals even at early stages of processing.


Leptin (P41159) (leptos=thin)

hunger

Peptide hormone produced in the intestinal L cells of the distal small intestine.

In the central nervous system it mediates vagal satiety signaling and

conditioned taste avoidance.


Glucagon-like-peptide (GLP-1)

hunger

There are other parts of the brain involved in

mediating the motivational (drive to eat),

cognitive (learning and decision-making), and

emotional components of food intake.

Hedonic Signals


• Normal reward systems can lead to overeating in our

modern, built environment of easily accessible and abundant

food and food cues.

• Food reward systems are essentially “go” systems and,

while they can be diminished by hunger and satiety signals,

they are normally never off.

• Experiences that evoked either extreme pleasure or

complete disgust generate the most salient memories.

• Representations contain a number of sensory attributes,

including shape, color, taste, and flavor, as well as links to

time, location, social context, cost, and reward expectation.

• Sensations & homeostatic signals must interact with brain reward

systems to create pleasure (liking) and desire (wanting)

– Sensory identification does not change based on internal need

• Preferences & aversions are learned

• Alliesthesia. Hunger & satiety states are enhanced or suppressed

depending our internal state (fasted or fed)

• Learning Ameliorates illness (e.g., vitamin

deficiency)

Evaluative Processes

- Provides motivation to try new foods.

- Eating food that ameliorates illness causes

food to be more liked.

• Learning Association with energy


• Help to explain eating components


Obtain nutrients

Salt-appetite

Sensory-specific satiety

‘Medicinal’ food-preference

• How do they influence the amount eaten?


Taste-associated

pleasure fluctuates

according to

internal state



Pleasure of eating a food will gradually

decrease with each bite (sensory specific satiety)

• Very hungry – pleasure starts

higher so you eat more

• Not hungry – pleasure starts

lower so you stop eating

sooner



• Pleasure may also make you

more likely to eat due to an

external cue (e.g., smell of

food, time of day, etc.)

• More likely to snack between

meals.

Meal

Snack Snack Snack

Meal Meal

Sweet, fatty and salty foods…YUMMY

• Bitter tastes are often

associated with toxic

alkaloids

• Acidity of many sour

substances indicate

spoilage or un-

ripeness

Bitter and sour… No thanks!

Experience

• Basic taste sensations: sugars, starches, fats and proteins only allow rough assessment of caloric content, but inaccurate at informing us of caloric density.

– But

• Caloric consequences are NOT necessary for simple (but provocative) taste such as a sweet taste to maintain food-seeking behavior.

• Nutritional value is not part of the sensory experience.

• Palatability is neither a physical property of a food nor a fixed response in an individual… but rather an interaction between the food, the external context and internal signals for the current physiological state.

• Virtually all acts of eating generate some degree of sensory pleasure.

Taste perception or “palatability”

FLAVOR• perceptual

experience created

by the synthesis of

the simpler oral

sensations

tastes

odors

touch

These senses combine in the

mouth which convey a food’s

textural, temperature and

chemical irritants e.g. hot

peppers.

• (Example: White chocolate is a poor substitute for true chocolate

which differs only in cocoa (which consumed by itself is bitter)).

But it adds complexity of flavor and aroma

that has no intrinsic nutritional value to

justify its appeal.

Flavor

Liking v. Wanting

• A model for understanding the motives (drives) to eat

REWARD: Liking v. Wanting

• Evidence that there are separate systems:

Liking v. Wanting

LIKING (PLEASURE):

system that underlies

sensory pleasure

Genetic (sweet) or learned

(classical conditioning)

Liking v. Wanting

WANTING (DESIRE): system that motivates behavior.

• Normally systems work together – things that are “liked”

are “wanted”

• Chemically separate them by manipulating brain systems

• Opioids also play a role in pleasure.

• Naltrexone, an opioid blocker, reduces short-term food intake. IMPORTANT: this effect may be limited to

palatable foods.

Naltrexone treatment does lead to reducedpleasantness ratings for foods, but it does notappear to affect hunger.

Liking

• The pleasure of sweet taste is hard-wired.

• Liking for sweetness is highest during

childhood and declines throughout

adolescence. Sweetness is also due in part

to early feeding experience.

Ganchrow et al. 1983 Infant Behav Dev; Mickley et al. 2004 Dev Psychobiol; Desor et al. 1987 Physiol Behav; Beauchamp et al. 1982 Appetite; Pepino et al. 2005 ChemSenses; Liem et al. 2004 Appetite

Liking

WantingWanting

Wanting is a disassociated process from liking and is based on

the motivation to obtain a reward as in drug addiction.

We take wanting to mean desire. It is

possible to want a stimulus without liking

it. Craving is simply a very strong desire

WantingWanting

A reasonable working hypothesis is that reward enhances

desire for and pleasure derived from a stimulus. Liking and

wanting differ from hunger in that they have specific objects of

reference.

Neurobiologically, pathological

overactivation of the dopamine systems

could cause enhanced “wanting” for

food and food-related cues.

WantingWanting

Evidence is emerging that hyper-reactivity (rather than reward

deficiency state and down-regulation) of the mesolimbic

dopamine system may be responsible for causing obesity.

Wanting

“Genetically engineered”

rats that have enhanced

dopamine functioning

will show equivalent

liking to a food but will

eat more of it

Activation leads to increased motivation

Wanting

Food – animals will show positive facial

displays for food but won’t swallow (people will

report liking food but no motivation to eat it)

Drugs – report liking the effects of drugs but no

motivation to use them

Suppression leads to reduced motivation “wanting” for food

(as well as other rewarding stimuli – sex, drugs, etc.)

Wanting

The medication, bupropion, acts on the

dopamine system and can lead to a reduction in

the ‘wanting’ of food.

FOOD

ENVIRONMENT

Learning

systems

Learning systems form the nexus between environment

and food hedonics

• Major shifts in how food is made,

distributed and marketed AND

changes in food variety,

composition and availability

affect appetite through learning

mechanisms.

• Some aspects of the modern

environment may fool these learning

mechanisms by providing

inconsistent, unreliable information

about foods’ properties, and those

failures may impair appropriate

cessation of eating.

Why whatwe eat we eat? What we learn about what we eat

Why OVERwe eat? What we learn about what we eat

Final Thoughts


The sensory and nutritional characteristics of modern foods, in the

context of ubiquity and convenience may contribute…


Neuro-

behavioral

Responses

…to a pattern of neurobehavioral responses in:

Motivation, Attention, Affect, Memory


Neuro-

behavioral

Responses

These consequences ultimately stem from a history of learning experiences.

Greater

food

INTAKE

Greater

food

CRAVING

Greater

food

SEEKING

REDUCED

self-

CONTROL

learning learning learning learning learninglearning learning learning learning learning

Results in:


FundingDK089503, (MNORC) DK020572-34 (MDRC)R24DK097153 (MRC)2

DK092322 (PRB), DK092926 (MCDTR) DK020572UL1 RR024986 (CTSA)BCBSM FoundationBlue Care Network

Robert C. and Veronica Atkins Foundation

A. Alfred Taubman Institute

Acknowledgements

Amy Rothberg, MD, PhD August, 2016education.endocrine.org/sites/default/files/Course Files... ·...

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