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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
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:
Environmental Factors
TASTE PRICE CONVENIENCE HEALTH
Others:
Environmental Factors
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
Important Hormones/Neurotransmittors: a description
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
Chambers et al., 2012 Gastroenterology
Vertical Sleeve Gastrectomy (VSG) in Ghrelin KO Mice
Chambers et al., 2012 Gastroenterology
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).
Important Hormones/Neurotransmittors: a description
cholecystokinin (P06307) (chole=bile, cysto=pouch, kinin=move the bile bladder)
hunger
Important Hormones/Neurotransmittors: a description
Important Hormones/Neurotransmittors: a description
Important Hormones/Neurotransmittors: a description
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.
Important Hormones/Neurotransmittors: a description
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.
Important Hormones/Neurotransmittors: a description
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
Evaluative Processes
• Help to explain eating components
Evaluative Processes
Obtain nutrients
Salt-appetite
Sensory-specific satiety
‘Medicinal’ food-preference
• How do they influence the amount eaten?
Evaluative Processes
Taste-associated
pleasure fluctuates
according to
internal state
• How do they influence the amount eaten?
Evaluative Processes
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
• How do they influence the amount eaten?
Evaluative Processes
• 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
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