Amy Rothberg, MD, PhD August, 2016 International Congress of - - PowerPoint PPT Presentation

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

• f 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 Eat Assimilate, 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 PORTIONS MACRONUTRIENT “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

Sal Salt-appet etite e Senso sory-spe specif cific s ic satie iety ‘M ‘Medic icin inal’ l’ f food- preferenc erence e

• 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

Sna Snack Sna Snack Sna 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 reduced

pleasantness ratings for foods, but it does not appear 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 Chem Senses; Liem et al. 2004 Appetite

Liking

Wanting

Wanting

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

Wanting

Wanting

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

• veractivation of the dopamine systems

could cause enhanced “wanting” for food and food-related cues.

Wanting

Wanting

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 what we eat we eat?

What we learn about what we eat

Why

OVER

we 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, Attenti Attention, Af Affect ect, Me Memory mory

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 learning learning learning learning learning learning Results in:

Funding

DK089503, (MNORC) DK020572-34 (MDRC) R24DK097153 (MRC)2 DK092322 (PRB), DK092926 (MCDTR) DK020572 UL1 RR024986 (CTSA) BCBSM Foundation Blue Care Network Robert C. and Veronica Atkins Foundation

• A. Alfred Taubman Institute

Acknowledgements