APPETITE
JF Morris
Objectives:
After this lecture and associated reading you should be able to summarise:
 the roles of different brain regions including the arcuate nucleus, lateral
hypothalamus, ventromedial hypothalamus, and orbitofrontal cortex in
the control of food intake;
 the roles of peripheral factors such as taste, smell, gastric distension,
intestinal stimulation, plasma glucose, and hormonal signals such as
leptin, ghrelin, CCK in the control of food intake;
 the relation between the signals that control food intake and the brain
mechanisms involved in reward.
Feeding behaviour - peripheral regulation
 Oropharyngeal factors (smell, taste, touch in mouth), reinforce feeding (reward), but do not cause satiety
 Gastric and intestinal factors do not reinforce (no reward), but do cause satiety.
 Therefore, there must be an interaction in the brain between oropharyngeal and gastric/intestinal signals.
Hunger - central regulation
1. Ventromedial hypothalamus (VMH) – ‘satiety centre’
• Frohlich’s syndrome (1902): overeating and obesity linked to
hyposexuality resulting from damage to the base of the brain.
• Experimental lesions of VMH cause overeating and obesity
• VMH neurons respond to glucose, free fatty acids and insulin
• VMH acts indirectly to affect body weight ‘set-point’. ‘satiety centre’
2. Lateral hypothalamus (LH) – ‘hunger/feeding centre’
• Electrical stimulation of the lateral hypothalamus elicits feeding.
• Lesions of lateral hypothalamus produce aphagia and adipsia
• Ibotenic acid lesions to LH, which only destroy cells, cause aphagia.
• LH neurons respond to the smell, taste, sight of food
• LH neuron responses to taste/sight of food is modulated by hunger
• ‘Sensory-specific’ satiety was discovered in LH neurons.
The lateral hypothalamus therefore acts as an interface between sensory
inputs which produce reward and hunger/satiety signals that modulate reward.
3. Input from olfactory and taste pathways (see Rolls 1999)
• Tuning becomes more specific from NTS though 1y taste cortex to
orbitofrontal (OF) 2y taste cortex, and from 1y to 2y olfactory cortex
• Some OF neurons respond to olfaction plus taste. i.e. flavour.
• Satiety and sensory-specific satiety occurs in 2y taste/olfactory cortex.
• Orbitofrontal taste and olfactory cortex have representations of reward.
• Learning influences the formation of olfactory-taste associations in OF
4. Input from visual pathways
• From inferior temporal cortex to OF cortex (directly and via amygdala).
• In OF cortex (but not inferior temporal cortex) neuronal responses to the
sight of food are modulated by hunger.
• Neurons in orbitofrontal cortex associate vision and taste
• Orbitofrontal cortex has reward associations for the sight of food.
• Damage to OF and amygdala impair discrimination e.g. food selection.
5. Role of the orbitofrontal cortex
• Contains 2y taste and olfactory cortices; builds representations of flavour.
• Satiety modulates representations of food in orbitofrontal cortex.
• Sensory-specific satiety for taste, smell, sight of food is computed in
orbitofrontal cortex.
• Orbitofrontal cortex also has a representation of the texture of food.
• Discrimination learning, especially rapid reversal, and food selection are
impaired by orbitofrontal damage.
• Orbitofrontal cortex involved in vision-to-taste, olfaction-to-taste learning.
Role of intrinsic sensitivity of neurons to glucose, free fatty acids, AMP
• Role AMP kinase
These a partly learned, but affect primarily SHORT-TERM control of feeding; learning affects LONG-TERM
Hunger – Peripheral Regulation
Important: Distinguish short-term from long-term: i.e. satiety after meals from long term control of body weight
1. Gastric distension: short-term signal - reduces feeding
2. Duodenal chemosensors: short-term signal
• Glucose: vagal route to NTS and brain
• Fats: hormonal route to brain e.g. CCK acts on vagal terminals
3. ‘Glucostat’ hypothesis: short-term signal
‘glucose utilisation controls feeding’
• arterio-venous [glucose] difference correlates with feeding.
• 2-deoxyglucose (inhibits glucose metabolism) elicits feeding.
• [glucose] sensed in medulla & VMH; 5-thioglucose to VMH elicits feeding.
4. Conditioned appetite and satiety: long-term
associate learned signals with their metabolic consequences.
5. Peripheral hormonal signals that modulate feeding
(a) Leptin: long-term signal
signals body fat mass – decreases feeding, stimulates metabolism
• Discovered many years after classic cross-circulation (parabiosis) expts by
Coleman on normal and strains of genetically fat mice ob/ob and db/db;
• ob/ob mice produce no leptin: very obese, low BMR, poor reproduction;
leptin administration to ob/ob mice reduces feeding, increases metabolism;
• db/db mice produce no functional leptin receptor; leptin administration to
db/db mice does not reduce feeding or fat mass;
• human fat cells secrete leptin; plasma leptin is proportional to fat mass;
insulin stimulates leptin secretion; leptin inhibits insulin secretion;
• leptin has a long time-course, fluctuates over 24h but NOT in relation to
individual meals;
• in fasting, leptin levels fall long before decrease in fat mass;
• homozygous leptin deficiency is a VERY rare cause of human obesity;
• leptin is transported into the CNS by receptors in the choroid plexus;
• leptin receptors are found in the arcuate nucleus, where they inhibit
neurons producing neuropeptide Y (NPY) which project to PVN, and
stimulate neurons producing αMSH from POMC;
• evolutionary aspect: to prevent starvation.
(b) Ghrelin: short-term signal
signals empty stomach – stimulates feeding
• Produced by the oxyntic glands of the stomach in fasting;
• Eating a meal decreases the secretion of ghrelin;
• Originally named because it causes the release of growth hormone (GH);
• Acts on receptors in the arcuate nucleus to stimulate NPY neurons and
inhibit αMSH neurons thereby stimulating feeding behaviour;
• Hypothalamic sensitivity to ghrelin is increased in fasting.
(c) Glucagon-like peptide 1 (GLP-1): short term signal
signals food in intestine, inhibits feeding
• produced by small intestine;
• acts in hypothalamus (paraventricular nucleus) and amygdala;
• powerful inhibitor of feeding.
(d) Peptide YY (PYY3-36): controversial; longer term
signals calorie content of a meal, inhibits feeding
• released from distal intestine (ileum, colon);
•
•
Inhibits NPY receptors in arcuate nucleus of hypothalamus;
Decreases appetite and reduces food intake for 24h (controversial)
(e) Insulin - inhibits feeding by action in arcuate of hypothalamus
6. Intrahypothalamic regulators of appetite and feeding
(a) Neuropeptide Y (NPY): produced by neurons in the arcuate nucleus which
project to paraventricular nucleus and lateral hypothalamus.
• When infused into the CNS causes massive increase in feeding;
• However, NPY-KO animals do not reduce appetite dramatically;
• Release inhibited by leptin, PYY, insulin; stimulated by ghrelin;
• PYY mimics effect on NPY receptor.
(b) αMSH melanocyte-stimulating hormone): produced from POMC by
neurons in the arcuate nucleus which project primarily to the lateral
hypothalamus.
• αMSH inhibits the feeding centre in the lateral hypothalamus via the
melanocortin MC4 receptor;
• Mutations in MC4 receptor are commonest monogenic cause of obesity;
• Release stimulated by leptin, insulin.
Cocaine and amphetamine-related transcript (CART)
• co-produced with αMSH; inhibits feeding;
• Release stimulated by leptin, probably inhibited by ghrelin.
Agouti-related peptide AgRP
• co-produced with NPY
• increases feeding by inhibiting MC4 receptor for αMSH
Orexins A, B
• produced in lateral hypothalamus (actions largely in PVN)
• weakly stimulate feeding; more important in arousal
•
Many other peptides (eg CRH - relation to stress) and amines (eg DA, 5-HT)
affect feeding behaviour.
Intrinsic sensitivity of VMH/arcuate neuron
• sensitive to glucose, free fatty acids, some amino acids;
• mutations in metabolic enzymes (e.g. fatty acid synthase) cause obesity;
• AMP kinase is important cellular regulator of appetite and metabolic rate;
• appetite/feeding behaviour and metabolic rate/activity are always linked.
OBESITY
The increasing incidence of obesity in western society is very worrying
because of its long-term association with cardiovascular disease, type II
diabetes, joint trauma etc.
All animals (including humans) are genetically programmed through
evolution to eat more than is needed for daily energy output when food is
available so that energy reserves can be stored in the body for times when
food is scarce.
The ‘thrifty genotype’ concept states that the mechanism is that we are
genetically somewhat resistant to insulin and to leptin in higher
concentrations. This is advantageous in conditions of food shortage/feeding
cycles as it increases energy storage and decreases muscle glucose use during
starvation. However, it is disadvantageous when food is continually available
and may account for the incidence of obesity and type II diabetes mellitus in
western societies.
The effect is heightened by the lack of physical work in western society.
The combination of constant availability of food and reduced energy output is
probably the major overall factor. Some people are more predisposed to
become obese and this is undoubtedly the result of many gene
polymorphisms.
Other physical and neurological factors
• Endocrine factors: insulin resistance in TII diabetes (very common); decreased leptin (very rare);
• Enhanced palatability of food causes oral rewards to outweigh gastrointestinal and post-absorptive satiety signals;
• Variety (‘cafeteria effect’): increased variety leads to increased intake because satiety is partly sensory-specific;
• Externality: obese people may be more reactive to the sensory properties of food;
• Meal pattern: inter-meal pattern is normally regulated; obese tend to eat more later in the day;
• Stress-induced eating: mildly raised glucocorticoids stimulate feeding;
• Poor regulation to internal signals - it takes 2 weeks to adjust to altered caloric composition of the diet.
Advanced reading:
Kola B et al (2006) Trends in Endocrinology & Metabolism 17:205 Role AMPkinase in appetite
Nature Neurosci 8(5) 2005 – devoted to Neurobiology of Obesity
Science (2003) 299:845-860 Obesity - What is to be done?
Luckman SM (2001) Is there such a thing as a healthy appetite? See http//www.neuroendo.org.uk
Dickson SL (2001) Ghrelin: a newly discovered hormone. Neuroendocrinology briefing 15 (same web site)
Rolls ET (1999) The brain and emotion. OUP Chapters 2, 4, 7
Carlson NR (1998) Physiology of behaviour. (Ed. 6) Allyn & Bacon, Chs 12 - thirst; 13 hunger.
Coleman DL (1978) Diabetologia 14:141-148 Parabiosis experiments.
Any queries - john.morris@dpag.ox.ac.uk