Hypothalamic pituitary axis 2 Flashcards
Determining body weight
belief that is held by most people
Energy intake = energy expenditure
Energy Expenditure
Thermogenesis –> adaptive, variable, Brown Adipose Tissue, regulated by SNS
Physical Activity –> voluntary, variable
Metabolic Rate –> obligatory expended in cell function
Frohlich’s Syndrome
Concluded that the adiposogenital syndrome seen in patients was due to injury to the pituitary gland (1901)
Aschner demonstrated that removal of the pituitary in dogs did not lead to obesity (1912)
Role of the hypothalamus in regulating food intake - Hetherington and Ranson (1940)
The dual centre hypothesis of feeding
experiment with mouse
lesion of the lateral hypothalamus —> lateral hypothalamic syndrome —> underweight
Lesion to ventromedial hypothalamus —> ventromedial hypothalamic syndrome —> obesity
What is the interaction between the periphery and the brain in setting body weight?
Lipostatic theory
The brain monitors the amount
of body fat and acts to “defend”
this energy store against changes
This theory requires there to be a link or a messenger between
body fat and the brain
The much sought after ob gene product which circulates in the blood in proportion to fat mass
Coleman’s parabiosis experiment
Ob/ob mouse lacks the Ob gene within its fats
parabiosis of Ob/Ob mouse and the normal mouse –> both mouse normal weight
Discovery of Leptin (leptos
ob gene normally, expressed in fat cells, was sequenced in the mid 90’s and the product named “leptin”.
Daily ip injections of leptin in mice
reduction of body weight
percentage body fat (12.2% to 0.7% !!)
decrease insulin and glucose
increase in temperature, metabolic rate and activity
a
Neuronal circuitry in the hypothalamus activated
by
peripheral hormones
arcuate nucleus
A collection of neurons (nerve cells) in the hypothalamus of the brain. Some arcuate neurons contain dopamine and act to inhibit the release of the hormone prolactin by the pituitary gland. Other arcuate neurons contain a substance called neuropeptide Y (NPY) and influence hunger.
which neurons in the hypothalamus promote feeding?
NeuropeptideY(NPY) + Agouti Related Peptide (AgRP)= “orexigenic
which neurons in the hypothalamus stop feeding?
Proopiomelanocortin (POMC) +
Cocaine Amphetamine RegulatedTranscript
(CART) = “anorexigenic”
Is leptin orexigenic or anorexigenic?
Leptin is an anorexigenic hormone, it inhibits the neurons that promote feeding and excite those neurons that would inhibit feeding
Net result= leptin results in reduction of feeding
What happens during starvation ?
Responses to decreased levels of leptinie in starvation (reduced body fat leads to reduced leptin levels)
Humoral
In low leptin level the release Hypophysiotropic hormones TRH and CRH are present in the paraventricular nucleus and act in the anterior pituitary to release ACTH and TSH which increase “metabolic rate” is inhibited —>Reduction of expenditure of energy
it stimulate the NPY and AgRP neruons which promote feeding
visceromotor
Not shown here change sympathetic outflow to sites which increase energy expenditure
somatic
Behavioral responses related to food seeking
Which homoeostatically increase our body weight
Responses to increased levels of leptinie weight gain
Leptin activate the anorexigenic neurons CART and POMC in the arcuate nucleus in the lateral hypothalamus which inhibits feeding
it stimulate the Hypophysiotropic hormones in the paraveticular nucleus which cause the release of TRH and CRH into the anterior pituitary gland which cause the release of ACTH, and TSH which increase the metabolic rate and energy expenditure
The role of the hypothalamus- Long term control of energy balance
. While short-term weight loss is readily achieved with diet and exercise, most individuals are unable to maintain the weight loss for an extended period. Avoiding weight regain is usually a challenge because physiologic mechanisms, some poorly understood, promote weight regain. Up to 75% of dieters, especially people on very low calorie diets (400-800 kcal/day) regain much of the lost weight within 1 year.22
As weight loss objectives are often not achieved through diet and behaviour modification alone, there remains a need for more efficacious approaches. An extensive study program has shown that Xenical, when used in conjunction with a mildly hypocaloric diet, produces significant weight loss, reduced weight regain, improvements in the comorbidities associated with obesity and an improved quality of life compared with diet alone.
ENERGY EXPENDITUR and weight
ENERGY EXPENDITURE CAN BE REGULATED IN MAN
10% weight gain–> 10% increased in energy expenditure
Why is it difficult to maintain weight loss?
It is difficult to maintain weight loss - metabolic adaptation occurs following weight loss
There’s a persistent need that is generated in weight loss t put that weight back on as the BMI decreases significantly difficult to maintain that weight loss
Short term regulation of food intake
Ghrelin: feeding promoting hormone
Satiety signals: hormones promoting stop feeding
Ghrelin produced in the stomach and acting on feeding centres (NPY and AgRP neurons)
in the brain builds up prior to a meal and then is reduced following the meal
Satiety Signals
Gastric distension and cholecystekinin (CCK) and insulin (produced by pancreases) acts on the vagus nerve that takes the signal to the nucleus of the solitary tact to produce satiety
During feeding stomach stretch, the stretch sensitive neurons detect that and send a signal to the brain to the nucleus of the solitary tact to produce satiety
How is body weight regulated?
Leptin produced by the fat cells PYY-3 36 produced by small intestine Amylin produced by pancreases CCK produced by pancrease Insulin and Ghrelin produced in stomach hedonic input stretch receptor in Stomach and duodenum
Ghrelin is an orexigenic hormones
The rest are satiety hormone
How do changes in these hormones after weight loss
make it difficult to maintain weight loss
The Ghreline hormone level keep increasing after 10 weeks and 62 weeks of diet
and the level of CCK,PYY and Amylin decreases
Schematic showing the flow of information amongst distributed neural networks
controlling food intake, energy expenditure and energy homeostasis
Orbital frontal cortex is intimately connected with other related areas of cortex including the pre- frontal, anterior cingulate and insula cortex together with the
amygdala and hippocampus form
the “paralimbic cortex” ??
Stored polymodal representations
of experiences with food
Hedonistic vs Homeostatic eating
Homeostatic feeding is necessary for basic metabolic processes and survival, while hedonic feeding is driven by sensory perception or pleasure.
Reward Pathways –
The basis of hedonistic feeding
Electrical self stimulation.
Excitation of dopaminergic neurons arising from the ventral tegmental area and projecting to the basal forebrain
The mesolimbic (dopamine) reward pathways
The mesolimbic dopamine pathway is thought to play a primary role in the reward system. It connects the ventral tegmental area (VTA), one of the principal dopamine-producing areas in the brain, with the nucleus accumbens, an area found in the ventral striatum that is strongly associated with motivation and reward.
There is a division amongst the core processes of reward into
‘liking”
“wanting”
‘liking
“Liking” is an objective affective reaction that is mediated for taste in the brain by distributed neural networks extending from the brain stem to the nucleus accumbens
Examples of hedonic “liking” reactions are stereotypical and preserved across species and exist without higher centres
What are the key brain regions and neurotransmitters involved? in liking
“Liking” is mediated by mu opioids acting at receptors in the nucleus accumbens (ie local injection
of morphine or the mu opioid receptor agonist DAMGO leads to appetite for highly palatable,
highfat, sweet foods)
selective mu opioid receptor antagonists reduce the “liking” of previously favoured
sweet solutions
What are the transmitters involved? wanting
Dopamine was originally thought to be the transmitter that mediated sensory
pleasure or “liking” however 6 OH DA lesions (which disrupt dopamine show otherwise
ie elimination of dopamine from the n accumbens and ventral striatum leads to aphagia
(reduced feeding) but no shift in “liking”
increasing levels of dopamine in the n accumbens does not change “liking” but
increases the motivational component of reward or “wanting”. “Wanting” is mediated by dopamine
wanting
“wanting” is an objective motivational process that is often termed incentive salience
