When things go wrong part 1 Flashcards
Energy sources for body & brain
1 - glucose
2 - glycogen
3 - Lipids
Detection system
- recognise deviation from set point
- alter physiology or behaviour to correct imbalance
- recognize when correction has been effective
(Does not apply to the long-term regulation of energy stores& feeding)
Glucostatic Hypothesis
- Brain monitors circulating blood glucose levels
- when they fall below a critical level, we become hungry
- after we eat & blood glucose levels return to normal - no longer hungry
BUT –> diabetics have high levels of glucose, always hungry without insulin
Lipostatic Hypothesis
- Brain monitors body fat stores
- If they fall below a critical level - makes us hungry
- After we’ve eaten & replaced missing body fat, not hungry anymore
BUT - get hungry ~ 4hrs after a meal - not lost any weight
Bottom-up modulation
Ascending modulatory influences determine the level of incentive salience directed to specific nutrients
CNS regulation of energy homeostasis
CNS integrates input from long-term energy stores (e.g. leptin) & short-term meal-related signals (nutrients & gut-derived satiety signals) to regulate food intake & EE that is able to maintain stable body fat stores over time
Functions of the hypothalamus
1 - regulation of food intake 2 - autonomic regulatory center (influences HR, BP, respiratory rate, GI mobility, pupillary diameter) 3 - regulation of thirst & water balance 4 - regulation of body T 5 - regulation of sleep wake cycle 6 - emotional responses 7 - hormonal control
Which structures does the hypothalamus influence secretion from in regulatin energy balance & metabolism?
1 - Thyroid gland
2 - Adrenal gland
3 - Pancreatic islet cells
Orexigenic substance
any substance that stimulates feeding behaviour
Anorexigenic substance
Any substance that inhibits feeding behaviour
AgRP/NPY Neurons
AgRP/NPY neuons express ghrelin receptors - detect ghrelin to facilitate energy intake (hunger-related metabolic molecule)
POMC neurons
POMC neurons express leptin or insulin receptors - respond to anorexigenic substances: adipose-originated leptin or pancreas-derived insulin
T/F POMC neurons expressing leptin receptors co-produce insulin receptors
False - POMC neurons expressing leptin receptors do not co-produce insulin receptors (& vice versa) indicating existence of heterogeneous subtypes of POMC neurons in hypothalamus
Dominant melanocortin receptors
MC3/4R
Arcuate Nucleus function
Integrates info for blood glucose & body fat levels
What are the 2 subtypes of arcuate nucleus neurons?
NPY & AgRP expressing neurons
POMC & CART expressign neurons
What does activation of NPY/AgRP neurons result in?
Increases food intake & decreases EE
What does activation of POMC neurons result in?
Decreases food intake increases EE
Short-term vs Long-term regulation of food intake
Short term regulation:
Preventing overeating at each meal
Long term regulation:
maintenance of normal quantities of energy stores in the body
Types of rapid feedback signals during a meal to regulate the amount eaten
- intestinal stretch receptors
2. Peripheral anorexic hormonal signals
Hormones released by lipid & carbohydrates
Lipid - CCK release
Carbohydrates - GLP-1, PYY, Insulin
CCK, GLP-1 & PYY role
CCK: released in response to fat entering the duodenum; Stimulates POMC/CART neurons
–> reduces food intake
GLP-1: released in response to carbohydrates in intestine; Stimulates POMC/CART neurons
–> reduces food intake
PYY: stimulated by food intake & released from GI tract; Inhibits the NPY/AgRP neurons
–> reduces food intake
Peripheral orexigenic signal
Ghrelin:
stimulates food intake; produced by stomach
NPY acts on which receptors in POMC
NPY acts on POMC NPY Y1 receptors -> inhibits POMC neurons
Adipokines
1 - leptin 2 - Resistin 3 - Adiponectin 4 - Visfatin 5 - TNF & IL
Action of leptin
Correlates with adipose tissue mass - increase concentration & resistance in obese individuals
Ineffective peripherally in humans
Action of resistin
Induced in obesity –> leads to insulin resistance
Action of Adiponectin
Insulin sensitizing & anti-inflammatory
Suppressed in obese paralleling insulin resistance
Increases EE & fatty acid metabolism
Action of TNF & IL-6
Promotes low level inflammation in fat & throughout body
How does Leptin disinhibit POMC neurons?
- Decreases GABAergic tone on POMC - mediated by AgRP neurons
- Inhibits AgRP neurons
- Inhibits pre-synaptic GABAergic neurons
Selective antagonist on D2 dopamine receptors
Raclopride
D2 receptor function
Activate inhibitory G-proteins by inhibiting adenylate cyclase - cAMP formation
Increased Raclopride binding in anteroventral striatum in recovered anorexics could be due to:
- Reduction in intrasynaptic DA concentration
- Elevation of density of D2/D3 receptors
- Increased affinity of D2/D3 receptors in this region
More evidence for role of DA in anorexia
- CSF DA metabolites reduced in malnourished AN patients & persists after recovery
- AN have impairment in visual discrimination learning - reflects defective DA signaling
- Anorexics have altered frequency of functional polymorphisms of DA D2 receptor genes - may effect receptor efficiency of receptor transcription & translation
Antagonist of H1 receptors
[11C]doxepin
When obese individuals restrict energy by dieting:
- > increased sympathetic activity - mobilize fatty acids from adipose stores
- > results drop in leptin production that exceeds loss of fat from storage deposits
- > reduced leptin - leads decreased muscle & other thermogenic organ sympathetic activity - leads to decreased resting EE
- > low leptin levels - disinhibit NPY/AgRP neurons & inhibits POMC/CART neurons - causing a strong drive to seek & ingest food
Diet induced weight loss increases baseline levels of :
Ghrelin
Surgically induced weight loss (gastric bypass) decreases:
ghrelin
+ prolonged suppression of ghrelin
weight loss possibly due in part to lack of appetite stimulation
The leading theory for maintenance of body weight as a result of long-term matching of food intake to EE relates to the:
Amount of fat stored in adipose tissue
A defect resulting in a lack of neuropeptide Y in the hypothalamus would likely result in:
Decrease in appetite
Leptin decreases the reward value of food by:
- Inhibition of the JAK-STAT pathway
- Inhibiting dopaminergic neurons in the ventral tegmental area
X - not by activating the JAK-STAT pathway in the ventral tegmental area
Peripheral anorexigenic substances act on the arcuate nucleus by:
Stimulating POMC/CART neurons & increasing EE
Insulin sensitizing & anti-inflammatory molecule that increases fatty acid metabolism & increases EE.
levels decrease in obese individuals
Adiponectin
Molecule thought to be one of the main contributors to insulin resistance in obese individuals
Resistin
Released in proportion to perceived pleasantness of food
Dopamine
This drug is responsible for increased anxiety, sedative effects & increased dysphoria in recovered ANs - response that is opposite to that experienced by healthy individuals
Amphetamine
Brain region that shows persistent hypoperfusion in recovered ANs even after weight gain
Anterior Cingulate Cortex (ACC)
Reduction in volumes of this brain region results in deficits in perceptual organization & conceptual reasoning in recovered ANs
Right parietal lobe
Increased density of these receptors (that bind [11C]doxepin) is thought to increase the vulnerability of women to develop anorexia
Histamine H1 receptors
