Hypothalamic control of metabolism Flashcards
(25 cards)
What is energy homeostasis?
Energy input = energy output
Feeding = thermogenesis + movement
Feeding is dependent on hunger drive
Why is it important to store energy?
Maintain sufficient energy delivery to tissues despite unpredictability of energy intake and expenditure.
How can you fractionate the reasons for feeding drive?
Hedonic drive:
* Pre-consummatory signals (e.g. vision and olfaction driving hunger)
Homeostatic drive:
* Nutritional signals (on current state of body detected in arcuate nucleus – e.g. leptin, glucose, insulin, leucine)
* Orosenory signals e.g. gustation, ghrelin
* Non-nutritional signals (cortisol, T3)
What is obesity? Why is it a problem?
Excessive or abnormal fat accumulation that presents a risk to health. Occurs when energy intake > energy usage for a long period.
- Fat accumulation can be beneficial (e.g. hibernation, pregnancy)
- Excess is determental – cholestrol build up, heart disease, diabetes, risk factor for many pathologies.
- Effects of ‘obesity epidemic’ are strongly apparent now.
What are the nutritional signals that energy is low?
There are many metabolites which need to be kept in a specific concentration (low or high is bad). Fluctuations below normal range can induce hunger:
* Low glucose (+ low insulin)
* Low amino acids
* high ketone bodies (signalling protein breakdown due to limited glucose)
What are some non-nutritional molecules acting as hunger signals in blood?
Stress signals: e.g. cortisol increases feeding
Thyroid hormone: increases metabolism, digestion and growth. T3 stimulates feeding at the hypothalamus level.
Why is it important to have top-down mechanisms driving hunger (as well as physiological signals)?
Signals from blood (e.g. glucose, insulin, amino acids, GLP-1, CCK) are feedback: give current state of metabolism and feeding occurance.
* Some have longer feedback times (leptin)
Feeding is not guarenteed, therefore there need to be mechanisms driving feeding even when not metabolically necessary at that moment:
* Apperceptive: good food is available now so eat it
* Food can give other benefits e.g. emotional eating for pleasure, socialising.
* Predictive eating: e.g. I will run a marathon so need energy tomorrow.
Why is there an obesity epidemic?
Obesity (define): energy intake > energy output
Hunger drive is caused by a combination of nutritional signals (from the body) and psychological signals from the brain (hedonic).
* When there are competing hunger and satiety signals, hunger wins
* Modern society increases feeding drive beyond what satiety can compensate for leading to excessive feeding.
Draw (imagine) a diagram of the hypothalamic circuit. What are the main areas?
Arcuate nucleus (detection):
* POMC neurons (satiety) produce α-MSH
* AgRP/NPY neurons (hunger drive)
Act on:
* LH = hunger centre
* VMH = satiety centre
Integrate signals and drive responses
Response areas (project to extra-hypothalamic areas)
* PVN: releases signals upregulating metabolism and thermogenesis (+ inhibits feeding)
* DMH: Similar effects to PVN and invovled in circadian rhythm.
What is the role of the PVN?
Output centre of energy homeostasis.
Stimulated by sateity/inhibited by hunger signals
* POMC produces MC-4 (melanocortin-4). PVN has highest proportion of MCR-4 receptors
Acts to inhibit hunger and increase energy expenditure:
* Stimulates thermogenesis (e.g. TRH) using BAT
* Evidence can turn iWAT into iBAT
* Ablation causes extreme weight gain (hyperphagia and reduced metabolism)
What is the role of the DMH?
Stimulates hunger and involved in circadian rhythm:
* Lesions induce hypohagia and disrupted circadian rhythm
* Suppressed by AgRP/NPY
Give evidence exposing the asymmetry of the AgRP/POMC connection
- Optogenetic activation of AgRP neurons sufficient to cause voracious eating (daily food consumed in 1hr) but inactivation of POMC neurons optogenetic/chemogenetic stimulation requires specific pattern of firing over 24hrs for a significant effect (effect not as significant even then)
- AgRP neurons inhibit POMC neurons when active but feedback in the other direction is not as strong (therefore if both active, hunger wins
What is the role of the amygdala in feeding drive? (Provide evidence)
Optogenetic activation of CeN (using ChR2) sufficient to increase motivation for feeding and induce feeding behaviour (e.g. chewing) even ingesting non-edible objects.
Suggest a mechanism for the monitoring of glucose levels in the hypothalamus:
Using glucose sensitive enzymes to control excitation levels:
In VMH (satiety centre):
* Glucokinase expressed (low Km, so high glucose needed to activate)
* Binding leads to ↑ATP and opening of Ca2+ channels
* Excitation of cells
* Inhibit hunger centres (e.g. LH) and detectors (AgRP neurons)
How does leucine cause appetite suppression?
Detection of leucine in the arcuate nucleus suppresses appetite (induces satiety).
* Cacna1g gene increases expression of CAV3.1
* Leucine binds to CAV3.1 Ca2+ channels exciting POMC cells
* ~25% of POMC cells identified as responsive to leucine
What experimental evidence is there for cacna1g and Cav3.1 importance in protein suppression of appetite?
Cacna1g gene causes expression of Cav3.1 Ca2+ channels. Leucine binds and causes excitation.
* Channels are necessary for response: blocking of channels (using TTA-P2 inhibitor) stops excitation. Cav3.1 knock-out leads to overeating but no metabolic effects
* Not sufficient for firing (excites cells but does not cause AP)
* Cacna1g is downregulated in Prader-Willis syndrome (may add to inability to suppress appetite since less protein mediated suppression).
Leucine is an example amino acid but is not representative of all (or longer peptides) or cumulative effects. Therefore inferences need to be made with caution.
Why are hypothalamic circuits set up so that ‘hunger wins’?
Evolutionarily advantagous to have excess energy than not enough:
* Running out of energy much greater risk
* Effects of excess energy (e.g. obesity) mainly seen post-reproductive age
What is the effect of pre-consummary detection of food on hypothalamic circuits?
Short term suppression of hunger but long term upregulation (if unfulfilled)
Short term anticipatory suppression (Chen et al).
* Mice subjected to over-night fast (awake hours since nocturnal)
* Activity of AgRP/NPY decreased and POMC increased on presentation with food.
* Strength of suppression depended on ‘value’ of food
However, if not fulfilled, hunger drive increases (Su et al):
* Calorie dependent detection of food necessary for ssustained suppression (particularly CCK, PYY, Amylin)
* Food withdrawal greatly increases hunger drive (problem with modern society when constant suppression needed.
Explain how pre-hibernation could be an extreme example of ‘hunger winning’
Preparation for hibernation (a period of anorexia during winter) requires extreme weight gain to build up surplus energy stores.
* Requires overcoming normal satiety signals
* Controlled by photosensitive cells signalling right period of year to make this change
What are the types of fat? Explain their functional redundancy:
White fat (for storage of energy rich fatty acids) and brown fat (thermogenesis)
Brown fat:
* Sympathetic innervation of brown fat causes increased adaptive thermogenesis
* UCP-1 uncouples oxidative phosphorylation from ATP production (leading to heat production)
White fat:
* Sympathetic innervation sufficient to induce lipolysis (NA release → hormone sensitive lipase → lipolysis (Zeng et al optogenetic stimulation in cre-mice)
* Continued NA release leads to ‘browning of fat’ which increases thermogenic capability
* Shows plasticity of fat tissue
How does AgRP activation affect fat?
AgRP neurons inhibit sympathetic nerve innervation (via PVN) of WAT and BAT:
* Inhibits thermogenesis
* Inhibits browning of WAT (for future thermogenesis)
What is the effect of mTORC1 signaling pathway?
Negatively regulates AgRP/NPY activity
* Rapamycin (inhibitor or mTORC1) causes increase in AgRP/NPY activity seen as reduction in iBAT temperature
* Activation of mTOR (using L-leuine) increased iBAT temperature
* Leptin activates mTOR to reduce hunger
What is the evidence for leptin suppressing appetite?
ob/ob mouse missing leptin receptor are extremely obese due to increased feeding and decreased thermogenesis and movement:
* Rarely but is seen in humans (causing obesity)
Why is obesity treatment with leptin not very successful?
Obese patients have plenty of leptin, but have become resistant.
* Increase in leptin from fat not sufficient to overcome feeding drive.
