Food Intake Flashcards
Energy Homeostasis
- The brain integrates information from internal and external cues to regulate energy homeostasis.
- Energy homeostasis is the balance between food intake energy expenditure
- and the brain does this by information about nutritional (e.g. glucose) hormonal (e.g. leptin) and and direct nervous cues (e.g. vagal)
What are the main drivers of food intake?
Homeostatic and Hedonistic feeding
- Homeostasis- which of us to the tendency towards a relatively stable equilibrium between interdependent elements especially as maintained by physiological processes.
- Hedonism- the pursuit of pleasure: sensual self-indulgence
Homeostatic and hedonistic regulation of feeding:
- is often regulated by different yet overlapping brain regions
- cortico-limbic system, hypothalamus, hindbrain and the interaction between these three.
Different elements of feeding behaviour
- Autonomic
- sensing of nutritional or energy reserve status (homeostatic signals)
- relaying homeostatic signals to the forebrain
- controlling adaptive thermogenesis - body temperature and energy expenditure - Executive
- decision to eat (prefrontal cortex) - Reward
- establishing the hedonic (“liking) and incentive or motivation salience (“wanting”) properties of eating-related stimuli
Dorsal Vagal Complex - homeostatic brain regions
- area of the brainstem where it records information from the vagus nerve
- dorsal vagal complex is comprised if three different brain nuclei:
—-> Area Postrema (CVOs)
—-> Nucleus of the solitary tract
—-> dorsal motor nucleus - the dorsal vagal complex is bi-directionally connected to the peripheral organs (pancreas, liver stomach) via the vagus nerve
- has direct nutrient and hormone sensing
- contains neurons expressing a variety of neuropeptides
- meal control and processing of sensory information
- direct projections to the hypothalamus specially PVN.
Central Melanocortin System
Consist of mainly two types of neuropeptide populations which are found in the accurate nucleus (ARC) of the hypothalamus and these express peptide:
- proopiomelanocortin POMC
- AgRP
Proopiomelanocortin (POMC)
- neurons containing POMC are found in the ARC
- corticotropes of the pituitary also produce POMC - which is cleaved to produce ACHT which is then released into the blood where is it then transported the adrenal gland where it exerts its actions.
Hypothalamic POMC
- cleaved by prohormones convertases to a variety of peptides that have differential effects
- these cleaved products have different pharmacological affinities for different melanocortin receptor types.
- there are 5 main melanocortin receptors subtypes and these are all GPCRs and have seven transmembrane domains:
1. MC1R
2. MC2R
3. MC3R
4. MC4R
5. MC5R
- The main once found within the brain are MC3R and MC4R and these are important for regulating energy homeostasis.
MC1R are found in the peripheral and are important for regulating coat colour
MC2R are crucial for HPA axis function and adrenal gland function
MC5R is less known but its debated that it plays a role in the production if sebum and glucose/ fatty acid metabolism
POMC deficiency/ loss
POMC deficiency / Loss of POMC function causes:
- Obesity (lack of MC3R and MC4R agonism)
- Endocrine abnormalities (lack of MC2R agonism)
- Changes in pigmentation (lack of MC1R agonism)
+/+ = WT has POMC
-/+ = Mice with POMC deficiency- some POMC is present (has 2 alleles- one normal and one deficient)
-/- = TG has no POMC
How do hormones affect the activity of POMC neurons?
——> Leptin directly regulates POMC neuron activity:
- fasting decreases hypothalamic POMC mRNA
- this can be reversed following laptin treatment
- leptin-deficient ob/ob mice do not show fasting-induced regulations of POMC
This suggests that the fasting -induced regulation of POMC is dependent on leptin treatment suggesting that the activity of these neurons is directly responding to leptin presence in the blood.
POMC neurons in the ARC and NTS are directly responsive to Leptin
- as they express leptin receptors on their membrane surface
- and following leptin administration they show pSTAT3 expression
pSTAT3 is used as a marker of leptin receptor activation, as phosphorylation of STAT is one of the signalling changes that happened downstream and binding to its receptor
It’s important to note that loss of lap and receptors on POMC neurons causes enhanced weight gain.
Another peptide in the melanocortin system is:
——> Agouti-related protein (AgRP)
- AgRP is co expressed with another peptide called NPY (neuropeptide-y) in ARC neurons and these neurons are predominantly GABAergic = so inhibitory neurotransmitters.
- The activity of AgRP neurons increases feeding:
— AgRP = inverse agonist at MC4R
— NPY/AgRP neurons inhibit the activity of ARC POMC neurons - which promotes food intake
— AgRP neurons increase feeding behaviour is by acting directly on MC4R
— Injection of AgRP in rodent brain stimulates feeding
— Ablation of NPY/ AgRP neurons in adults animals leads to a loss of drive to eat and starvation
Ontogenetic technique
- This is where genetic modifications of neurons occurs
- Neurons express light sensitive ion channels
- When light is signed specifically of these neurons it can either increase or inhibit the activity of these neurons
And it was found that after genetic stimulation of AgRP neurons alters feeding- so when neurons were stimulated by light there was a massive, instantaneous increase in the feeding behaviours.
The more the neurons are affected with the light sensitive channels the more food they ate/ more food intake
POMC and NPY/ AgRP neurons is regulated by energy state and leptin
- fasting increases NPY and AgRP gene expression in the hypothalamus
- fasting increases basal firing activity (spiking frequency of ARC NPY/ AgRP neurons)
- Laptin treatment reverses the fasting induce changes in NPY and AgRP gene expression and activity of the neurons —> receptors found on NPY/ AgRP neurons.
Empty neurons NPY/ AgRP neurons are directly sensitive to both energy state and leptin- so in state of low energy, fasting for example there is alteration in the circulating leptin levels which are being sensed by these neurons.
NPY/AgRP neurons are directly responsive to ghrelin
Ghrelin is a home and produced from the stomach that stimulates appetite
- Fed animals are more sensitive to ghrelin
NPY/AgRP neurons are directly responsive to ghrelin
- As they express ghrelin- receptors (GHSR)
- Ghrelin treatment increases ACR NPY/AgRP levels
- Ghrelin increases the firing rate of NPY/AgRP neurons
MC4R- Melanocortin 4 Receptor
- is one of the main receptors implicated in the regulation of energy homeostasis
- GPCR with constitutive activity = meaning that it can initiate a downstream signalling without an agonist being bound
—-> evidence of coupling through multiple alpha subunits: Alpha-s, Alpha-i and Alpha-q
Alpha s/i = increased energy exposure, blood pressure and heart rate
Alpha q = in action of food intake
Together, they they cause negative energy balance with cardiovascular side-effect 
—-> agonists = POMC cleavage product (melanocyte stimulating hormone) - activation of MC4R by MSH peptides decreases food intake and —-> inverse agonist = AgPR at MC4R increases food intake.
- has GPCR independent coupling to Kir channel (inwardly rectifying potassium channel)- Kir7.1
Loss of MC4R signalling results in obesity:
- CNS MC4R expression within:
Hypothalamus
DVC
Mesolimbic-dopamine system
MC4R in the PVN are crucial for regulating feeding:
- MC4 neurons in the PVN are important for regulating food intake via AgRP neurons
- Impact of MC4R on energy expenditure mediated by another brain region
MC3R - Melanocortin 3 Receptor
- GPCR
- expressed in the CNS but has limited expression sites then MC4R
- expressed on ARC POMC neurons (auto-inhibitory)
- loss of MC3R = increases adiposity (baseline) and alters the response to deviations in energy availability (high/low)
Summary
The central melanocortin system is critical for energy homeostasis regulation
—->There are 2 main peptides producing neurons in the arcuate nucleus of the hypothalamus:
1. NPY/ AgRP/ GABA containing neurons which stimulate feeding
2. POMC neurons which inhibit feeding.
—-> Producing neuropeptide ligands which act in opposition at MC4 are receptors in downstream target sites e.g. PVN
- Alpha -MSH = agonist
- AgRP = inverse agonist
—-> Central melanocortin system integrates information from our variety of hormonal cues:
- Leptin
- Ghrelin
Leptin deficient mice - ob/ob mice
Leptin deficient mice have brought neuroendocrine defects:
- Hyperphagic - very hungry
- Glucose intolerant
- Hypermetabolic links to weight gain
- Hypothermic
- Low fertility
- Reduced immune function/delayed wound healing
- Defects in HPA axis
- Reduced linear growth
Lipton can be used to treat functional hypothetic amenorrhea
- Causing loss of adipose mass leads to amenorrhea
- leptin receptors are expressed on GnRH neurons = Leptin increases GvRH secretion and Low Leptin = reduces GnRH
- Leptin administration used to treat amenorrhea
