Appetite Pharmacology

NPY/AgRP neurons
LH activation
NPY
AgRP
Orexin
MCH
Galanin
MOR
Anandamide

Ghrelin

POMC neurons
VMH activation
Serotonin (5HT2c)
Histamine
MSH
MC3/MC4
Nicotinic receptors

GLP-1
Leptin
Insulin
Glucose
Amylin
PYY
Oxyntomodulin
CCK

homeostatic pathway and hedonic regulation

When the body increases the motivation to eat following depletion of energy stores.

Reward-based, can override the homeostatic pathway during periods of relative energy abundance by increasing the desire to consume foods that are highly palatable.

Neurons in the Aruate Nucleus (ARC) are located in an anatomically strategic place, close to fenestrated capillaries at the base of the hypothalamus, giving them access to various humoral signals that are restricted from other portions of the brain. These signals tell the brain how much fuel is available.

ARC

It sends signals to other hypothalamic brain regions that drive or inhibit feeding

pro-opiomelanocortin (POMC)

neuropeptide Y (NPY) and agouti-related peptide (AgRP)

Ventromedial nucleus of hypothalamus (VMH)

Lateral hypothalamic area (LHA)

They increase

the high levels of glucokinase will break down glucose, which will activate neuropeptide Y (NPY) and agouti-related peptide (AgRP)

Ghrelin is excreted when the stomach is empty, is used to induce appetite in cancer patients.

Activates POMC neurons (decrease feeding), promotes energy expenditure and fat metabolism, administering leptin to an obese human with genetic leptin deficiency reduces weight.

Insulin dampens appetite by inhibiting NPY/AgRP-secreting neurons and by activating POMC-releasing neurons.
Resistance to insulin is very often associated with obesity and the loss of insulin's regulation of metabolism as seen in diabetes type 2.

Co-secreted with insulin from the ß-cells of the Islets of Langerhans (Pancreas).
Slows gastric emptying and reduces appetite.

It is secreted from intestine after meals, acts on Y2 receptors in the hypothalamus to inhibit NPY/AgRP neurons

Released by the gut after eating
Promotes satiety when injected to humans. Reduces appetite.
Increases insulin, lowers blood sugar, new anti-obesity/diabetes drugs

CCK is release by the gut after eating
satiety signal, promotes digestion, reduces appetite.
May be stimulated by fat in GI tract.
Also found in CNS.

Oxyntomodulin reduces appetite and increases energy expenditure.

reduces feeding

α-MSH, a melanocortin

POMC neurons

increases food intake via inhibition of MC3/MC4.

Increases feeding.
Stimulation of the NPY-neurons in arcuate nucleus (by exercise, fasting, energy loss) is followed by increased appetite and food intake.

NPY involved in aggression when hungry (hangry)

5HT2C receptor activation reduces feeding
Remember: side effect of typical antipsychotics is weight gain likely by inhibition of 5HT2C

Histamine reduces appetite (and also increases energy expenditure [arousal]).
H1 blockade in hypothalamus increases appetite.
Leptin (and GLP-1) may work by activating histamine neurons.

Peptide that increases feeding
3 Receptors
GalR1, 2 and 3.
May also be involved in stress.

Central administration of orexins is associated with increased EEG arousal, wakefulness, and locomotor activity.
Highly adaptive for a hungry individual not only to seek sustenance but also to remain fully alert to dangers in the environment.
Bridge the transition from eating to resting in animal’s feeding-sleep cycle.
Obesity is often seen in narcolepsy patients

Neurons located in LHA
Intermingled with orexin neurons
Acute MCH injection increases food consumption followed by a gain of body weight and fat mass.

Reduce appetite and lower food intake.
Catecholamine – CNS Stimulants, amphetamines.

Generally, DA inhibits eating in hypothalamus (but not limbic).
NE decreases eating in LH but can also increase eating in other areas of hypothalamus.
Also autonomic (thermogenic) effects
Also increased activity.

Inhibit VMAT, promote DA/NE release

MAT inhibitor, also promotes NE release

Stimulate NE/DA release

Stimulate NE release (more than DA)

worked, but, withdrawn due to association with pulmonary hypertension and valvular heart disease. Fenfluramine binds to 5HT2b receptors which are highly expressed on cardiac valves.

Inhibit voltage gated cation channels, AMPA-R, enhance GABA-AR. (Net result: reduce excitatory activity).

May work to reduce appetite and enhance satiety.
May also affect energy expenditure and taste of food.

May be involved in the control of lipid metabolism, possibly from fat assimilation in the digestive tract, triglyceride storage and mobilization in adipose tissues.

Beta 3 receptors found in adipose tissue, it acts on them to cause increased lipolysis, fat oxidation, energy expenditure, and insulin sensitivity.

Opiate receptor antagonists suppress eating, inhibits POMC neurons.
Naloxone/Naltrexone, mu opiate receptor blocker, reduce consumption of sweet, high-fat foods, especially in obese individuals.

failed trials or still in testing

5HT2C Agonist, being specific to 5HT2C avoided potential side effects, but it was pulled from market due to cancer risks.

Inhibits presynaptic uptake of norepinephrine, dopamine, and serotonin, SNDRI, Initial use of tesofensine in patients with Parkinson's or Alzheimer's disease produced unintentional weight loss. Potential antidepressant activity, cognitive improvement.

Inverse relationship between cigarette smoking and body weight, with smokers weighing significantly less than non-smokers of the same age and sex, may stimulate POMC [melanocortin].

Acts on CB1, induce hyperphagia, dronabinol (Marinol) approved for treatment of AIDS-related anorexia/wasting.

CB1 inverse agonist, devolped as anti-obesity drug, but caused depressive disorders or mood alterations in up to 10% of subjects and suicidal ideation in around 1%, withdrawn from market.

Anti-diabetic medication, GLP-1 receptor agonist, peptide

FDA-approved 2021 for long-term weight management
GLP-1 receptor agonist, peptide, more effective than Liraglutide.

MC4 receptor agonist
Appetite suppressant, increases resting energy expenditure