Make feeding rewarding

Make hunger uncomfortable

Diabetes

Hypertension

Congestive heart failure

Stroke

Sleep apnea

Muscloskeletal and joint diseases

Cnacer

Psychosocial stress and anxiety

Paraventricular nucleus (PVN): projects to second-order neurons, signals are relayed through the NTS to the body

Arcuate nucleus (ARC): neurons project to PVN (stimulatory and inhibitory neurons)

NE when injected into PVN will increase feeding behavior mediated by alpha-2 receptors (agonist inc., antagonists dec.)

(alpha-2 receptors are inhibitory)

Increases consumption of carbs but no change in fats or proteins

Increases meal size and duration but no change in frequency

Potentiated by neuropeptide Y (NPY) (can released with NE) and corticosterone

Both increase with circadian rhythm - parallel changes in NE

Increase in food intake

Cna get this by destroying 5-HT neurons, inhibiting 5-HT synthesis, or blocking 5-HT receptors

Decrease of overall food intake - can get this from SSRI (selective serotinin reuptake inhibitor) such as Prozac, Zoloft, etc. or increase serotonin release using drugs such as Fenfluramine

5-HT1B agonists influence meal size

5-HT2C agonists influence rate of eating

A serotonergic drug - indirect agonist that promotes the release of serotonin and inhibits its reuptake

Decreases meal SIZE, rate and duration of feeding

Chronic administration leads to weight loss - cessation of drug leads to weight regain

Increases feeling of satiety

Decreases gastric emptying

Catecholaminergic drug - stimulant that acts at catecholamine (NE/DA) sites

Reduces NUMBER of meals

Pro: fast weight loss

Con: high doses of fen are damaging to 5-HT axon terminals, inc. abuse potential, inc. risk for severe cardiovascular disease (primary pulmonary hypertension and valvuopathy - damage to heart valves)

Cannot be synthesized in the body. Can only get from diet.

The precursor L-Trp

Large neutral amino acids from protein degradation compete with Trp to cross the BBB

LNAA include: Leu, Ile, Val, Phe, Tyr, Met

Neurons in lateral hypothalamus are sensitive to glucose causing neurons to fire stimulating feeding behavior.

- Neurons express 5-HT1 inhibitory receptors.

PVN also has 5-HT receptors and important in feeding control.

- Refusal to maintain body weight at or above a minimally normal weight for age and height (15% or more under ideal body weight)

- Intense fear of gaining weight or becoming a fatty even though underweight

- Disturbance in teh way one's body weight or shape is experienced

- Amenorrhea: loss of menstrual cycle

Voluntary starvation: restricted vs. binge/purge type

Exercise stress

Obsessive-compulsive behaviors relations to food, food consumption, or physical activity

Role of serotonin in feeding behavior: inc. 5-HT -> dec. feeding

Gene polymorphisms: anorexics express genetic cariant for 5HT1A and 5HT2A receptor

Imaging Studies: anorexics exhibit lower binding of 5HT2A receptor in cortical areas

5-HT1A: eating, anxiety

5-HT1B: meal size

5-HT2A: feeding regulation, mood, anxiety

5-HT2C: rate of eating

The 5-HT Transporter Linking Promoter Region (5-HTTLPR):

- "L"ong allele: greater txn of 5-HT transporter

- "S"hort allele: reduced txn of 5-HT transporter, implicated in anorexia and anxiety disorders

Acute tryptophan depletion (ATD)

ATD demonstrates a reduction in anxiety that is proporionate to the decrease in Trp/LNAA ratio in anorexic patients (reward of food restriction, faulty feedback mechanisms)

Neuropeptide Y

Proopiomelanocortin (POMC) - MSHs

Agouti Related Protein (AgRP)

NPY is the most powerful appetite stimulant known.

When injected, there is inc. feeding, weight gain, inc. [plasma] of insulin and leptin

It is increased. In hypoglycemic mice - increased NPY

NPY is also increased in suckling and lactating rats

GPCR: Y1-Y6

Activation leads to an inhibition of Ca2+ influx therefore inhibiting neurons

Increased latency to feed

Decreased meal duration and size

No effect on meal number or eating rate

Has same effect in Y5 KO mice!

Couple through Gs to activate AC

MC3R and MC4R expressed in CNS - MC4R involved in feeding

Feeding is inhibited.

Inhibition of melanocortin receptors stimulates feeding.

Normally expressed with NPY neurons of the arcuate nucleus.

Functions as an endogenous inibitor of melanocortin receptors (MC1 and MC4 receptors)

Synthesized in the stomach.

Levels decrease with food intake and increase with food deprivation.

Receptors expressed in arcuate nucleus on NPY neurons

Ghrelin activates NPY neurons and induces feeding behavior. Effect can be blocked by NPY antagonists.

Synthesized in white adipose tissue.

Levels increase with food intake and decrese with food deprivation

Leptin inhibits feeding.

It is a long-term regulator of body weight and appetite.

Inhibits the NPY neurons (feeding neurons)

Rats given leptin decrease levels of NPY (mRNA and protein)

Expressed in the pancreas.

Circulates in the blood at [] proportional to body-fat mass

Inhibits feeding as a long-term regulator

Expressed in the colon.

Released into the bloodstream in relation to the caloric content of the meal.

Inhibits feeding by binding to NPY receptors.

Short-term effect (meal-to-meal mediator)

Receptors are GPCR

CCK-1 in GI tract, CCK-2 in brain, both in hypothalamus (PVN)

Inhibits feeding be acting on hypothalamus.

Also acts on pancreas and vagal nerve.

Released in response to food ingestion, particularly carbs and fats.

Receptors are expressed on vagus nerve, pancreas, and hypothalamus.

Binding of GLP-1 to receptors on vagus nerve mediates decrease  in feeding.

May also bind to receptors in the hypothalamus to inhibit feeeding in CNS

Mechanism i thought to be similar to glucose-mediated release fo insulin from pancreas.

Glucose entering the cell increases ATP prduction -> ATP causes K_ATP channels to close -> depolarization of cell -> voltage-gated Ca²⁺ channels open -> exocytosis of GLP-1

Leptin potentiates response to CCK:

- augments response at the vagus nerve

- augments CCK signals in the CNS: hypothalamic and vagal input

They can synergize to decrease feeding.

Short-term: CCK, GLP-1, PYY

Long-term: Leptin, Insulin

Pancreatic beta cells

Portal vein glucose sensor

Carotid bodies

NTS

Hypothalamus