Lecture 7

Neuropeptide Y

36 AA peptide with homologies to PYY (PP-fold family) binds to Y receptors (GPCRs) in the brain Expression in the ARC is stimulated by fasting and suppressed by high-fat feeding Hypothalamic injection of NPY stimulates food intake and long-term infusion leads to obesity NPY KO mice have only subtle phenotype- knock out NP Y mice dont stop eating --- All of signaling is mediated through small peptide hormones. (don't concern cell too much with Y receptors) Longer fast stronger the apeptite signal is because making more orexigenic signals. High fats decrease hunger. Can inject it into your blood stream but nothing would happen due to blood brain barrier and receptor is behind the blood brain barrier

Leptin

Leptin is the product of the ob gene. (dp gene=receptor for leptin gene. Ob gene-leptin) ob/ob and db/db mice lack leptin or the leptin receptor respectively and are hyperphagic, hyperinsulinemic, and obese. Obese humans are leptin resistant. Leptin excerpts its anorectic effect in the ARC by down-regulating NPY, MCH, orexin, and AgRP while up-regulating α- MSH and CART. During periods of energy equilibrium leptin levels reflect adipose mass. During periods of negative or positive energy balance rapid changes in leptin levels trigger corrections in feeding behavior and energy expenditure Leptin release is regulated by a nutrient sensing mechanisms that are incompletely understood. Activation of mTOR can increase leptin expression. Increased glucose and fatty acid uptake lead to enhanced product of the hexosamine pathway endproduct, UDP-GlcNAc, leading to increased glycosylation of proteins, including transcription factors such as SP1, resulting ultimately in increased leptin expression. --- How do adipocytes know how full they are? What releases leptin? We are unsure but one reason would be mTOR. Another would be the pathway on next slide producing UDPGlcNAc described below Precursors for covalent modification of proteins. More of this gives more glycoslyated. Only have increased levels of this if increased lipids and glucose. The principle endproduct of this pathway, uridinediphosphoglucose-n-acetylglucosamine (UDP-GlcNAc) serves as substrate for virtually all glycosilation pathways.

Signal integration by hypothalamic AMPK

Many central and peripheral signals including leptin and ghrelin, converge on AMPK in the hypothalamus. Orexigenic signals increase AMPK activity while anorexic signals inhibit. -- If your AMPK is activated bc body nutrients are low then will be hungry. If say energy stores are full then turn off AMPK and suppress feeding behavior.

Central Orexigenic signals

Neuropeptide Y Agouti-related protein Orexins "reward system" for palatable food

Pancreatic Peptides- Glucagon

Released by the α-cells of the pancreatic islets Glucagon stimulates adenylcyclase in hepatocytes activating glycogenolysis, gluconeogenesis, and ketogenesis Also insulin but already discussed not on this slide. Also somatostatin and pancreatic polypeptide but want go into these

"Reward System"

Rewarding nature of palatable food stimulates feeding. Components of the reward circuity include opioids, the dopaminergic system, endocannabinoids, and serotonin. Exogenous cannabinoids lead to robust increase in food intake and weight gain while endocanabinoid receptor antagonists (Rimonabant) are sold as anti- obesity drugs. -- Tasty food elicits a response in the reward center in our brain that has to do with signals of endocannabinoids. Munchies have to do with reward system engaged that makes you want to eat more. Signaling throughout different brain areas not only hypothalamus. Rimanobant is anti-munchy to block endocannabinoids but it also created depression.

Melanocortins (POMC)

Several bioactive peptides derived from one precursor molecule, pro- opiomelanocortin (POMC). POMC is expressed by many tissues but the specific products vary depending on the endoproteases (convertases). In the ARC prohormone convertase 2 generates α-melanocyte stimulating hormone (α-MSH). Rare mutations in POMC that abrogate α-MSH expression lead to severe obesity (and red hair). α-MSH signals anorectic behavior through the melanocortin-4 receptor. Note, AgRP acts through MC4 receptors too

Energy homeostasis signals organ

Short- and Long-term Energy Homeostasis Signals from the periphery are integrated by the Brain Stem and Hypothalamus A particularly important Nucleus within the Hypothalamus is called the Arcuate Nucleus (ARC)

Orexins

Two homologous peptides A and B derived from the same 130 AA precursor expressed by dorsal and lateral hypothalamic neurons. Disruption of Orexin or Orexin receptor genes causes Narcolepsy Orexins delay the onset of normal satiety. Expression is increased in response to severe fasting and hypoglycemia. ----- Orexins determine when u feel full after a meal. determines how much food u eat at a meal. Dogs falling asleep video bc Orexin receptor mutation

Ghrelin

28 AA peptide hormone with a unique octanoyl modification and acts on ghrelin receptors (growth hormone secretagogue receptor) on AgRP/NPY neurons in the ARC. Released by the (empty) stomach into the circulation and has a potent stimulus to feeding (a.k.a."hunger hormone"). Levels peak just before meal then drop rapidly. Immunization against Ghrelin prevents weight gain in rats. Lack of sleep increases Ghrelin. --- Released by stomach in response to being distended or not distended. If not distended will be hungry. Ghrelin is suppressed during the night.

Agouti-related Peptide (AgRP)

AgRP is a 132 AA peptide that acts as an inverse agonist (decreases G alpha binding and signaling upon binding) for MC4 receptors Co-expressed by NPY neurons in the ARC Hypothalamic injection of AgRP stimulates food intake and long- term infusion leads to obesity. Loss of MC4 receptors leads to obesity in humans and mice. AgRP is related to the Agouti coat color gene in mice.Agouti normally binds to MC1 receptors in the skin but a mutation in the Agouti (Ay) mice leads to ectopic expression leading to yellow coat color and obesity --- Stimulates feeding behavior. Short peptide. Signals through a receptor that is upstream on neurons called MC4 (GPCR) if you infuse brains with AgRP then leads to obesity. MC4 also changes the fur color white to brown

Cocaine and Amphetamine regulated transcript (CART)

Identified as mRNA that is greatly increased following cocaine or amphetamine administration in rats. CART peptides are widely distributed in the CNS and are involved in regulating many processes, including food intake and the maintenance of body weight, reward and endocrine functions Expressed by ARC neurons (and others). Expression is decreased by fasting. CART administration profoundly reduces (re-)feeding and blocks NPY signaling while CART-Ab injections stimulate feeding. CART peptides are also found outside the CNS and have been suggested to regulate islet cell function in the pancreas. CART mutations in humans have been linked to obesity, depression, and alcoholism. While CART peptide injections decrease addictive behavior. --- Discovered when people looked cocaine or amphetamine in rats. CART made in neurons and is involved in the anorectic signal. Signals to upstream neurons and supresses feeding behavior. Blocks signal that is generated by NPY

AMPK and cellular energy status

In general, activation of AMPK switches on alternate catabolic pathways that generate ATP while switching off ATP consuming processes, especially anabolic pathways. AMPK achieves these effects through rapid direct phosphorylation of metabolic enzymes and through regulation of gene and protein expression.

Glucagon-like Peptide (GLP)

Peptides (GLP1 & 2) derived from proglucagon in intestinal L-cells and released in response to intestinal carbohydrate sensing. Intestinal and lingual carbohydrate sensing share similarities. Acts via GLP1 receptors in the hypothalamus. Strongly stimulates insulin release and inhibits appetite and food intake. -- Taste receptors tongue. Sweet receptor on intestine too Receptor expressed on endocrine cells in intestine signals peptide to body saying carbohydrates are in the intestine. The peptide is GLP1 and can act on the brain and periphery once released. In brain ir suppresses appetite. If too much GLP1 will feel nauseous and throw up GLP1 antiobesity treatment or an insulin sensitive

Central Anorectic Signals

Signaling that surpesses feeding behavior Cocaine and Amphetamine regulated Transcript (CART) Melanocortins (POMC) Others (such as glucagon-like peptides, corticotropin releasing factor, serotonin, etc.)

melanocortin (MC4) receptor

TWO OPPOSING SIGNALS, ONE RECEPTOR? Melanocortin receptors are G-protein coupled receptors. Unlike other GPCRs a significant percentage of the MC-4R population is constitutively active. α-MSH binds to MC-4R and stabilizes the active conformation -> agonist. AgRP binds to MC-4R and disrupts the active conformation -> inverse agonist. Loss of MC4 receptors leads to obesity in humans and mice while Mutations in the human POMC gene are associated with early onset obesity, adrenal insufficiencies, and red hair.

Feeding control- GI system

The GI track produces many hormones involved in energy homeostasis including: Ghrelin * Cholecystokinin Peptide YY Glucagon-like peptide * Oxyntomodulin Pancreatic polypeptide

Feeding control- peripheral signals

The Hypothalamus receives both orexigenic and anorexic signals from peripheral organs including: Stomach Pancreas Intenstine Adipose tissue

Arcuate Nucleus neurons important for feeding control

Two sets of neurons in the Arcuate Nucleus: AgRP/NPY (When activated, food intake behavior is elevated. Making you feel hungry- Orexigenic) POMC/CART (POMC opposing affect than AgRP. Food intake goes down- anorectic) Stimulating agouti-related protein (AgRP)/neuropeptide Y (NPY) neurons has orexigenic effects while proopiomelanocortin (POMC)/ cocaine- and amphetamine- regulated transcript (CART) neurons are anorectic Both are regulated by circulating hormones.

Adipokines

White adipose tissue is an endocrine organ that secretes many bioactive factors (a.k.a. adipokines) including leptin (leptos, Greek = thin). -- Adipocytes can secrete hormones. Is an endocrine tissue, can have insulin sensitive properties. Leptin is the principle hormone that mediates long term body weight homeostasis. Signaling molecule that tries to maintain your overall body weight over time.