Appetite Regulation

Presented by: Alden ParkerBS – 860: Endocrinology

3/9/2015

http://www.grubgrade.com/2009/02/23/celebrity-grubbers-homer-simpson/

Appetite Regulation Overview• Introduction/Background

– Organs/Systems• Purpose, Initiation, Regulation

– Hormones & Other Players• Synthesis Sites & Targets

– Effects• Gene Activation/Repression • 2nd Messenger Systems/Signal Transduction• Receptor modification

• Regulation, Crosstalk, Psychology and Treatment– Opposing Systems, Concerted Systems– Location Dependence– Gray Areas– Psychology/Behavior– Consequences of Dysfunction/Behavioral Excess– Treatment/Beating the system

• Case Studies

• Summary

https://robliano.files.wordpress.com/2011/12/food_for_thought1.jpg

Purpose

• Control of Food Intake to replenish depleted nutrients (i.e. glucose and FAs)

• Maintain energy homeostasis for proper function of ALL systems

• In other words, to avoid malnutrition (under OR over nutrition) and obesity

Organs

(Zheng & Berthoud, 2007)

Regulation/Modulation: “the appestat”

Appetite Initiation:

http://xernt.com/DIRECT-SALE-Direct-Sell-Sell-Tips-Duble-Priced-Method

http://guardianlv.com/2013/11/male-and-female-nose-size-related-to-oxygen-demand/

http://www.forbes.com/sites/pauljankowski/2013/02/27/quick-what-are-they-saying-about-your-brand/

http://doctorstevenpark.com/earremedies

→

Central Melanocortin System• Involved in pigmentation, appetite regulation, energy expenditure, cardiovascular function, inflammation, and

sexual function. (Gantz & Fong, 2003)

• Made up of 3 peptides (α-, β-, γ-MSH) and ACTH, 5 GPC melanocortin receptors, and endogenous melanocortin antagonists Agouti – related Protein (AgRP) and Neuropeptide Y (NPY). (Gantz & Fong, 2003)

(Greenwood et al., 2011)

Hormones – Major Players

• Leptin (↓ appetite, adipose cells CNS receptors)

• Ghrelin(↑ appetite, stomach CNS receptors)

• α-Melanocyte-Stimulating Hormone (↓ appetite, hypotalamus many downstream targets, neurons and tissues)

• Insulin (↓ appetite)

• Thyroid Hormone (↑ appetite)

Other orexigens (some major, some minor)

• Neurotransmitters– Dopamine (↑ appetite, ventral tegmenal areareleased in Pre-frontal cortex) (Schultz,

2007)– Orexin/Hypocretin (Hcrt is precursor) (↑ appetite, hypothalamusCNS)

• Hypothalamic Neuropeptides– Agouti-related Protein (AgRP, ↑ appetite, hypothalamusCNS) – Neuropeptide Y (NPY, ↑ appetite, hypothalamusCNS)– Melainin concentrating hormone (MCH, hypotalamusCNS)

• Ancillary molecules– Glutamate/GABA/Galanin/Cerebellin1(↑ appetite, hypothalamic signaling)

• Glucagon/TH/Cortisol/ACTH/GH (↑ appetite) Kim et al., 2014; Crespo et al., 2014

Other anorexigens (some major, some minor)

• Neurotransmitters– Seratonin (↓ appetite, ~90% made and stored in enterochromaffin cells in small intestine,

~10% made in Raphe Nuclei throughout whole brain) (Berger et al., 2009)

• Hypothalamic Neuropeptides– Pro-opiomelanocortin (POMC, ↓ appetite, hypothalamusCNS)

• Ancillary peptides– Cholecystokinin (CCK) (↓ appetite, duodenum/jejunumhypothalamus)– Cocaine/Amphetamine – Related Transcript (CART) (↓ appetite, widely expressed in

CNS/PNS, concentrated in hypothalamus, receptors not ID’d yet(Lin et al., 2011)) – Peptide YY (PYY) (↓ appetite, ileum/colonhypotalamus, ↑POMC/↓NPY)– Ciliary Neurotrophic Factor (CNTF) (↓ appetite, olfactory bulb?)– Glucagon-like peptides (GLP) (↓ appetite, pancreas, gut, brainstemCNS)– Vassopressin (↓ appetite, HPA BV and kidneys)

• Insulin/Amylin, Glucagon, TRH, TSH, Adiponectin(↓ appetite)

Kim et al., 2014; Crespo et al., 2014

Brain “Appetite Active” Sites

• Hypothalamus (GHSR1aNPY, AgRP, LepRbPOMCα-MSH), Pituitary

• Brainstem (POMC neurons in commisural nucleus of solitary tract, NT synthesis)

• Downstream targets expressing Melanocortin -3 or -4 receptors (i.e. target neurons throughout CNS/Cortex)

• Regulation: BBB, receptor expression, peptide production, activation/repression, etc.

Vagus Nerve• Gut hormones

– Leptin– CCK– PP– GLP-1– Ghrelin

• Adiposity Signals– Leptin

Bloodstream• Gut Hormones

– PYY– Oxyntomodulin

• Adiposity Signals – Adiponectin– Leptin

• Insulin

Transportation of Peripheral Signals to ARC

Complexity in the Brain

(Horvath & Diano, 2004)

Leptin• Greek “lepto” means thin

• Produced in WAT, 16kDa protein of 167 AA’s.

• Interacts with 6 receptors derived from alternative splicing of Ob-R gene, but anorexigenic effects only on long form of leptin receptor

http://thenaturalhistorian.com/2014/04/04/elusive-bird-leptin-finding-missing-hormone/Kim et al., 2014; Crespo et al., 2014

Leptin Regulation (long term)

Flier, 2004

CB1 – cannabinoid receptor 1MCH – melanin concentrating hormoneBDNF – brain derived neurotrophic factor

Leptin Signaling (long term)

Ahima & Antwi, 2008

PIP – Phosphatidylinositol bi/tri PhosphateSOCS3 – Suppressor of Cytokine Signaling 3JAK – Janus KinaseSTAT- Signal Transducer and Activator of T(x)IRS – Insulin Receptor SubstratePI3K - Phosphoinositide 3 - Kinase

JAK/STATPI3KMAPK

Leptin Effects

• Upon binding to LepRb neurons in arcuate nucleus: – ↑POMC mRNA, ↓NPY/AgRP mRNA

– Depolarizes (activates) POMC neurons, hyperpolarizes (deactivates) NPY/AgRP neurons

– Mediates synaptic input organization in hypothalamus (POMC upregulated, NPY/AgRP downregulated)

Kim et al., 2014; Crespo et al., 2014

Ghrelin• Growth Hormone Release-Inducing = Ghrelin

• Produced in ghrelin cells in GI (Sakata & Sakai, 2010)

• 28 aa acylated peptide, cleavage product of preproghrelinproghrelinghrelin

• Orexigenic effect through GHSR

http://www.chemblink.com/products/304853-26-7.htm

Kim et al., 2014; Crespo et al., 2014

Ghrelin Regulation (short & long term)

CCK – CholecystokininGLP1 – Glucagon-like peptide 1PYY – Peptide YY

http://www.nutridesk.com.au/stomach-intestine-ghrelin-cck-glp-1-gut-hormones.phtml

Primarily regulated by feeding

(Crespo et al., 2014)

Ghrelin Signaling (short & long term)

(St. Pierre et al., 2003)

Ghrelin Effects

• Upon binding to GHSR neurons in arcuate nucleus: – ↓ POMC mRNA, ↑NPY/AgRP mRNA, ↑electrical activity in

NPY/AgRP neurons

– Activates NPY/AgRP neurons

– Activates prolyl carboxypeptidase (enzyme for α-MSH degradation), inhibits MC4 activation

– Mediates synaptic input organization in hypothalamus (POMC upregulated, NPY/AgRP downregulated)

Kim et al., 2014; Crespo et al., 2014

α – Melanocyte Stimulating Hormone

• Acetylated, 13aa peptide produced in POMC neurons of the hypothalamus from cleavage of POMC

POMCACTHα - MSH

• Anorexigenic effect mediated via MC3 and MC4 receptors

http://www.chemblink.com/products/75921-69-6.htm

NPY/AgRP + α – MSH Signaling/Effects

(Cyr et al., 2013)

Insulin• Insulin signaling in AgRP neurons = ↓ hepatic glucose production

• Insulin signaling in POMC neurons = ↑ hepatic glucose production and energy expenditure (Lin et al., 2010)

• Insulin & Leptin signaling have opposing effect on POMC for body weight regulation, but concerted effect on glucose homeostasis

• Thus IR and LepRb may be differentially expressed in POMC neurons Insulin and Leptin activate separate subsets of POMC neurons (Williams et al., 2010)

• Amylin – co-released, decreases appetite by slowing gastric emptying (Crespo et al., 2014)

Thyroid Hormone

• T3 in hypothalamus↑UCP2 ↑NPY/AgRP mRNA, ↓POMC mRNA ↑ appetite

• fasting-induced suppression of TRH(↓appetite) mRNA in PVN

(Kim et al., 2014)

Others • Adrenals

– Cortisol/ACTH - ↑appetite, regulates POMC production (Kim et al., 2014) (Cushing’s obese, Addison’s thin)

• Gut – PYY, CCK, GLP-1, PP - ↓appetite, released as stomach stretches

and glucose levels rise. Takes some time (eat slowly, small plates, etc.). Downregulated as stomach shrinks and glucose levels fall

• CNS – Orexin (Hcrt) - ↑appetite, neurotransmitter inhibited by Leptin,

activated by Ghrelin– Oxyntomodulin - ↓ appetite, reduces neuronal activity in ARC

Crespo et al., 2014

Concerted Sytsems vs. Opposing Systems

Concerted• Ghrelin, AgRP/NPY, TH,

cortisol, glucagon• Leptin/POMCα-MSH• Leptin/Insulin• Leptin/gut hormones

Opposing• Leptin+gut

hormones+insulin vs. Ghrelin, etc.

• POMC vs. AgRP+NPY

Regulation – Location & Temporal dependence• Leptin must make it into the brain to exert its effect because Hepatocyte-specific

leptin-deficient mice have a normal phenotype (Cohen et al., 2001; De Luca et al., 2005)

• bIR deficient mice are obese, but bIR specific to arcuate melanocortin neurons have no alteration in energy homeostasis and only a dysfunction in hepatic glucose suppression (Konner et al., 2007)

• Central POMC’s role is not replaced by peripheral POMC (Kim et al., 2014)

• POMC KO in pre-natal early onset obesity+hyperphagia, POMC KO post-natal decreased energy expenditure, but no hyperphagia (Kim et al., 2014).

• “Different receptor expression in different tissues for different effects”

Gray Areas• Insulin & Leptin signaling have opposing effect on POMC for body weight regulation, but

concerted effect on glucose homeostasis (Williams et al., 2010)

• Leptin inhibits AgRP synthesis while Insulin stimulates it (Crespo et al., 2014)

• Evidence for both insulin and glucagon to be appetite inhibitors (Kim et al., 2014; Parker et al., 2013)

• Peripheral administration does not equal Central administration (likely due to BBB)

• TRH and TSH decrease appetite, TH increases it (Amin et al., 2011)

• Foods that smell/look bad but taste good and vice versa

• Cravings for particular foods (pregnancy)

• Food “addiction”

Psychology: Thought for Food?

https://pmg503.wordpress.com/tag/psychology/

http://www.marathontalk.com/boyontherun/tag/donkey/

Dysfunction

• Hyperphagia/ overnutrition– Obesity– Overweight– Hypertension– Hyperglycemia– Mineral imbalance

↘

• Hypophagia/ undernutrition– Emaciated– Underweight– Hypotension– Hypoglycemia– Mineral imbalance

↙

Organ/Systems FailureHealth Problems DEATH

Treatment• Caloric limitation (diet) + increase in energy expenditure (exercise)

• Ghrelin receptor antagonists to block orexigenic signals from the gut to the brain or ghrelin receptor inverse agonists that would block constitutive activity of the ghrelin receptor, thereby increasing the response to inhibitory signals to block “between-meals" food intake (Holst & Schwartz, 2004)

• Bombesin Treatment (SNS activation, Crespo et al., 2014)

• Drugs– Metreleptin – Leptin analog (Chou & Perry, 2013)– Orlistat (aka Alli GSK) – lipase inhibitor reduces fat breakdown and caloric absorption (O’Meara et

al., 2004)– Rimonabant (Acomplia) – CB1 receptor antagonist, may increase thermogenesis and energy

expenditure (Akbas et al., 2009)– Many many others

• Gastric Balloon/Bypass in severe cases of obesity

Treatment

http://www.bmb.leeds.ac.uk/illingworth/metabol/2120lec4.htm

Case Studies – Ghrelin KO

Wortley et al., 2005

Taste Discrimination in drosophila

Masek & Scott, 2010

Leptin Deficiency (ob/ob)

Leibel RL, 2008

Leptin and Mood

Yamanada et al., 2011

High fiber, more soup, fruits, and veggies more satiety “Volumetric Diet” (Barbara Rolls, Ph.D Penn State)

http://howtostoyno.altervista.org/volumetrics-diet-plan/

Volumetric Diet

Flood-Obaggy & Rolls, 2009

Prader-Willi syndrome• Elevated plasma Ghrelin

• Low muscle tone, short stature, incomplete sexual development, cognitive disabilities, problem behaviors, and a chronic feeling of hunger that can lead to excessive eating and life-threatening obesity (Cassidy et al., 2011)

VAS = “how much could you eat now?” visual analog score

(Purtell et al., 2011)

Effect of Adequate Rest

→

Morselli et al., 2011

Flaw in circadian rhythm of obese people?

(Yildiz et al., 2004)

Summary of Hunger Regulators

(Austin & Marks, 2009)

Summary of Satiety Regulators

(Austin & Marks, 2009)

Summary of Peripheral Signaling

Stanley et al., 2005

Summary of Peripheral Signaling

(Zheng & Berthoud, 2007)

CNS Integration Site – ARC Summary

Stanley et al., 2005

CNS summary

(Zheng & Berthoud, 2007)

Summary of Melanocortin system• Peripheral signals (hormones, glucose, lipids, peptides, and AA’s) act on

the melanocortin system in the CNS, where there are intra and extracellular mechanisms that create changes in peptide and receptor expression levels

– Change synaptic output/organization

– Change intracellular organelle organization/function

– Dysfunction can cause serious systems issues leading to significant health problems and even death

– GeneticChemical basis for dysfunction, but functional system can be over-ridden by psychological inputs (mood, emotional state, sensory input, memory, etc.)

Kim et al., 2014

Questions?

http://diningout101.com/blog/page/3/

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