Hormones and Neurons

Hormones and Neurons Appetite Regulation and Weight Control The Story of Leptin, Ghrelin, and PYY and the Treatment of Obesity Michael A. Bush, M.D. CA-AACE Annual Meeting Symposium May 5, 2017 1

phat 1. (adj) Cool; very good; very attractive. Man, she is phat. [Georgia Tech, Atlanta, GA, 1998; North Carolina Central University, Durham, NC, 1998; Clark Atlanta University, Atlanta, GA; Jefferson County, MO] 2. (adj) Pretty hot and tempting. Your girl is phat! [Central Oregon Community College, Bend, OR, 1998; University of Nebraska, Lincoln, Georgia Tech, Atlanta, GA] 2

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HORMONES, THE BRAIN, AND EATING (1) The Brain: Neurons and Eating Behavior (2) Leptin: History and Significance (3) Ghrelin: Gastro-Endo-Neuro-Biology (4) PYY: Making it Work? 4

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RODENT OBESITY MODELS ob/ob mouse Zucker fatty rat db/db mouse 6

PARABIOSIS EXPERIMENTS X Coleman, D.L. & Hummel, K.P. Am. J. Physiol. 217, 1298 1304 (1969) 7

PARABIOSIS EXPERIMENTS ob Mouse lacks something present in normal & db mice (and can respond to it!) Coleman, D.L. & Hummel, K.P. Am. J. Physiol. 217, 1298 1304 (1969) 8

PARABIOSIS EXPERIMENTS db Mouse has something that affects other mice (but can t respond to it!) Coleman, D.L. & Hummel, K.P. Am. J. Physiol. 217, 1298 1304 (1969) 9

OB PROTEIN Detection in Mouse and Human Plasma Mouse Human Leptin: from leptos, meaning thin 16 kd protein (gr.) Halaas J: Science (1995), 269: 543-546 10

EFFECT OF OB PROTEIN ON MOUSE FOOD INTAKE AND BODY WEIGHT LEPTIN DEFICIENT LEPTIN RESISTANT Halaas J: Science (1995), 269: 543-546 11

SERUM LEPTIN AND BODY FAT IN LEAN AND OBESE HUMAN SUBJECTS We are not obese, but dbese! Considine R: N Engl J Med (1996), 334: 292-295 12

CONGENITAL LEPTIN DEFICIENCY The Human OB Mouse The subjects are two children (Ob1 and Ob2) Cousins within a highly consanguineous family of Pakistani origin. FAMILY Siblings: normal weight Parents: not morbidly obese. WEIGHT normal at birth severe, intractable obesity from an early age. no additional clinical features to suggest a genetic syndrome associated with obesity, such as Alstrom's or Prader-Willi. Montague C: Nature (1997), 387: 903-908 13

CONGENITAL LEPTIN DEFICIENCY Montague C: Nature (1997), 387: 903-908 14

CONGENITAL LEPTIN DEFICIENCY HOMOZYGOUS FRAME-SHIFT MUTATION LOSS OF A SINGLE NUCLEOTIDE AT CODON 133 ON CHROMOSOME 6 Montague C: Nature (1997), 387: 903-908 15

CONGENITAL LEPTIN DEFICIENCY HOMOZYGOUS FRAME-SHIFT MUTATION LOSS OF A SINGLE NUCLEOTIDE AT CODON 133 ON CHROMOSOME 6 Montague C: Nature (1997), 387: 903-908 16

YOUR BRAIN 17

HYPOTHALAMUS Open to the Blood-Brain Barrier 18

ARCUATE NUCLEUS CONTROL OF EATING BEHAVIOR + - POMC/ CART 19

BRAIN NEUROPEPTIDES INVOLVED IN APPETITE REGULATION STIMULATE FEEDING BEHAVIOR Neuropeptide Y + Adrian TE. et al Neuropeptide Y distribution in human brain. Nature (1983). 306: 584-6 ARCUATE NUCLEUS 20

Polymorphisms in the Neuropeptide Y Gene and the Risk of Obesity Data from the Nurses Health Study JCEM (2011). 96: E2055-62

BRAIN NEUROPEPTIDES INVOLVED IN APPETITE REGULATION Pro-Opio-Melano-Cortin (POMC) INHIBIT FEEDING BEHAVIOR Mutations that disrupt POMC present with cortisol deficiency Red or light colored hair lack of skin pigmentation severe obesity in early life - Nature Genetics 19, 155-157 (1998) 22

MSH RECEPTORS Importance in Eating Behavior Melanocortin Receptor (MC4R) [activation inhibits eating behavior] POMC 23

9 y.o. BOY WITH MC4R MUTANT GENE AND HIS 16 y.o. BROTHER Farooqi: N Engl J Med (2003), 348: 1085-1095 24

MUTATIONS IN MELANOCORTON 4 RECEPTOR GENE ASSOCIATED WITH SEVERE CHILDHOOD OBESITY 5.8 percent of subjects with severe obesity commencing in childhood had pathogenic mutations in MC4R Farooqi: N Engl J Med (2003), 348: 1085-1095 25

MUTATIONS IN THE MC4R RECEPTOR IS ASSOCIATED WITH BINGE EATING 5.1 % of adults with BMI > 35 have MC4R mutations Oral MC4 Receptor Antagonists Stimulate Food Intake and Reduce Cancer-Induced Cachexia in Mice http://dx.doi.org/10.1371/journal.pon 100% of obese subjects with MC4R mutations meet criteria for binge eating a variant in the human MC4R 14.2 % of obese subjects without mutation e.0004774 0 : % March (I215 L) locus that enhances basal of normal-weight 19, 2009 subjects without mutation activity of the receptor is associated with improved outcomes after RYGB. Gastroenterology 2013;144:580 90 Poor Candidate for Gastric Surgery? Branson R et al. N Engl J Med (2003). 348;1096-1103

Additional Neurotransmitters Involved in Appetite Regulation Agouti-Related Peptide blocks MSH binding to MC4 Receptor X POMC/ CART 27

Additional Neurotransmitters Involved in Appetite Regulation Stimulates MC4R POMC/ CART Cocaine- Amphetamine Regulated Transcript 28

POMC/ CART 29

LEPTIN RECEPTORS IN THE ARCUATE NUCLEUS LEPTIN RECEPTORS NEUROPEPTIDE Y POMC 30

CONCEPTS OF LEPTIN ACTION NPY, AgRP STIMULATE EATING LEPTIN INHIBITS NPY, AgRP AND INHIBITS EATING MSH, CART INHIBIT EATING LEPTIN STIMULATES MSH, CART AND INHIBITS EATING 31

CONGENITAL LEPTIN DEFICIENCY Can we treat it with Leptin? Farooqi I: N Engl J Med (1999), 341: 879-884 Farooqi Clinical Endocrinology (2015) 82, 23 28 32

Boy with Biologically Inactive Leptin Treated with Metreleptin [(Amino)-Methionine Leptin] Wabitsch M et al. N Engl J Med 2015;372:48-54

WILD-TYPE HUMAN OBESITY Can we treat it with Leptin? Heymsfield S: JAMA (1999), 282: 1568-1575 37

Amylin Restores Sensitivity to Leptin Combined Therapy for Obesity Takeda, Amylin discontinue pramlintide/metreleptin development program for obesity Neutralizing Antibodies Published on August 5, 2011 at 5:57 AM Roth JD et al. Proc Natl Acad Sci U S A. 2008 ; 105: 7257 7262. 38

POMC/ CART 39

SEARCH FOR NATURAL MOLECULES THAT BIND TO THE GH SECRETAGOGUE RECEPTOR We designate the GH-releasing peptide 'ghrelin' (because) ghre is the Proto-Indo-European root of the word 'grow'. Kojima M: Nature (1999), 402: 656-660 40

SPECIFICITY OF GHRELIN EFFECT Pituitary Cells IV in Rats Kojima M: Nature (1999), 402: 656-660 41

GHRELIN AND EATING BEHAVIOR 42

GHRELIN RISES PRE-MEAL AND FALLS AFTER EATING IS GHRELIN THE SIGNAL TO EAT? Cummings D: Diabetes (2001), 50: 1714-1719 43

WHERE DOES GHRELIN WORK IN THE BRAIN? CNS INJECTION OF GHRELIN Wren A: Diabetes (2001), 50: 2540-2547 44

GHRELIN IS PHYSIOLOGIC CNS ANTI-GHRELIN REDUCES FOOD INTAKE Nakazato M: Nature (2001), 409: 194-198 45

CONCEPTS OF GHRELIN ACTION NPY, AgRP STIMULATE EATING MSH, CART INHIBIT EATING GHRELIN STIMULATES NPY, AgRP AND STIMULATES EATING 47

Is Excess Ghrelin Responsible for Excess Eating in Obese Subjects? 48

GHRELIN LEVELS ARE DECREASED IN OBESE SUBJECTS NORMAL WEIGHT BMI 27 OBESE BMI 48 APPROPRIATELY! Cummings D: N Eng J Med (2002), 346: 1623-1630 49

GHRELIN AND DIET-INDUCED WEIGHT LOSS (17% OF INITIAL BW LOST) AFTER WEIGHT LOSS BEFORE WEIGHT LOSS APPROPRIATELY! Cummings D: N Eng J Med (2002), 346: 1623-1630 50

GHRELIN LEVELS ARE INCREASED IN ANOREXIA NERVOSA APPROPRIATELY! Shiiya: J Clin Endocrinol Metab (2002), 87: 240-244 51

BUT GHRELIN IS INCREASED IN PRADER-WILLI SYNDROME! NOT APPROPRIATE! IS IT CAUSATIVE? Cummings: Nature Medicine (2002); 8: 643-644 52

CHANGE IN GHRELIN LEVELS AFTER GASTRIC BYPASS SURGERY Cummings: J Clin Endocrinol Metab (2004), 89: 2608-2615 54

CHANGE IN GHRELIN LEVELS AFTER GASTRIC BYPASS SURGERY PROSPECTIVE STUDIES HAVE REPORTED: ABNORMALLY LOW LEVELS 3 studies DECREASE IN LEVELS 5 studies NO CHANGE 4 studies INCREASE IN LEVELS 2 studies Cummings: J Clin Endocrinol Metab (2004), 89: 2608-2615 55

Can Ghrelin be Used Therapeutically? Not for OBESITY, of course! 56

Oral Ghrelin Mimetic (MK-677) in Elderly Subjects Effects After 12 Months Fat-free Mass Nass R et al. Annals Int Med (2008), 149:602

I.V. GHRELIN EFFECTS IN PATIENTS WITH METASTATIC CANCER AND LOSS OF APPETITE 3hrs after standard breakfast 1.5 hrs after starting ghrelin infusion Food Intake at a Lunch Buffet Neary: J Clin Endocrinol Metab (2004), 89: 2832-2836 58

PYY is released from the L CELLS in the distal intestine ALONG WITH GLP-1 It is secreted as PYY 1-36, and is then cleaved by the enzyme DPP-4 to give the active form, PYY 3-36 The function is inhibitory, (so-called) jejunal, ileal and colonic brakes Related to Pancreatic Polypeptide from islet PP Cells POMC/ CART Peptides (2002). 23: 403-7 Ther Adv Chronic Dis (2014) 5(1): 4 14. Adrian TE, Ferri GL, Bacarese-Hamilton AJ, Fuessl HS, Polak JM, Bloom SR. Human distribution and release of a putative new gut hormone, peptide YY. Gastroenterology 1985;89:1070-7. 61

CONCEPTS OF PYY ACTION NPY STIMULATES EATING PYY INHIBITS NPY AND INHIBITS EATING MSH INHIBITS EATING PYY STIMULATES MSH AND INHIBITS EATING 62

PYY LEVELS IN HUMAN SUBJECTS OBESE SUBJECTS ARE DEFICIENT in PYY! Really OBESE Batterham R: N Engl J Med (2003), 349: 941-948 64

PYY LEVELS IN HUMAN SUBJECTS RISES AFTER EATING (BUT LESS IN OBESE SUBJECTS) Saline Saline IS THIS A SATIETY SIGNAL? Batterham R: N Engl J Med (2003), 349: 941-948 65

OBESE & NORMAL WEIGHT SUBJECTS Decreased intake at buffet 2 hours after PYY infusion AT BUFFET LUNCH 2 HOURS AFTER PYY Batterham R: N Engl J Med (2003), 349: 941-948 66

STUDIES WITH PPY: Rodents & Humans Nasal route in humans Buccal spray in mice Genetic manipulation to upregulate PYY expression in the salivary glands in mice Oral administration conjugated to vitamin B 12 in rats Oral PYY with a lipophilic complex to facilitate transport in the GI tract Results variable, nausea an important side effect 67

PYY COMBINED WITH Amylin and PYY Roth JD. Endocrinology (2007), 148(12):6054 6061 Oxyntomodulin and PYY Diabetes (2010) 59:1635 1639

with GLP-1 The overall key to achieving successful PYY therapy will lie in delivering stable levels for extended periods of time to avoid sharp peaks and subsequent development of nausea. Neary NM, et al. Endocrinology 2005; 146: 5120 7 69

Bloomberg April 6, 2011 Novo Nordisk filed a patent application for analogues of the hormone PYY Novo Nordisk is using experience in creating synthetic hormones, gained from work on insulin and GLP-1. Chief Science Officer Mads Krogsgaard Thomsen said in a phone interview, we tend to believe we should play around with Mother Nature s own appetite modulators. 70

CAN WE TREAT OBESITY WITH THIS INFORMATION? OBESE PEOPLE ARE:. OBESITY COULD BE TREATED WITH: RESISTANT TO LEPTIN... APPROPRIATELY LOW IN GHRELIN. DEFICIENT IN PYY LEPTIN? MODIFIED LEPTIN WITH PRAMLINTIDE? GHRELIN ANTAGONIST? UNCERTAIN ROLE NOX-B11? PYY? COMBINATION TREATMENT? SHORT TERM Rx SUGGESTS REAL BENEFIT 71

Obesity Drugs Mechanisms of Action Kim et al., Clin. Pharm. Ther 2013

THE BAYLISS-STARLING PRIZE LECTURE Can Gut Hormones Cure a Worldwide Pandemic? Gut hormones have provided a focus in obesity research for more than 40 years it is now possible to reliably make a fat mouse thin. However, at present, ( in humans) there is no simple solution Scott RV, Tan TM & Bloom SR J Physiol (2014) pp 1 14 73

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