Weight Regulation after Bariatric Surgery New Jersey Chapter of the American Association of Clinical Endocrinologists 11 th Annual Meeting October 6, 2018 Judith Korner, MD, PhD Professor of Medicine Director, Weight Control Center Columbia University Medical Center
Disclosures Research Support: NIH, Covidien/Medtronic Scientific Advisory Board/ Stock Options: Digma Medical
Objectives 1. Describe the gut hormone responses to dietinduced weight loss 2. Describe the gut hormone responses to bariatric surgery 3. Describe changes in hypothalamic hormones that regulate appetite after weight loss
Pulmonary disease abnormal function obstructive sleep apnea hypoventilation syndrome Nonalcoholic fatty liver disease steatosis steatohepatitis cirrhosis Gall bladder disease Medical Complications of Obesity Gynecologic abnormalities abnormal menses infertility polycystic ovarian syndrome Idiopathic intracranial hypertension; neurocognitive impairment Stroke Cataracts Coronary heart disease Diabetes Dyslipidemia Hypertension GERD Severe pancreatitis Cancer breast, uterus, cervix colon, esophagus, pancreas kidney, prostate Osteoarthritis Skin Gout Phlebitis venous stasis
Prevalence of Self-Reported Obesity Among U.S. Adults by State and Territory, BRFSS, 2011
Prevalence of Self-Reported Obesity Among U.S. Adults by State and Territory, BRFSS, 2012 Prevalence estimates reflect BRFSS methodological changes started in 2011. These estimates should not be compared to prevalence estimates before 2011.
Prevalence of Self-Reported Obesity Among U.S. Adults by State and Territory, BRFSS, 2013
Prevalence of Self-Reported Obesity Among U.S. Adults by State and Territory, BRFSS, 2014
Prevalence of Self-Reported Obesity Among U.S. Adults by State and Territory, BRFSS, 2015
Prevalence of Self-Reported Obesity Among U.S. Adults by State and Territory, BRFSS, 2016
Prevalence of Self-Reported Obesity Among U.S. Adults by State and Territory, BRFSS, 2017
Prevalence of Self-Reported Obesity Among Non-Hispanic Black Adults, by State and Territory, BRFSS, 2015-2017
Long-Term Weight Loss: Non-Pharmacologic Treatment VLCD: 800 kcal/day BMOD: behavior + 1200kcal/day Combined: VLCD + behavior Wadden Annals of Int Med 119:688 1993
Neurohormonal Changes Associated with Weight Loss Korner & Aronne, J Clin Invest 111:565-570 (2003)
Leptin Deficient (ob/ob) Mouse Phenotype: hyperphagia, obesity, decreased energy expenditure, body temperature and immune function, infertility, hyperglycemia/diabetes, hypercortisolemia
MC4R Deficiency 9 yo boy MC4R -/- 16 yo brother MC4R +/+ Farooqi et al NEJM 348 2003
Lorcaserin (Belviq)- Mechanism of Action Sargent B and Henderson A. Current Opinion in Pharmacology. February 2011, 11(1): 52 58 5-HT 1B: pulmonary HTN; 5-HT 2B: pulmonary HTN and cardiac valvulopathy
Sjostrom, J Intern Med 2013; 273:219 234 adapted from JAMA. 2012;307(1):56-65
Adjustable Gastric Band < Vertical Sleeve Gastrectomy < Roux-en-Y Gastric Bypass
Mechanisms of Weight Loss After Bariatric Surgery Gastric Restriction: limits the amount of food consumed at one sitting. However, if this were the only mechanism constraining food intake, patients would be predicted to increase the frequency and caloric density of their meals. Dumping: encompasses nausea, flushing, bloating, faintness, fatigue, and diarrhea triggered by consumption of foods high in sugar and may cause patients to severely limit the intake of sweets. However, the severity of dumping does not correlate well with the amount of weight loss. Malabsorption: clinically significant malabsorption of macronutrients does not occur. Neurohormonal?
Gut Hormones Hunger Satiety Meal Size Meal Frequency Insulin sensitivity Insulin Secretion Nature 444, 854-859(14 December 2006)
Are there hormonal changes that may account for differences in weight loss between bariatric procedures? Adult men and women scheduled to undergo either laparoscopic adjustable gastric banding (LAGB) or Roux-en-Y gastric bypass surgery (RYGB) were recruited A liquid meal challenge (320 kcal: 50% CHO; 35% protein; 15% fat) for hormone analysis was performed prior to surgery and at 6 months afterwards, followed by annual visits J Korner - unpublished
Subject Characteristics Band Bypass N (F/M) 18 (13/5) 38 (31/7) Age (y) 47 ± 2 44 ± 2 Weight (kg) 119.9 ± 1.3 125.6 ± 0.9 BMI (kg/m 2 ) 41.8 ± 0.9 47.2 ± 0.7*
BMI (kg/m 2 ) Wt change (%) BMI and Weight Change 50 45 LAGB RYGB 0-5 -10 40 35-15 -20-25 30-30 -35 0 1 2 3 4 Year -40 0 1 2 3 4 Year Y0 Y1 Y2 Y3 Y4 LAGB 18 18 10 (56%) - - RYGB 38 37 25 (82%) 20 (71%) 16 (66%)
GHRELIN - a hunger hormone Ghrelin is produced mainly in the stomach Ghrelin enhances appetite and food intake, and decreases insulin sensitivity Plasma levels of ghrelin are suppressed after a meal Plasma levels of ghrelin increase after diet-induced wt loss Increases levels of counterregulatory hormones: GH, cortisol and epinephrine
Ghrelin Enhances Appetite and Increases Food Intake Wren et al, JCEM 86:5992, 2001
Circulating Ghrelin Levels Are Decreased in Human Obesity (a physiological adaptation to positive energy balance) Tschöp at al, Diabetes, 50:707, 2001
Plasma Ghrelin is Elevated in Prader-Willi syndrome Cummings et al, Nat Med 8:643-644 2002
Plasma Ghrelin Levels Decrease After a Meal And Increase After Diet-Induced Weight Loss Cummings et al, NEJM 346:1623, 2002
Ghrelin (pg/ml) Ghrelin (pg/ml) Ghrelin LAGB RYGB 550 550 500 500 450 450 400 350 15.4% 400 350 30.5% 300 300 250 250 200 0 30 60 90 120 Min 200 0 30 60 90 120 Min
Ghrelin AUC (x 10 3 ) Ghrelin (pg/ml) Ghrelin (pg/ml) LAGB Ghrelin RYGB 550 550 500 500 450 400 15.4% 450 400 29.6% 350 350 300 300 250 250 200 0 30 60 90 120 Min 200 0 30 60 90 120 Min 80 * * * * * 60 40 20 0 LAGB RYGB
Ghrelin Suppression (%) Ghrelin - % Postprandial Suppression 35 30 25 20 15 10 5 * * * 0 LAGB RYGB
Peptide YY (PYY) - a satiety hormone PYY is produced in the ileum and colon and is secreted postprandially in proportion to the calorie content of a meal Cleavage of PYY(1-36) produces PYY(3-36) which acts as a satiety factor, delays gastric emptying and improves insulin sensitivity
PYY infusion decreases appetite and food intake at a buffet meal in lean and obese humans Batterham et al, NEJM, 2003
PYY AUC (x 10 3 ) PYY (pg/ml) PYY (pg/ml) LAGB PYY RYGB 700 700 600 600 500 400 15.4% 500 400 300 300 200 200 100 100 0 0 30 60 90 120 Min 0 0 30 60 90 120 Min 80 * * * * * * * 60 40 20 0 LAGB RYGB
Glucagon-Like Peptide-1 (GLP-1) GLP-1 is produced by L cells and is released in response to food intake. Stimulates insulin secretion Inhibits glucagon secretion Induces proliferation and inhibits apoptosis of pancreatic beta-cells Inhibits gastric emptying Increases satiety and decreases food intake
GLP-1 AUC GLP-1 (pmol/l) GLP-1 (pmol/l) LAGB GLP-1 RYGB 80 80 70 60 50 40 30 20 10 0 0 30 60 Min 70 60 50 40 30 20 10 0 0 30 60 Min 3500 3000 2500 2000 1500 1000 500 0 LAGB * * * * RYGB
Sweet Craving AUC Sweet Cravings Decrease after RYGB 6000 * * * * 5000 4000 3000 2000 1000 0 LAGB RYGB
Wt change (%) Sleeve Gastrectomy Band Bypass Sleeve N (F/M) 18 (13/5) 38 (31/7) 22 (16/6) Age (y) 47 44 44 Weight (kg) BMI (kg/m 2 ) 119.9 125.6 126.9 41.8 47.2 46.6 0-5 -10-15 -20-25 -30-35 0.0 0.5 1.0 LAGB Year SG RYGB 15.4% 26.5% 30.5%
Ghrelin (pg/ml) Ghrelin (pg ml -1 xmin) Sleeve Gastrectomy Ghrelin 600 500 400 300 200 100 80000 60000 40000 20000 0 0 30 60 90 120 Min 0
PYY (pg/ml) GLP-1 (pmol/l) Sleeve Gastrectomy 250 200 150 PYY 60 40 GLP-1 100 50 20 0 0 30 60 90 120 Min 0 0 15 30 60 Min
PYY (pg/ml) GLP-1 (pmol/l) SG vs RYGB - Year 1 PYY GLP-1 600 500 RYGB SG 60 RYGB SG 400 40 300 200 20 100 0 0 30 60 90 120 Min 0 0 15 30 60 Min
Why Not?
Leptin (ng/ml) Leptin 50 40 * * * * * * * * 30 20 10 0 LAGB RYGB
Effect of Leptin on Neuropeptide mrna Levels In the Hypothalamus of Fasted Rats Korner et al, J of Neuroendocrinology, 2001, 13:959-966
Leptin (ng/ml) Will leptin administration cause further weight loss in post-rygb subjects who are still overweight? 50 40 * * * * * * * * 30 20 10 0 LAGB RYGB Leptin Resistant Leptin Sensitive
Mean leptin level in RYGB group was 35% lower than BMI-matched non-surgical controls (P<0.0001)
Weight change was not different between leptin vs placebo administration No difference in weight change between treatments was noted when adjusted for baseline leptin, % wt loss after surgery, or duration of post-op period Korner, Conroy et al, Obesity 2013 21:951-956
Leptin Administration Attenuates Sweet Cravings Conroy et al, Int J Obesity, 2014
HbA1c, % Lifestyle Intervention and Medical Management With vs Without Roux-en-Y Gastric Bypass and Control of Hemoglobin A1c, LDL Cholesterol, and Systolic Blood Pressure at 5 Years in the Diabetes Surgery Study 0% 10.0 weight change, % -5% -10% -15% -20% -25% IMM RYGB 9.0 8.0 7.0 6.0 IMM RYGB -30% 0 12 24 36 48 60 5.0 0 12 24 36 48 60 Month after randomization Month after randomization Ikrammadin, Korner, Lee et al JAMA. 2018;319(3):266-278
glp-1 pm/l AUC GLP-1 110 100 90 80 70 60 50 40 30 20 10 0 0 15 30 60 90 120 minutes LS/IMM baseline RYGB baseline 6000 LS/IMM 12 mos 5000 RYGB 12 mos 4000 GLP-1 AUC 3000 2000 1000 0 LS/IMM RYGB * p g =0.005 Nguyen et al, Diabetes 2015;64:3104-3110
Bile Acids Decrease lipogenesis and VLDL-TG export Stimulate GLP-1 secretion Increase skeletal muscle and BAT energy expenditure Stimulate FGF19 secretion Fibrobast Growth Factor 19 Inhibits AgRP/NPY neurons Increases metabolic rate Feedback inhibition of bile acid synthesis Induces resistance to high fat diet-induced obesity Less weight loss after VSG in FXR deficient mice
Bile Acids and FGF19 increase after RYGB Sachdev et al Obes Surg. 2016 26:957-65
HbA1c correlates with FGF-19 levels after RYGB Sachdev et al Obes Surg. 2016 26:957-65
% weight loss % Weight change and HbA1c % weight loss versus HbA1c M12 40 r=0.1236, p=0.0414 r=0.2994, p=0.0008 20 0 5 10 15 HbA1c M12
LS/IMM RYGB Spearman partial R adjusting for age and sex R P R P Duration of DM 0.35 0.05 0.13 0.49 BMI at baseline 0.05 0.80-0.15 0.42 % weight change 0.41 0.02 0.46 0.008 HbA1c at M0 0.43 0.01 0.08 0.68 90 minute C-peptide M0-0.29 0.13-0.50 0.007 Insulinogenic Index M12-0.30 0.10-0.57 0.001 C-peptide Index M12-0.42 0.02-0.54 0.003 HOMA-IR M12 0.25 0.17 0.24 0.19 Matsuda Index M12-0.24 0.19-0.10 0.58 odi M12-0.52 0.009-0.69 <0.0001 AUC ISR/AUC glucose 0-30 min - M0 - M12-0.28-0.32 0.18 0.13-0.48-0.71 0.02 <0.0001 Adiponectin M12-0.17 0.34-0.40 0.03 Nguyen et al, Diabetes 2015;64:3104-3110
Summary LAGB/Diet SG RYGB Wt Loss Leptin Ghrelin PYY GLP-1 Bile Acids - FGF-19
Nat Med. 2015 Jan;21(1):27-36
Weight Change and Health Outcomes at 3 Years After Bariatric Surgery Among Individuals With Severe Obesity JAMA. 2013;310(22):2416-2425. doi:10.1001/jama.2013.280928
Wt Loss (%) RYGB: Inter-individual Wt Loss Variability 50 40 30 20 10 0 Y1 Y2 Y3 Y4
Changes in Hormones Tip of the Iceberg Genetics Psychological Behavioral Gut nutrient sensing Nutrient Absorption Energy Expenditure Microbiome
Acknowledgments Columbia University Heather Bainbridge Irene M. Conwell Gerardo Febres Donald J. McMahon Saachi Sachdev Amanda Tsang Sharon Wardlaw Diabetes Surgery Study Site Sayeed Ikrammudin (University of Minnesota) Center for Obesity Surgery at Columbia University Medical Center Marc Bessler Leaque Ahmed Melissa Bagloo William Inabnet (Mt. Sinai) Leptin Studies Louis Aronne (NYP/Weill Cornell) Sharon Wardlaw Rudolph Leibel Streamson Chua Funding Sources NIH/NIDDK CTSA Covidien/Medtronic