Weight Regulation after Bariatric Surgery

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1 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

2 Disclosures Research Support: NIH, Covidien/Medtronic Scientific Advisory Board/ Stock Options: Digma Medical

3 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

4 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

5 Prevalence of Self-Reported Obesity Among U.S. Adults by State and Territory, BRFSS, 2011

6 Prevalence of Self-Reported Obesity Among U.S. Adults by State and Territory, BRFSS, 2012 Prevalence estimates reflect BRFSS methodological changes started in These estimates should not be compared to prevalence estimates before 2011.

7 Prevalence of Self-Reported Obesity Among U.S. Adults by State and Territory, BRFSS, 2013

8 Prevalence of Self-Reported Obesity Among U.S. Adults by State and Territory, BRFSS, 2014

9 Prevalence of Self-Reported Obesity Among U.S. Adults by State and Territory, BRFSS, 2015

10 Prevalence of Self-Reported Obesity Among U.S. Adults by State and Territory, BRFSS, 2016

11 Prevalence of Self-Reported Obesity Among U.S. Adults by State and Territory, BRFSS, 2017

12 Prevalence of Self-Reported Obesity Among Non-Hispanic Black Adults, by State and Territory, BRFSS,

13 Long-Term Weight Loss: Non-Pharmacologic Treatment VLCD: 800 kcal/day BMOD: behavior kcal/day Combined: VLCD + behavior Wadden Annals of Int Med 119:

14 Neurohormonal Changes Associated with Weight Loss Korner & Aronne, J Clin Invest 111: (2003)

15 Leptin Deficient (ob/ob) Mouse Phenotype: hyperphagia, obesity, decreased energy expenditure, body temperature and immune function, infertility, hyperglycemia/diabetes, hypercortisolemia

16 MC4R Deficiency 9 yo boy MC4R -/- 16 yo brother MC4R +/+ Farooqi et al NEJM

17 Lorcaserin (Belviq)- Mechanism of Action Sargent B and Henderson A. Current Opinion in Pharmacology. February 2011, 11(1): HT 1B: pulmonary HTN; 5-HT 2B: pulmonary HTN and cardiac valvulopathy

18 Sjostrom, J Intern Med 2013; 273: adapted from JAMA. 2012;307(1):56-65

19 Adjustable Gastric Band < Vertical Sleeve Gastrectomy < Roux-en-Y Gastric Bypass

20 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?

21 Gut Hormones Hunger Satiety Meal Size Meal Frequency Insulin sensitivity Insulin Secretion Nature 444, (14 December 2006)

22 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

23 Subject Characteristics Band Bypass N (F/M) 18 (13/5) 38 (31/7) Age (y) 47 ± 2 44 ± 2 Weight (kg) ± ± 0.9 BMI (kg/m 2 ) 41.8 ± ± 0.7*

24 BMI (kg/m 2 ) Wt change (%) BMI and Weight Change LAGB RYGB Year Year Y0 Y1 Y2 Y3 Y4 LAGB (56%) - - RYGB (82%) 20 (71%) 16 (66%)

25 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

26 Ghrelin Enhances Appetite and Increases Food Intake Wren et al, JCEM 86:5992, 2001

27 Circulating Ghrelin Levels Are Decreased in Human Obesity (a physiological adaptation to positive energy balance) Tschöp at al, Diabetes, 50:707, 2001

28 Plasma Ghrelin is Elevated in Prader-Willi syndrome Cummings et al, Nat Med 8:

29 Plasma Ghrelin Levels Decrease After a Meal And Increase After Diet-Induced Weight Loss Cummings et al, NEJM 346:1623, 2002

30 Ghrelin (pg/ml) Ghrelin (pg/ml) Ghrelin LAGB RYGB % % Min Min

31 Ghrelin AUC (x 10 3 ) Ghrelin (pg/ml) Ghrelin (pg/ml) LAGB Ghrelin RYGB % % Min Min 80 * * * * * LAGB RYGB

32 Ghrelin Suppression (%) Ghrelin - % Postprandial Suppression * * * 0 LAGB RYGB

33 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

34 PYY infusion decreases appetite and food intake at a buffet meal in lean and obese humans Batterham et al, NEJM, 2003

35 PYY AUC (x 10 3 ) PYY (pg/ml) PYY (pg/ml) LAGB PYY RYGB % Min Min 80 * * * * * * * LAGB RYGB

36 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

37 GLP-1 AUC GLP-1 (pmol/l) GLP-1 (pmol/l) LAGB GLP-1 RYGB Min Min LAGB * * * * RYGB

38 Sweet Craving AUC Sweet Cravings Decrease after RYGB 6000 * * * * LAGB RYGB

39 Wt change (%) Sleeve Gastrectomy Band Bypass Sleeve N (F/M) 18 (13/5) 38 (31/7) 22 (16/6) Age (y) Weight (kg) BMI (kg/m 2 ) LAGB Year SG RYGB 15.4% 26.5% 30.5%

40 Ghrelin (pg/ml) Ghrelin (pg ml -1 xmin) Sleeve Gastrectomy Ghrelin Min 0

41 PYY (pg/ml) GLP-1 (pmol/l) Sleeve Gastrectomy PYY GLP Min Min

42 PYY (pg/ml) GLP-1 (pmol/l) SG vs RYGB - Year 1 PYY GLP RYGB SG 60 RYGB SG Min Min

43 Why Not?

44 Leptin (ng/ml) Leptin * * * * * * * * LAGB RYGB

45 Effect of Leptin on Neuropeptide mrna Levels In the Hypothalamus of Fasted Rats Korner et al, J of Neuroendocrinology, 2001, 13:

46 Leptin (ng/ml) Will leptin administration cause further weight loss in post-rygb subjects who are still overweight? * * * * * * * * LAGB RYGB Leptin Resistant Leptin Sensitive

47 Mean leptin level in RYGB group was 35% lower than BMI-matched non-surgical controls (P<0.0001)

48 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 :

49

50 Leptin Administration Attenuates Sweet Cravings Conroy et al, Int J Obesity, 2014

51

52 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 IMM RYGB -30% Month after randomization Month after randomization Ikrammadin, Korner, Lee et al JAMA. 2018;319(3):

53 glp-1 pm/l AUC GLP minutes LS/IMM baseline RYGB baseline 6000 LS/IMM 12 mos 5000 RYGB 12 mos 4000 GLP-1 AUC LS/IMM RYGB * p g =0.005 Nguyen et al, Diabetes 2015;64:

54 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

55 Bile Acids and FGF19 increase after RYGB Sachdev et al Obes Surg :957-65

56 HbA1c correlates with FGF-19 levels after RYGB Sachdev et al Obes Surg :957-65

57 % weight loss % Weight change and HbA1c % weight loss versus HbA1c M12 40 r=0.1236, p= r=0.2994, p= HbA1c M12

58 LS/IMM RYGB Spearman partial R adjusting for age and sex R P R P Duration of DM BMI at baseline % weight change HbA1c at M minute C-peptide M Insulinogenic Index M C-peptide Index M HOMA-IR M Matsuda Index M odi M < AUC ISR/AUC glucose 0-30 min - M0 - M < Adiponectin M Nguyen et al, Diabetes 2015;64:

59 Summary LAGB/Diet SG RYGB Wt Loss Leptin Ghrelin PYY GLP-1 Bile Acids - FGF-19

60 Nat Med Jan;21(1):27-36

61 Weight Change and Health Outcomes at 3 Years After Bariatric Surgery Among Individuals With Severe Obesity JAMA. 2013;310(22): doi: /jama

62 Wt Loss (%) RYGB: Inter-individual Wt Loss Variability Y1 Y2 Y3 Y4

63 Changes in Hormones Tip of the Iceberg Genetics Psychological Behavioral Gut nutrient sensing Nutrient Absorption Energy Expenditure Microbiome

64 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

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