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Regulation of Energy Balance in Bariatric Surgery for Obese Rats

Explore the integration of hormonal and nutrient stimuli from the periphery in the context of bariatric surgery. Discover how gut-brain communication impacts energy balance regulation in obese rats.

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Regulation of Energy Balance in Bariatric Surgery for Obese Rats

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  1. Paper 3 Bariatric Surgery in Obese Rats

  2. Regulation of Energy Balance • Mainly controlled in the hypothalamus • Integration of hormonal and nutrient stimuli from periphery • ANOREXIGENIC • Eat less, increase energy expenditure • OREXIGENIC • Eat more, less energy expenditure

  3. Gut– Brain Communication Short Term Signals – hunger and satiation pancreatic polypeptide (PP) ANOREXIGENIC ghrelin OREXIGENIC ANOREXIGENIC glucagon Like Polypeptide-1 (GLP-1) cholecystokinin (CCK) ANOREXIGENIC peptide YY (PYY) ANOREXIGENIC

  4. PYY • High after feeding • Secreted as N-truncated form PYY3-36 • ANOREXIGENIC • Decreases appetite • Increases sensation of fullness • About 30% reduction in feeding in buffet tests • Similar effects in both lean and obese • But obese have lower fasting and post-prandial rises

  5. GLP-1 • Glucagon-like peptide-1 • From pro-glucagon peptide, several different variations • Amidation, splicing • Made in intestinal L-cells – distal small bowel • ANOREXIGENIC • High after feeding – secretion stimulated by nutrients in gut • Slows gastric emptying • INCRETIN effect • Stimulates insulin secretion • Insulin is an important anorexigenic factor itself • Obese subjects have lower levels and faster gastric emptying • Trialed as both anti-obesity and anti-diabetic agent • Quickly degraded by peptidase in serum (2 min half-life) • Resistant analogs (exendin) • Inhibitors of the peptidase

  6. GIP • Glucose dependent insulinotropic peptide • Made in intestinal K-cells – duodenum • Previously known as gastric inhibitory peptide • Slows gastric emptying • INCRETIN effect • High after feeding – secretion stimulated by glucose • NIDDM subjects lower response • Note that incretins cause oral glucose to give larger insulin response to intravenous glucose

  7. Lifestyle Managementdiet and physical activity • How much weight loss is appropriate to aim for? • ‘ideal’ weight probably unachievable • MAINTAIN (don’t put on more) • this may be the best option • LOSE 5-10% • even this results in 20% less mortality, 10 mmHg drop in blood pressure, 15% lowering of lipids/cholesterol, etc Dietary Therapy for Obesity: An Emperor With No Clothes Hypertension. June 2008;51:1426-1434 “Over 5 decades, it has been demonstrated repeatedly that dietary therapy fails…” “In an era when we pride ourselves on practicing evidence-based medicine, why then does dietary and behavioral therapy still reign?”

  8. Bariatric Surgery • Manipulation of the Digestive system • Malabsorbtive • shorten the digestive tract • by-pass the small intestine or parts of it • Restrictive • reduce the size of the stomach http://www.bariatricsurgeons.com/options.htm

  9. Before and after

  10. Banding O’Brien & Dixon (2006) in Clinical Obesity, Kopelman et al Laproscopic adjustable gastric band (LAGB) Minimally invasive Adjustable (even reversible)

  11. Banding • Convenient • 35 min operation • Inexpensive, Not permanent • Safe • 0.05% deaths • Late complications common (15%) • Slippage, infection, stomach erosion, leakage • Relatively slow weight loss • But >50% excess weight (EW) loss over 2 years • Some lose 120% EW • But easy to ‘cheat’

  12. Small Bowel By-Pass O’Brien & Dixon (2006) in Clinical Obesity, Kopelman et al

  13. Stapling & Biliopancreatic By-Pass Still 250 ml stomach O’Brien & Dixon (2006) in Clinical Obesity, Kopelman et al

  14. Roux en Y (Gastric Bypass) • Small stomach, less digestive juice • Restriction and malabsorbtion • 80% excessive weight loss • Stop diabetic medication • 85% cure from Type II diabetes • IN TWO DAYS!!!! • “Metabolic Surgeons” • All other obesity related problems affected • Angina, hypertension, sleep apnoeas, arthiritis • Skin excess a big disadvantage • Also hair thinning, gall stones • 90 min operation, 0.5% deaths • Cutting and joining… Leak 2% • Cheating still possible if force stomach to stretch!

  15. Diabetes Reversal • Very rapid • Within a few days • Even before any significant weight loss • Same applies to sleep apnoea • Mechanism? • Food-gut interactions affecting incretin secretion? • Intestinal gluconeogenesis? • Cell Metab 2008 Sep 8(3):201-11 • But still not clear how the communication works

  16. Sustained Weight Loss N Eng J Med 357;8 (2007)

  17. Short vs Long term costs? N Eng J Med 357;8 (2007)

  18. Costs of Surgery soon Recouped • Diabetes Care 2009;32:567-574 and 580-584. • Randomised controlled study in Melbourne • Looking at Type 2 diabetes in obese patients • Surgery vs drug/diet interventions • Surgically induced weight loss is cost-effective relative to conventional therapy • in the short term (2 years) • projected over a patient's lifetime

  19. Bariatric Surgery in Australia • 1996 frequency was 1.2 per 100,000 • In 2006 it was 36 per 100,000 • In 2008 12,000 banding operations performed • Many see as the ONLY option • Ensures compliance • Reversal of diabetes • Can we persevere with lifestyle therapy? • Surely this can’t be the answer…. • And would we recommend it for children?!

  20. Why is Bariatric Surgery so Effective? • Changes even before weight loss has occurred • Not all types of surgery so rapid in effect • Adipokines? • Surely not... No change in adipocyte size • Gut hormones? • Seems much more likely!

  21. Roux-en-Y in Zucker rats • Zuckers • fa/fa – defect in leptin receptors • Hyperphagic obesity • All the usual hallmarks of insulin resistance • Measure • Insulin sensitivity • Tolerance tests, euglycemic clamp • Fat stores (subcutaneous, visceral) • Fuel metabolism • Hormones • GLP-1, GIP, glucagon, PYY

  22. Surgery • Don’t worry about surgical details • Sham surgery groups • Pair feeding • Solid food commenced on Day 3 after surgery • Post-operative day 3 (POD 3)

  23. Oral Glucose Tolerance • OGTT on POD 21 • Given by gavage • Blood by tail snipping • HOMA and QUICK • Ways of gauging insulin sensitivity from fasting glucose and insulin

  24. Fat Measurements • Before surgery and POD 28 • Magnetic resonance imaging • Very specialised analysis • Hard for us to judge if it has been done properly

  25. Indirect Calorimetry • Oxygen consumption • measure of metabolic rate • ATP use = fuel oxidation = O2 consumption • Carbon dioxide production • Also measure of metabolic rate • CO2 produced:O2 consumed ratio • Respiratory quotient (RQ) • Tells us if fat or carbohydrates are being burnt • RQ is 1  carbs • RQ is 0.7  fatty acids

  26. Euglycemic Clamp • Explained before • WebCT developer has done animation • Involves even more surgery • To implant cannulae • Infusion of [3-3H] glucose • Bolus followed by continuous infusion • Label lost as glucose is used

  27. Hormones • Radioimmunoassay • Don’t worry about details • Similar in principle to that in prac.

  28. Weight Loss

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