Paper 3 Bariatric Surgery in Obese Rats

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

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

PYY High after feeding – Secreted as N-truncated form PYY 3-36 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

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

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

Lifestyle Management diet 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: “In an era when we pride ourselves on practicing evidence-based medicine, why then does dietary and behavioral therapy still reign?” “Over 5 decades, it has been demonstrated repeatedly that dietary therapy fails…”

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

Before and after

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

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’

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

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

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!

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): – But still not clear how the communication works

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

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

Costs of Surgery soon Recouped Diabetes Care 2009;32: and 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

Bariatric Surgery in Australia 1996 frequency was 1.2 per 100,000 – In 2006 it was 36 per 100,000 In ,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?!

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!

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

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)

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

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

Indirect Calorimetry Oxygen consumption – measure of metabolic rate – ATP use = fuel oxidation = O 2 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

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

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

Weight Loss