OBESITY CONUNDRUM 1: Is There Evidence That a Food Solution Can Impact Overweight Through Biological Mechanisms: Appetite, Satiety and Energy Balance

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OBESITY CONUNDRUM 1: Is There Evidence That a Food Solution Can Impact Overweight Through Biological Mechanisms: Appetite, Satiety and Energy Balance Stephen C. Woods University of Cincinnati IFT Summit,
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OBESITY CONUNDRUM 1: Is There Evidence That a Food Solution Can Impact Overweight Through Biological Mechanisms: Appetite, Satiety and Energy Balance Stephen C. Woods University of Cincinnati IFT Summit, New Orleans, 2004 The Dilemma Kg Decades Mean Daily Consumption (Calories) In the last three decades, American men increased their caloric intake by 7% and American women by 22% Women Men CDC Morbidity and Mortality Weekly Report, Feb 05, 2004 Energy Balance Equation Intake Expenditure Hunger Satiety Nutrient Absorption Metabolic Rate Thermogenesis Activity Accuracy! Energy Intake in a Year 955,570 calories Gaining 1 pound (0.45 kg) in a year ~4000 calories Error of 0.4%, or 11 calories/day THE PUZZLE If energy homeostasis is regulated so precisely, Does this imply the existence of a set point? Is the control system overwhelmed by environmental factors? Evidence suggests that there is a body weight range rather than a body weight set point. Upper Level of Acceptability Body Weight (Fat) Environmental Influences: Stress Palatability Exercise Lower Level of Acceptability Age Upper and lower boundaries are genetically and ontogenetically determined. The control system over energy homeostasis is complex, relying upon several types of signals. MW Schwartz, SC Woods et al., Nature, 2000 MEALS Meals are the fundamental unit of food intake. GP Smith MEALS Meals are the fundamental unit of food intake. GP Smith Factors that control when meals will occur are distinct from factors that control when meals will end; i.e., different signals control meal initiation and meal size. CONTROL OF MEALS There is scant evidence that meal initiation is controlled by metabolic or hormonal signals. CONTROL OF MEALS There is scant evidence that meal initiation is controlled by metabolic or hormonal signals. The best evidence is that under normal circumstances, meal initiation is based upon learned associations, convenience or the social situation. CONTROL OF MEALS There is scant evidence that meal initiation is controlled by metabolic or hormonal signals. There is compelling evidence that meal cessation (meal size) is controlled by preabsorptive signals from the gastrointestinal system. CONTROL OF MEAL SIZE FOOD INTAKE GUT (+) SENSOR METABOLIC EFFECTS (-) GASTROINTESTINAL PEPTIDES SATIETY FACTORS CHOLECYSTOKININ (CCK) BOMBESIN FAMILY (GRP, NMB) GLUCAGON Putative Satiety Factors: Cholecystokinin (CCK) Peptides in the bombesin family Bombesin, GRP, Neuromedin B Apolipoprotein A-IV (apo A-IV) Peptide YY (PYY) GLP-1, enterostatin, amylin, glucagon, somatostatin Ghrelin Reduction of Meal Size by CCK 30-Min Food Intake * * * * * * DOSE From: J Gibbs & GP Smith, 1976 Satiety Signals: Secreted during meals, create a sensation of fullness or satiety Reduce meal size without causing malaise Interact with other controllers of meal size Features of satiety signals: Most are made in both the GI tract and the brain. Features of satiety signals: Most are made in both the GI tract and the brain. This includes CCK, bombesin peptides, somatostatin, PYY, apo-a-iv and GLP-1, as well as ghrelin. Features of satiety signals: Most are made in both the GI tract and the brain. They are efficacious in humans. Reductions of Meal Size in Humans Administered IV CCK Subjects from Control Reference Men -3% Kissileff, AJCN, 1981 Obese Men -24% Pi-Sunyer, PB, 1982 Men -39% Muurahainen, PB, 1988 Men, Women -32% Muurahainen, AJP, 1991 Men, Women -8% Geary, AJP, % Geary, AJP, % Geary, AJP, 1992 Obese Women -31% Geary, AJP, 1992 Men, Women -20% Lieverse, Gut, 1995 Men -21% Ballinger, Clin Sci, 1995 Men -7% Gutzwiller, AJP, 2000 IV CCK is More Effective at Reducing Meal Size in Men and Women After Eating a Standard Preload Test Meal Intake (gm MB) CCK Saline * gm Soup Preload Condition 500gm Soup Muurahainen NE, Am J Physiol 1991;260:R672-80 Features of satiety signals: Most are made in both the GI tract and the brain. They are efficacious in humans. Blocking their action leads to increased meal size. The CCK-A Receptor Antagonist, Loxiglumide (22 µμol/kg, iv), increases Caloric Intake in Men 2000 * p SAL LOX Adapted from Beglinger C, Am J Physiol Regul Integr Comp Physiol 2001;280:R Chemical and physical information is integrated in vagal sensory nerves as well as in the brain to control meal size. Hormones, Nutrients Forebrain Hindbrain Food Intake Vagus Nodose Ganglion CCK released from cells in the duodenum acts locally on CCK-A receptors on vagal afferent nerves that project to the hindbrain. Forebrain Hindbrain Food Intake CCK CCK-A Receptors Nodose Ganglion (Makes CCK-A Receptors) The effects of CCK and stomach stretch are integrated in vagal afferent fibers. Forebrain Hindbrain Food Intake CCK Stretch The effects of CCK and stomach stretch are integrated in vagal afferent fibers. Forebrain Hindbrain Food Intake CCK Stretch The effects of CCK and stomach stretch are integrated in vagal afferent fibers. Forebrain Hindbrain Food Intake CCK Stretch Knocking out CCK-A receptors, vagal transmission, or hindbrain relay nuclei attenuates CCK-induced satiety. Forebrain Hindbrain Food Intake CCK CCK-A Receptors Gastric ghrelin increases food intake, and the effect is dependent upon an intact vagus nerve. Ghrelin Forebrain Hindbrain Food Intake Nodose Ganglion (Makes Ghrelin Receptors) Habits, Social Factors, Stress and Emotions, Learning, etc. Adiposity Signals Forebrain Hindbrain Food Intake Vagus Satiety Signals Can foods be used to increment endogenous CCK (or other satiety signals), leading to reduced meal size? Can foods be used to increment endogenous CCK (or other satiety signals), leading to reduced meal size? Soybean trypsin inhibitor (SBTI) stimulates CCK and inhibits ghrelin secretion. Potato proteinase inhibitor (POT II) stimulates CCK secretion. Phenylalanine (stimulates CCK secretion). Other (green tea, calcium [milk], water, etc.) Is mimicking or triggering CCK or other satiety signals a worthwhile strategy for the food industry? CCK REDUCES THE SIZE OF EVERY MEAL PERCENT OF CONTROL CONTROL CCK West et al., AJP 246:R CCK INCREASES THE NUMBER OF MEALS PERCENT OF CONTROL MEAL NUMBER CONTROL CCK West et al., AJP 246:R CCK, GIVEN ALONE, HAS NO NET EFFECT ON FOOD INTAKE OR BODY WEIGHT IN FREELY FEEDING RATS PERCENT OF CONTROL MEAL SIZE MEAL NUMBER DAILY INTAKE CONTROL CCK CONTROL CCK CONTROL CCK West et al., AJP 246:R The control system over energy homeostasis is complex, relying upon several types of signals. MW Schwartz, SC Woods et al., Nature, 2000 Humoral Regulation of Adiposity CNS Regulatory Mechanisms Food Intake, Energy Expenditure Adiposity Hormones Stored Calories CONTROL OF BODY FAT Strong evidence that key signals reach the brain via the blood Adiposity Hormones * Insulin Pancreatic insulin secretion is directly proportional to the size of the fat mass. INSULIN PANCREAS WHITE FAT Obese Humans Secrete More Insulin in Proportion to Adiposity Normal Obese Glucose (mg/dl) Insulin ( (µu/ml) Clock Time (hours) Clock Time (hours) Polonsky KS, J Clin Invest 1988;81:442-8 CONTROL OF BODY FAT Strong evidence that key signals reach the brain via the blood Adiposity Hormones * Insulin * Leptin Leptin secretion is directly proportional to the size of the fat mass. LEPTIN WHITE FAT Serum Leptin is Increased in Obesity Serum Leptin (ng/ml) Log Serum Leptin Body Fat (%) Body Fat (%) Considine RV, N Engl J Med 1996;334:292-5 Increased Insulin or Leptin Decreased Food Intake and Increased Energy Expenditure INSULIN Increased Insulin or Leptin Woods, Nature,1979 Cumulative Food Intake (g) * LEPTIN ICV Leptin Control * Time (hours) Seeley, Horm Metab Res,1995 * * Decreased Food Intake and Increased Energy Expenditure Decreased Insulin or Leptin Action Increased Food Intake and Decreased Energy Expenditure INSULIN FOOD INTAKE Decreased Insulin or Leptin Action Sal I-Ab McGowan, Behav NSci,1985 LEPTIN FOOD INTAKE WT ob/ob Coleman, Diabetologia, 1972 Increased Food Intake and Decreased Energy Expenditure Humoral Regulation of Adiposity CNS Regulatory Mechanisms Food Intake, Energy Expenditure Insulin, Leptin Stored Calories The adiposity hormones, leptin and insulin, enter the hypothalamic arcuate nucleus and stimulate α-msh/ CART neurons while inhibiting NPY/AgRP neurons, thus activating catabolic pathways while inhibiting anabolic pathways. NPY/AgRP PVN LHA α-msh/cart CRH GRP, Oxytocin MCH Orexins Catabolic: Food Intake Energy Expenditure Anabolic: Food Intake Energy Expenditure ARC LEPTIN INSULIN The control system over energy homeostasis is complex, relying upon several types of signals. MW Schwartz, SC Woods et al., Nature, 2000 Features of satiety signals: Most are made in both the GI tract and the brain. They are efficacious in humans. Blocking their action leads to increased meal size. Their efficacy is enhanced when adiposity signals are elevated. IVT insulin dose-dependently reduces body weight over 6 days (g) in rats 10 SUBTHRESHOLD DOSE Dose of IVT Insulin (mu/day) Riedy et al., P&B, 58: 755,1995 Subthreshold insulin increases the satiating effect of IP CCK % of Baseline Intake * * Con Ins CCK Ins + CCK Ins: 0.5 mu/day CCK: 4 µg/kg Riedy et al., P&B, 58: 755,1995 Why are insulin and leptin called adiposity signals, and CCK and other GI peptides called satiety signals? ADIPOSITY SIGNALS BODY WEIGHT CONTROL/SALINE i3vt TIME M Chavez et al., Behav Neurosci, 1995 ADIPOSITY SIGNALS BODY WEIGHT CONTROL/SALINE i3vt INSULIN i3vt TIME M Chavez et al., Behav Neurosci, 1995 100% * Food Intake BODY WEIGHT CONTROL/SALINE i3vt INSULIN i3vt TIME M Chavez et al., Behav Neurosci, 1995 ADIPOSITY SIGNALS BODY WEIGHT Food Restriction CONTROL/SALINE i3vt INSULIN i3vt TIME M Chavez et al., Behav Neurosci, 1995 ADIPOSITY SIGNALS BODY WEIGHT CONTROL/SALINE i3vt INSULIN i3vt Return to ad lib food TIME M Chavez et al., Behav Neurosci, 1995 100% * * Food Intake BODY WEIGHT CONTROL/SALINE i3vt INSULIN i3vt TIME M Chavez et al., Behav Neurosci, 1995 ADIPOSITY SIGNALS BODY WEIGHT CONTROL/SALINE i3vt INSULIN i3vt? INSULIN i3vt TIME M Chavez et al., Behav Neurosci, 1995 ADIPOSITY SIGNALS BODY WEIGHT CONTROL/SALINE i3vt INSULIN i3vt INSULIN i3vt TIME M Chavez et al., Behav Neurosci, 1995 100% * * * Food Intake BODY WEIGHT CONTROL/SALINE i3vt INSULIN i3vt INSULIN i3vt TIME 100% Effect of CCK * * * * 100% * * * Food Intake BODY WEIGHT CONTROL/SALINE i3vt INSULIN i3vt INSULIN i3vt TIME Satiety signals: Reduce meal size comparably In lean animals In genetically obese animals In diet-induced obese animals Have minimal effects on body weight Adiposity signals: Reduce body weight by enhancing the effect of satiety signals on each meal. Have to be increased locally in the brain or else decreased systemically, and on a chronic basis, to be efficacious. Leptin (Prevention of weight regain) Insulin (Mimetics) MW Schwartz, SC Woods et al., Nature, 2000 What are the best targets for intervention by the food industry? Meal-Related Signals Sight and Smell Sight and Smell Taste Sight and Smell Taste Stomach Signals (Ghrelin, GRP, Stretch) Sight and Smell Taste Stomach Signals (Ghrelin, GRP) Duodenal Signals (CCK) Sight and Smell Taste Stomach Signals (Ghrelin, GRP) Duodenal Signals (CCK) Lower Intestinal (PYY, Apo A-IV GLP-1) Sight and Smell Taste Pancreatic Signals (Amylin) Stomach Signals (Ghrelin, GRP) Duodenal Signals (CCK) Lower Intestinal (PYY, Apo A-IV GLP-1) Sight, smell, palatability, mouth feel Gastric and duodenal signals Ileal signals Ileal Transposition GLP-1, PYY, Apo A-IV Ileal Transposition A short segment of ileum is transposed anteriorly such that chyme stimulates it earlier in the sequence of digestion. Ileal Transposition (IT) Body weight (g) IT causes a small but reliable loss of weight Ileal transposition (n=8) Sham (n=8) Days post surgery Ileal Transposition Cumulative food intake (g) *p 0.05 * IT rats eat less food. 200 Sham Ileal transposition Ileal Transposition Plasma GLP-1 (pmol) Glucose tolerance test (post-surgery day 28) Sham (n=3) Ileal transposition (n=9) Sham (pair-fed) (n=6) Preproglucagon mrna (% of sham - relative to L32) *p 0.05 sham ileal transposition Surgical group * Time ( minutes) IT rats make and secrete more GLP-1. Ileal Transposition PYY (pmol) 500 Sham * Ileal transposition * * * *p 0.05 PeptideYY mrna (% of sham - relative to L32) *p 0.05 sham ileal transposition Surgical group * Minutes post gavage IT rats make and secrete more PYY. What are the best targets for intervention by the food industry? Perhaps foods or food additives could be developed that stimulate the ileum early during meals. The control system over energy homeostasis is complex, relying upon several types of signals. MW Schwartz, SC Woods et al., Nature, 2000 Possible Food Approaches 1. Foods/nutrients that uniquely influence satiety signals a. Soybean trypsin inhibitors West CCK-1 KO; half-lives b. Density a la Rolls 2. Foods/nutrients that uniquely influence adiposity signals a. GLP-1/Apo A-IV 3. Foods/nutrients that mimic the effects of bypass 4. Foods/nutrients that reduce cephalic responses Why the mouth isn t the place DeCastro People don t eat food that they Perceive as unpalatable Sham eating: Internal signals must arise distal To the stomach
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