Obesity 2.pdf

Metabolism of Weight Loss and Adaptations NUTR 344 - 2024 Reading Material Nelms, chapter 17, pp. 484-488. Background review on hormonal control of energy metabolism. Sumithran & Proietto. The defence of body weight: a physiological basis for weight regain after weight loss. Clinical Science 201...

Metabolism of Weight Loss and Adaptations NUTR 344 - 2024 Reading Material Nelms, chapter 17, pp. 484-488. Background review on hormonal control of energy metabolism. Sumithran & Proietto. The defence of body weight: a physiological basis for weight regain after weight loss. Clinical Science 2013. References: Cahill Jr GF. 1988. Starvation: Some biological aspects. In: Nutrition and Metabolism in Patient Care. Kinney et al. WB Saunders: 193-204. 1988 Hall KD and Guo J. Obesity energetics-Body weight regulation and the effect of diet composition. Gastroenterology 2017. Fothergill E et al. Persistent metabolic adaptations 6 years after “The Biggest Loser”. Obesity 2016. Outline      The fed state Adaptations to fasting, protein sparing The refeeding syndrome Metabolic adaptations to weight loss toward weight regain Effects of diet composition physical activity: skeletal muscle will increase sleeping: brain will increase Percentage of energy expenditure at rest remainder 16% liver 21% brain 20% heart 9% kidneys 8% adipose tissue 4% skeletal muscle 22% Adapted from: Introduction to Nutrition and Metabolism, 4th edition, CRC Press. ©David Bender 2007 Fuels in a 75-kg man available kilograms Adipose tissue triglycerides 12 kilocalories 110 000 stored in protein Protein Muscle 6 wants to spare this as much as 25 000 body possible Other* 6 25 000 Carbohydrates Muscle glycogen 0.5 Liver glycogen 0.1 400 Free glucose 0.02 80 *mainly non-utilizable able to use it onsite (only the muscle 2000 only can use it) Grams Weight of using 100 kcal of glycogen, protein, and lipids 100 90 80 70 60 50 40 30 20 10 0 Burning glycogen and protein: will show up on a scale as a greater weight loss, but it’s mostly the water that’s being loss Fat Protein Glycogen Water not a lot of water that comes with it smaller weight of fat to use 100 kcal, but less significant on the scale Glycogen Protein tissue Adipose tissue Adapted from: Kinsell, L.W. (1959) Am J Clin Nutr 2:350-352 Blood Glucose and the Fed Signal Liver VLDL CNS Adipocytes  Ingested glucose RBC + = requires insulin  Muscle Blood Glucose Curve DECAY SLOPE High Insulin : Blood glucose (mmol/l) 8.0 6.0 ↑Tissue uptake of glc, so glc goes down ↑Glycogenesis extra glc —> glycogen, so glc goes down UPTAKE SLOPE ↑GI absorp on of glc 4.0 ↓Glycogenolysis ↑Glucagon counteract effect of insulin ↑Glycolysis 2.0 ↓Gluconeogenesis ↑Gluconeogenesis response to glc 1 not insulin ↓Insulin:Glucagon RATIO, or glucagon by itself ↑ Glycogenolysis Insulin release in 0 STEADY PHASE 2 3 4 Hours Response to a Meal – Insulin: Glucagon Initial increase Initial decrease Insulin Glucagon Glucose Free Fatty Acids Lactate Ketoacids Pyruvate Glycerol Triglycerides Alanine BCAA branched chain amino acid Total Amino Acids I:G insulin:glucagon ratio Urea Nitrogen bc not degrading protein look at overall trend, not the tiny differences Response to a Meal 6 mM need to know if it increases or decreases (don’t need to know the specific minutes/mM) Glucose 4 2 Lactate mM 1 0.2 mM Pyruvate 0.1 -15 0 30 60 120 Minutes 180 240 Response to a Meal 150 mg/dL trend going up and it’s slower 130 Triglycerides 110 90 700 Free Fatty Acids μM 500 300 0.13 mM 0.11 Ketone Bodies 0.09 -15 0 30 60 120 Minutes 180 240 Response to a Meal 90 Glycerol μM 50 500 μM 400 Alanine 300 600 μM 500 BCAA 400 -15 0 30 60 120 Minutes 180 240 Response to a Meal 2500 μM 2100 Total Amino Acids 1700 17 mg/dl 16 Urea Nitrogen 15 14 -15 0 30 60 120 Minutes 180 240 need insulin to get aa to muscle How high and how long glc goes after a meal Blood Glucose Curve Spike is higher and takes longer to go down (area under the curve twice as high as normal one) bc body don’t respond to insulin normally Insulin resistance/ Early diabetes 12 Associated with high BMIs Blood glucose (mmol/L) 10 8 Normal 6 4 Reactive hypoglycemia delayed glucagon response feedback to release glucagon not efficient, so less endogenous glc is produced and blood glc will go down 2 0 1 2 3 4 Hours Application in “fad” dieting: the “carbohydrate-insulin model of obesity” Allegation: Carbohydrates have the most profound effect on insulin release therefore are the most likely of macronutrients to favor energy storage and weight gain. Ra onale of low carbohydrate (high fat) diets: ↓ I ↑G Many diets make use of the Glycemic Index (GI): ranks foods based on the rate take into consideration glycemic load: at which different carb sources raise blood glucose levels.don’t watermelon has a high GI, but need to eat a lot for that Supporters of this theory (Montignac, The Zone) claimed that eating foods with a low GI favors weight loss by controlling the amount of carbohydrate and insulin in the blood. Even high protein diet can stimulate insulin release, especially if high in arginine and leucine Summary of evidence Ratio Insulin: Glucagon dictates energy storage tells if storage or spending it Fed signals cause changes in several blood parameters over a four-hour period Changes in I:G and glucose curves are the basis for several fad diets High carbohydrate intake + high fat intake (i.e. excess energy) causes fat storage – not necessarily a function of high GI foods alone Adapting to Fasting: Goals 1. Meet energy needs 2. Meet glucose requirements 3. to have to use energy Spare protein (lean mass) going going to do its best to not use protein bc need to maintain glucose blood level for brain and RBC If goes down too low/too long = can result in coma and death Energy paradox Brain can use ketones 1. The brain needs ≈500 kcal of water-soluble fuels (usually glucose) per day. 2. Almost all energy is stored as fatty acids, not as glycogen. Glycogen store for 1 day 3. Fatty acids cannot be converted to glucose. Glycerol part of fat can be converted to glc Fatty acid part can’t be converted to glc, can only be burn for energy Illustrative case A 70-kg adult male illusionist decides to have himself suspended over the Thames River in London and do a total fast, taking vitamins and water. How long will he survive and what energy fuels will he use? don’t need to know the specific numbers, but need to know proportions (where is the energy coming from) Low insulin, high glucagon: stimulates release of glc coming from liver and muscle Decrease insulin : catabolism in muscle to produce aa —> glc Cori cycle (lactic acid —> liver glc —> glc muscle) and alanine cycle (aa from muscle —> glc) Gluconeogenesis from glycerol (adipose tissue) Glycolysis First couple of days Fuel Flux – Early Fasting (2000 kcal/24 h) Breaking down of lipids for energy No more glycogen Less amount of aa coming from muscle Start protein sparring Relies on ketones as a survival mechanism, can detect it in the urine Less glc, more ketones > or = 3 days Fuel Flux – Prolonged Fasting (1500 kcal/24 h) Always using a combination of different fuel, but different proportion 12 hours: half from glycogen and half from GNG Ketogenesis increases early, but slowly Glucose utilization from different sources 40 I II III Glucose used (g/h) Exogenous IV V glc that we just consumed 30 20 Glycogen 10 Gluconeogenesis Ketogenesis 0 4 8 12 16 20 Hours 24 28 2 8 16 24 Days 32 40 Glucose Utilization same table as the one before but in words I Origin of blood glucose Tissues using glucose Major fuel for brain II III IV V Exogenous Glycogen; Hepatic gluconeogenesis Hepatic gluconeogenesis; Glycogen Gluconeogenesis – Hepatic and renal Gluconeogenesis – hepatic and renal All All except liver All except liver; Brain, RBC, renal medulla Brain at diminished rate Small amount by muscle RBCs, renal medulla Glucose, ketone bodies Ketone bodies, glucose Muscle and AT at Muscle and AT at dimished rates rates intermediate between II and IV Glucose Glucose Glucose Ketoacids (ketones, ketone bodies) Acetoacetate, β-hydroxybutyrate Produced as a result of overwhelming fatty acid oxidation Used as fuel for brain; reduces need for gluconeogenesis Even after overnight fast urinary ketone reading: 1+ on keto stick Excreted via lungs (acetone) and kidneys Implications:  When ketones are excreted via kidneys they must be “salted” out which involves the loss of either Na, K, H, or NH4  Ideally NH4 is excreted because it is a waste product  BUT K is the preferred ion to be excreted hypokalemia Substrate and Hormone Levels Well-Fed Post-Absorptive (12 h) Fasting (3 d) Starving (5 wk) Insulin µU/ml 40 15 8 6 Glucagon pg/ml 80 100 150 120 0.5 0.15 0.05 0.05 Glucose mM 6.1 4.8 3.8 3.6 Fatty acids mM 0.14 0.6 1.2 1.4 Ins:Gluc Ruderman NB, et al. 1976. Gluconeogenesis and its disorders in man. In: Gluconeogenesis, its regulation in mammalian species. New York: Wiley. p. 515 Substrate and Hormone Levels Well-Fed Post-Absorptive (12 h) Fasting (3 d) Starving (5 wk) Acetoacetate mM 0.04 0.05 0.4 1.3 B-OHbut mM 0.03 0.1 1.4 6.0 Lactate mM 2.5 0.7 0.7 0.6 Alanine mM 0.8 0.3 0.3 0.1 Ruderman NB, et al. 1976. Gluconeogenesis and its disorders in man. In: Gluconeogenesis, its regulation in mammalian species. New York: Wiley. p. 515 True fat loss requires time can’t speed up glycolysis: linear Urinary Nitrogen Constituents grams Normal Starvation (Several weeks) 15 10 Urea 5 don’t have a lot of protein available and don’t want to lose it, so less urea more ammonia bc ketoacids Urea Ammonia Ammonia Others Others Consequences of Starvation: Renal Need normal kidney function maintain acid base balance in the body if the person is not consuming Ammonia is toxic so need for more water for excretion so enough water, ammonia can build up and cause toxicity Acid/base balance changes in response to starvation need to be controlled by kidney Relationship among nitrogen intake, energy intake, and N balance N balance (g/24 h) + Energy balance: most likely in + Nitrogen balance except if diet really low on protein +4 1.5 intake > expenditure 1.25 1.0 intake = expenditure energy surplus: have enough protein +2 EI/EE 0 Nitrogen balance 0 0.5 intake < expenditure 0.33 0.2 -2 -4 When you lose weight: you lose fat and lean mass -6 -8 If lower, even if you take protein, won’t reach 0 Nitrogen balance, but the loss can be negligible energy deficit: need more protein -10 0 2 4 6 8 10 12 14 16 N intake (g/24 h) Both diets are low in calories and in energy deficit Average daily nitrogen balance (g/d) at different weeks for two weight reduction diets Nitrogen balance ± SE 1 0 -1 -2 red one can’t reach 0 Nitrogen balance bc not enough prot -3 1.5 g pro/kg protein 0.8 g pro/kg -4 -5 0 1 2 3 4 5 6 7 8 Weeks When someone with BMI 35 is starting weight loss, will lose more fat than somebody who’s BMI is 25 As they lose weight, will start to lose more LBM than fat PREDICTION I: 0.4 0.6 ◦ During fast, obese individuals will lose less nitrogen (hence less LBM) than will thin people 0.2 PREDICTION II: 0 LBM: W 0.8 Forbes Equation (Nutrition Reviews, 1987) 0 20 40 60 80 Body fat (kg) ◦ The fatter the subject the less the contribution of LBM to total weight loss on energy restricted diets When they are losing weight, will lose more fat than LBM Physiological Changes to Severe Weight Loss Cardiovascular and Renal ◦ ↓ Cardiac output, heart rate, BP at first lower heart rate, and then tachycardia will kick in ◦ ↑ Tachycardia (compensatory mechanism) ◦ ↑ Stress on kidney (acid/base balance) Immune Function ◦ ↓ T-cell function/lymphocytes Physiological Changes to Severe Weight Loss Gastrointestinal Function ◦ ↓ Lipid absorption – steatorrhea ◦ ↓ Gastric, pancreatic and bile secretion/production ◦ ↓ Villous surface area less substrate available for turnover Electrolytes ◦ Potassium losses (LBM and intracellular losses) CNS Functions Illustrative case A 70 kg adult male magician decides to have himself suspended over the Thames River in London and do a total fast, taking vitamins and water. How long will he survive and what energy fuels will he use? David Blaine fasted for 44 days (2003) Lost 24.5 kg (25% of initial BW) BMI 29 to 21 The Refeeding Syndrome Refeeding Syndrome Metabolic complications associated with nutritional repletion Causes: shift back to glucose as the main fuel  Rapid fluxes of insulin due to CHO load  Rapid shift of electrolytes and intracellular anions and cations to intracellular space (PO4, K, Mg)  Sodium and water retention Symptoms:  Fatigue, lethargy, dizziness, muscle weakness, arrythmia, hemolysis, edema most dangerous, want to avoid it Refeeding Syndrome Occurs rapidly (first days of repletion) Physiological changes during repletion  ECF expansion  Edema from increased Na intake and electrolyte imbalances  Glycogen synthesis  May lower serum PO4 and K concentrations  Increased REE  Due to reversal of starvation and LBM rebuilding  Increased insulin secretion from carbohydrate intake great but don’t want to do it too fast  Fed signal is now present and uptake into cells resumes  Stimulates N retention  Stimulates cell synthesis, growth, and rehydration Shils et al. 2000. Chapter 41. p. 660 If someone was still consuming CHO, but severe energy deficiency: no refeeding syndrome bc they have been using glc this whole time, not a switch from ketones to glc Refeeding Syndrome Steps in refeeding:  Normalize fluid and electrolyte imbalances need to go slow in the rehydration too  PO4, K and Mg using supplementation  Limit Na and fluid in the first few days  Provide a mixed diet at maintenance energy levels  To establish tolerance and avoid refeeding syndrome  Aim for 100-150 g glucose to stop LBM breakdown but start with 25% of dose and increase gradually  Thiamine (or multivitamin) supplementation bc can’t give right away all the energy they need  Provide protein at 1.5-2 g/kg current body wt/d  Start with 20 g/day due to urea cycle enzyme adaptation  To replenish LBM  Monitor serum electrolytes, weight, intake, output Adaptations to weight loss toward weight regain Weight loss trajectories Typical Successful Energy balance + adaptations Body fat Energy intake Energy expenditure *Required reading (Sumithran and Proietto, Clin Sci 2013) Physiological changes after diet-induced weight loss  Energy expenditure  Fat oxidation  Thyroid hormones Energy storage  Cortisol  Leptin  PYY  Amylin  Insulin Food intake  Ghrelin, appetite Altered neural activation *changes may persist >1 year after weight loss (Sumithran and Proietto, Clin Sci 2013) Weight loss countermeasures ↓Energy expenditure ◦ REE ↓ ≅15% kcal per kg lost: more than expected from changes in body weight and composition  metabolic adaptation ◦ Usual decrease in physical activity, more with severe restriction ◦ Decrease in TEF, from lower E intake ◦ Persists > 1 y after weight loss, perhaps permanently? studies follow ppl for 1 year, so don’t know after Appetite ◦ ↑ Soon during energy deficit and persists >1 y ◦ With accompanying hormonal adaptations Improved food reward, palatability and olfaction Energy compensation with time = weight relapse Doucet E et al. Obesity Reviews 19(Suppl 1); 36-46, 2018 study followed up 50 ppl that lost weight over 62 weeks 10 week program to lose weight and see that ppl started gaining weight slowly from week 10 to 62 Persistence of hormonal adaptations to weight loss n=50 n=34 appetite higher after weight loss goes up Sumithran P. et al. New Engl J Med 365: 17, 2011 Obesity Energetics REE variability - 70% predicted from body composition, sex, age - 30% residual: organ mass + metabolic fluxes (protein turnover, GNG, lipogenesis, lipolysis, …) Hall and Guo, Gastroenterology 2017; 152, 1718-1727. Metabolic adaptations In response to energy deficit and weight loss: Reduction in energy expenditure to a greater degree than predicted from changes in body composition (measured REE< predicted REE) ◦ Leads to an energy gap of 200-250 kcal ◦ May continue for years after E balance is reset at a lower weight ◦ Probably related to reduced sympathetic drive, thyroid function, reduced leptin In response to increasing exercise: ◦ Initial increments in EE can be greater than expected from energy cost of exercise ◦ With training: no further increase in EE despite increased volume and intensity of exercise ◦ Possibly due to biomechanical efficiency Hall and Guo, Gastroenterology 2017; 152, 1718-1727. Fothergill et al. Obesity 2016; 24, 1612-1619 Fothergill et al. Obesity 2016; 24, 1612-1619 Everything increased, especially weight and fat mass Fothergill et al. Obesity 2016; 24, 1612-1619 Conclusions after 6-year follow-up: - RMR remained suppressed (- 500 kcal) despite important weight regain - The magnitude of metabolic adaptation increased after 6 years, but not related to weight regain - No correlations between degree of metabolic adaptation and fasting metabolites and hormones - Overall: 12% mean weight loss - 57% of participants maintained >10% weight loss most of them regained what they have lost - Caution: extreme and public nature of this intervention does not translate to all weight loss interventions bc really drastic, it’s a TV show Fothergill et al. Obesity 2016; 24, 1612-1619 Effect of diet – macronutrient composition Energy partitioning: isocaloric diets differing in macronutrient composition may result in preferential partitioning of energy storage toward body fat and away from body protein. Basis for the carbohydrate-insulin model and low carb diets: would decrease insulin secretion, increase lipolysis (favor use of endogenous fat stores) and use of FFA for a « metabolic advantage » of 400-600 kcal/d. Evidence: Meta-analysis, 32 controlled studies (n=563 participants), isocaloric diets low/high in carbs and fat, comparable protein content: Mean difference in EE = - 26 kcal/d with low fat diets Mean difference in body fat loss = - 16 g/d with low fat diets Significant, but meaningless No difference in effects of carbohydrates and fat ratio in EE and fat loss. Hall and Guo, Gastroenterology 2017; 152, 1718-1727. Effect of diet – macronutrient composition Diets high in protein positively influence fat-free mass during weight loss and weight gain:  During energy reduced-low fat diets, higher protein diet offset REE by about 150 kcal/d  During overfeeding, higher protein diet increased REE (in line with increased FFM)  Help maintain weight after weight loss Hall and Guo, Gastroenterology 2017; 152, 1718-1727. Summary oExcess energy (> expenditure) is the main driver of weight gain, not macronutrient composition. oThe body adapts to fasting by switching the main fuels from glucose to fatty acids and keto acids, to spare lean mass as a survival mechanism. oEnergy restriction and weight loss induce signals to increase appetite and food intake and decrease metabolism to conserve energy, all converge to favor weight regain. oIn weight-reduding diets, the macronutrient composition (fat to carbohydrate ratio) does not have a major effect on total weight loss. A high-protein diet favors the maintenance of lean mass and REE, and maintaining the new weight.