1. Obesity leads to metabolic syndrome leads to diabetes David A Bender Emeritus Professor of Nutritional Biochemistry University College London d.bender@ucl.ac.uk http://www.david-bender.purplecloud.net Presentation copyright © 2011 David A Bender for treatment that works http://www.healthwatch-uk.org

2. painted by Benjamin Marshall, Leicestershire Museum and Art Gallery postcard Obesity Daniel Lambert, 1770-1809 weight 330 kg (52st 11lb)

3. American Cancer Society Study: 750,000 people followed for 15 years (Lew & Garfinkel, 1979) Body weight and (premature) mortality

4. BMI 20 - 25desirable range BMI 25 - 30overweight BMI 30 - 40obesity BMI > 40severe obesity Body Mass Index = weight (kg) / height 2 (m)

6. Michelangelo’s David is to return to Italy after 2 years on loan to the USA Obesity

7. Percent of UK population overweight or obese 1980 1991 UK Department of Health data Health of the Nation target to halve obesity within a decade

8. UK Department of Health data, Chief Medical Officer’s report, 2002 Health of the Nation target to halve obesity within a decade Percent of UK population obese (BMI >30)

9. Overweight and obesity in UK men women

10. USA – meals outside home Critser, G. (2003) Fatland – how Americans became the fattest people in the world, Penguin Books, London Food is cheaper  higher in fat (especially saturated fat)  higher in high fructose syrups

11. Average PAL in UK (occupational + leisure) = 1.4 Desirable PAL for fitness = 1.7 In UK this is achieved by: 22% of men 13% of women Average and desirable physical activity

12. The distribution of fat is important Abdominal obesity – the male pattern Hip-thigh obesity – the female pattern

13. Source: Wilkin TJ, Ch 4 in Adult obesity: a paediatric challenge, Voss LD & Willkin TJ, Eds, Taylor & Francis, 2003 CT scan of the abdomen in an obese female; black areas show fat Subcutaneous fat Visceral (abdominal) fat The distribution of fat is important

14. Larsson et al, 1992 Sex difference in mortality from cardiovascular disease The distribution of fat is important

15. Diabetes with obesity and waist : hip ratio – women Hartz et al, 1984 The distribution of fat is important

16. insulin resistance dyslipidaemia (elevated triacylglycerol, low HDL) hypertension (high blood pressure) abdominal obesity polycystic ovary syndrome hyperuricaemia and gout Diagnosed by 3 or more of: Abdominal obesity waist circumference > 102cm (men) or 88 cm (women) Hypertriglyceridaemia > 150 mg /dL Low HDL cholesterol < 1 mmol /L (men) or < 1.3 mmol /L (women) High blood pressure > 130 / 85 mm Hg Fasting hyperglycaemia > 6.2 mmol /L Increased risk of atherosclerosis and cardiovascular disease Insulin resistance – the metabolic syndrome Globally 239 million people affected in 2010

17. White adipose tissue insulin receptor LPL glucose uptake fatty acid and triacylglycerol synthesis expression of lipoprotein lipase chylomicron and VLDL triacylglycerol fatty acids triacylglycerol synthesis The adipocyte before 1994 adrenaline receptor activation of hormone-sensitive lipase nefa + glycerol

18. The ob/ob obese mouse  Hyperphagic  but obese even when pair-fed  Poor cold adaptation

19. The ob/ob obese mouse Hypothesis A defect in non-shivering thermogenesis (facultative uncoupling of electron transport in mitochondria) Led to discovery of thermogenin in brown adipose tissue then other uncoupling proteins in muscle. white adipose tissue brown adipose tissue

20. Cinti S. Nutrition, Metabolism and Cardiovascular Disease 16: 579-74 2006. Brown and white adipose tissue in the same region Brown adipose tissue immunostained for UCP-1 40 µm

21. Brown and white adipose tissue in the same region Brown adipose tissue immunostained for UCP-1 multiple small lipid droplets 15 µm White adipose tissue single large lipid droplet Cinti S. Nutrition, Metabolism and Cardiovascular Disease 16: 579-74 2006.

22. Transdifferentiation of brown and white adipose tissue Adipose tissue dissected from a mouse maintained at 29°C for 10 days. In response to cold adaptation, areas of white adipose tissue differentiate into brown adipose tissue. In response to a high fat diet, areas of brown adipose tissue differentiate into white adipose tissue.

23. The ob/ob obese mouse Parabiosis Circulating factor from lean animals suppresses appetite in obese 1994 Zhang et al cloned the ob gene  expressed in adipose tissue  peptide has a signal sequence, suggesting it is secreted Injection of the peptide into obese mice led to weight loss  called leptin (Greek leptos = lean) Initial studies showed it acted on the hypothalamic appetite centres  depressing appetite  signalling state of adipose tissue reserves Great excitement that leptin or a leptin agonist would be a cure for obesity, but obese people secrete higher than normal amounts of leptin because they have more adipose tissue.

24. The main function of leptin is to signal the state of adipose tissues reserves and decrease food intake in the long term when they are adequate Leptin stimulates uncoupling proteins in brown adipose tissue and muscle so increasing energy expenditure Leptin There is synergy between insulin and leptin in control of food intake Insulin stimulates leptin synthesis and secretion Pancreatic islet  -cells have leptin receptors, leptin increases insulin secretion Leptin causes insulin resistance / antagonises some actions of insulin

25. In response to insulin resistance (i.e. hyperglycaemia) there is increased insulin synthesis and secretion – hyperinsulinism Insulin resistance – the metabolic syndrome

26. Signalling through the insulin receptor

27. Rapid actions via protein kinase B phosphorylation cascade:  stimulation of glucose transport  stimulation of glycogen synthesis  inhibition of lipolysis  stimulation of fatty acid synthesis  stimulation of translation / protein synthesis These responses are impaired in insulin resistance Signalling through the insulin receptor

28. Slower actions via mitogen-activated protein kinase (MAP kinase) no role in metabolic actions, involved in nuclear and mitogenic actions These responses are not affected by insulin resistance hence exaggerated responses in response to hyperinsulinism Increased proliferation of vascular smooth muscle leading to atherosclerosis and hypertension Signalling through the insulin receptor

29. Possible factors in insulin resistance  visceral adipose tissue has high lipolytic activity and releases nefa  nefa inhibit glucose metabolism  nefa may inhibit the PKB-mediated insulin signalling pathway  leptin antagonises some actions of insulin  various cytokines may cause insulin resistance:  tumour necrosis factor TNF-    interleukins IL-1 and IL-6  monocyte chemotactic protein  resistin  chemerin  cortisol may cause insulin resistance Insulin resistance – the metabolic syndrome

30. White adipose tissue cytosol nucleus triacylglycerol fatty acids cytokines leptin adiponectin angiotensinogen resistin complement C3 chemotactic agent for macrophages The adipocyte now: a variety of cytokines secreted chemerin

31. Adiponectin – low in obesity Adiponectin  increases insulin-induced tyrosine phosphorylation of insulin receptor  hence enhances insulin action  and decreases liver glucose output  activates 5’-AMP kinases so increases glucose and fatty acid oxidation  increases expression of genes involved in fatty acid transport and oxidation  increases expression of uncoupling proteins  decreases surface expression of vascular adhesion molecules  inhibits proliferation of vascular smooth muscle cells  so protective against atherosclerosis and thrombosis Secretion is inversely proportional to adipose tissue mass

32. Resistin – increased in obesity Inhibits adipocyte differentiation hence possible feedback inhibitor of adipogenesis Administration to mice increases hepatic glucose production Hence insulin antagonist

33. Chemerin pro-inflammatory actions chemoattractant for macrophages Chemerin impairs insulin signalling in muscle by phosphorylation of kinases reduced glucose uptake in muscle increased fatty acid uptake and intracellular esterification to TAG possible lipotoxic effect on muscle Large adipocytes (from obese subjects) secrete more chemerin per cell than smaller adipocytes (from lean subjects)

34. Source: Xu H et al, Journal of Clinical Investigation 112:12 1821-30, 2003 lean mouse x 100obese mouse x 100obese mouse x 400 lean mouse x 100obese mouse x 100obese mouse x 400 stained with toluidine blue immmunostained with anti-macrophage antibody Macrophage infiltration into adipose tissue

35. Macrophages form “crown-like structures” around larger adipocytes that are really lipid droplets that are the remnants of dead adipocytes. Hypertrophy of white adipocytes leads to cell death and macrophage infiltration. There is histological evidence of adipocyte death before macrophage infiltration. White adipose tissue is poorly vascularised and blood flow does not increase in obesity. Large adipocytes are too far from blood vessels to be adequately oxygenated; hypoxia leads to lactate production, which may be cytotoxic, leading to macrophage infiltration.

36. Macrophage infiltration into adipose tissue The critical size for visceral adipocytes to undergo necrosis and attract macrophages is smaller than that for sub-cutaneous adipocytes. Although brown and white adipocytes can undergo trans-differentiation, sub-cutaneous adipocytes develop from white adipocyte precursors visceral adipocytes arise develop from brown adipocyte precursors. The evolutionary function of visceral adipose tissue was presumably thermogenesis; it has differentiated into storage adipose tissue in response to a high fat diet.

37. Source: Wellen KE & Hotamisligil GK, Journal of Clinical Investigation 112:12 1785-8, 2003 Macrophages secrete TNF , stimulates preadipocytes and endothelial cells to secrete macrophage attractants phosphorylates critical serine residues in insulin receptor and IRS hence impairs insulin signalling Macrophage infiltration into adipose tissue

38. Source: Furukawa S et al, Journal of Clinical Investigation 114:12 1785-8, 2004 Oxidative stress in adipose tissue Significant positive correlation between: plasma TBARS and BMI or waist circumference Significant negative correlation between: plasma adiponectin and BMI or waist circumference

39. Source: Furukawa S et al, Journal of Clinical Investigation 114:12 1785-8, 2004 Increased oxidative stress and H 2 O 2 production in adipose tissue from obese mice Oxidative stress in adipose tissue

40. Source: Furukawa S et al, Journal of Clinical Investigation 114:12 1785-8, 2004 Decreased activity of superoxide dismutase and glutathione peroxidase in adipose tissue from obese mice Oxidative stress in adipose tissue

41. Source: Furukawa S et al, Journal of Clinical Investigation 114:12 1785-8, 2004 Elevated expression of NADPH oxidase Reduced expression of antioxidant enzymes in adipose tissue of obese mice NADPH + 2 O 2 Ž NADP + + 2 O 2 - + 2H + Oxidative stress in adipose tissue

42. Glucocorticoids are formed in adipose tissue abdominal obesity  insulin resistance / hyperglycaemia  hypertension due to excessive production and secretion of corticosteroid hormones Cortisol acts in the liver to increase gluconeogenesis and glucose release and in adipose tissue to increase lipolysis and release of nefa Cushing’s syndrome

43. 11-  hydroxysteroid dehydrogenase in adipose tissue converts inactive cortisone into active cortisol Plasma levels of cortisol are not elevated in obesity Cortisol formed in adipose tissue acts in the cells where it is formed Thiazolidinedione (PPAR  agonist) represses 11  HSD expression in cultured human adipocytes Glucocorticoids are formed in adipose tissue

44. Transgenic mice, overexpressing 11  HSD in adipose tissue  corticosterone unchanged in plasma, increased 15-30% in adipose tissue  after 15 weeks, body weight 16% higher than controls  mainly abdominal fat  hyperglycaemic  hyperinsulinaemic  insulin resistant  serum nefa and TAG elevated  plasma leptin increased  leptin resistance – leptin : body fat ratio 2x higher than controls  resistin expression reduced  brown fat uncoupling protein expression decreased Summarised by Wolf G, Nutrition Reviews 60:5 148-51, 2002 Is cortisol production in adipose tissue a factor in the metabolic syndrome? Is obesity a mild form of Cushing’s syndrome? Glucocorticoids are formed in adipose tissue

45. Obesity is a disease There are two problems: How to lose weight How to maintain lower body weight