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Obesitythe challengehow effective are current strategies?Cheap readily accessible energy dense food in generous portions and a sedentary life style in conjunction with socioeconomic factors such as food insecurity have been the subject of much research and are certainly important contributing factors to obesity.1Frustratingly limited or lack of long term success, and weight regain after a period of weight loss, are predominant outcomes in most intervention programmes.2,3 Weight loss is presumed to be a simple matter of reducing intake and increasing energy expenditure highlighted in the public mind by frequent references to excessive consumption of cfastd or junk food. This, more than anything else, sets the scene for a high level of covert and sometimes overt blaming of fat people. However, this simplistic view does not explain why in all societies there are those who manage to stay lean while others in the same obesogenic environment do not.Some instead become locked into a demoralising cycle of dieting and weight regain while some acquire eating disorders.3-5 The proportion who struggle with their weight, are restrained eaters or have undiagnosed binge eating disorders compared to those who stay slim with very little effort or awareness is not known. What is apparent is that obesity cannot be explained by psychosocial factors alone and occurs in all social strata.The bioscience: new insights into factors that cause weight gain and regainKennedys proposal (over 50 years ago) that difficulty in maintaining a normal weight might be due to physiological factors, that determineand defendbody fat stores was received with a considerable amount of scepticism at the time. However, a vast amount of research involving animal models and human data has validated this core concept. An overview summary that illustrates the complexity of energy homeostasis and the many physiological factors that are involved is summarised in Figure 1 and Table 1. Table 1. Non-psychosocial factors that affect energy turnover and fat storage Genetic factors Genes that influence obesity risk Genes that affect weight loss and its maintenance Physiological responses to environmental factors Epigenetics Neural plasticity Transcription factors e.g. PPARs and PGC-1 03b1which are important in regulating energy metabolism by regulating gene expression in muscle, liver and adipose tissue in response to environmental factors such as diet and exercise. Neuroendocrine factors in the hypothalamic regulation of food intake Hypothalamic orexigenic peptides: neuropeptide Y (NPY) agouti-related peptide(AgRP) orexin, galanin melanin concentrating hormone (MCH ) Hypothalamic anorexic peptides: cocaine & amphetamine regulated transcript (CART) pro-opiomelanocortin (POMC) 03b1-melanin stimulating hormone(MSH ) corticotrophin releasing hormone (CRH) thyrotrophin releasing hormone (TRH) Neuroendocrine factors that modulate the hypothalamic regulation of food intake and/or affect energy turnover and fat storage GI tract hormones e.g. Choleocystokinin (CCK), grehlin, glucagon-like peptide 1 (GLP-1 ) Adipokines e.g. leptin, adinopectin Insulin- central satiety action and peripheral actions that promote glucose uptake and lipogenesis Opioid, dopaminergic, serotonergic and cannabinoid systems HPA axis and adrenal corticosteroid action Circadian clock Adrenergic stimulation Thyroid function Sex steroids Oxytocininsensitivity to its anorexic effect is important for weight gain during pregnancy Metabolic factors Raised blood glucose, lipids Nutrients, e.g. folate Oxidative stress Low grade inflammatory activation Oxidative metabolism Basal metabolic rate Body composition, e.g. low muscle/high central fat mass Mitochondrial function Thermogenesis Uncoupling proteins Transcription factors e.g. PPARs, SREBPs that regulate gene expression and fat metabolism in response to metabolic states Environmental factors Impacts of energy dense processed foods on physiological appetite regulation mechanism Low dietary fibresatiation factors High glycemic index carbohydrates High fat dietcauses leptin resistance Other nutrients, e.g. vitamins, antioxidants, phytochemicals Toxins, e.g. endocrine disrupters Side effects of medicationse.g. Atypical antipsychotics, De-Provera, Tricyclic antidepressants Prevailing temperature PPAR = Peroxisome proliferator -activated receptors the antidiabetic thiazolidinediones drugs such as such as ACTOS act as highly selective PPAR agonists; PGC-1 03b1 = PPAR gamma coactivator-1 03b1; SREBP = sterol regulatory element binding proteins Refs 6-23, 25, 26,2932, ,41, 42. Figure 1. Schematic representation of the hypothalamic regulation of the input side of energy homeostasis Note: Consumption of food results in the release of satiation signals that limit meal size such ascholeocystokinin(CCK), glucagon-like peptide 1(GLP-1 ) and vagal stimulation that act in the hypothalamus to reduce food intake. Conversely ghrelin released by gastric cells stimulates eating via activation of neuropeptide Y (NPY) and Agouti-related peptide (AgRP) neurons in the lateral hypothalamic area (LHA) and inhibits the pro-opiomelanocortin (POMC) and cocaine & amphetamine regulated transcript factor (CART) neurons in the arcuate nucleus (ARC). Ghrelin levels rise during fasting but also anticipated meal times and its suppression after eating depends on the kilojoules consumed. Leptin and insulin can reduce food intake by activating the POMC and CART neurons via 03b1-melanocyte stimulating hormone (MSH) acting on melanocortin receptors (MCR3 and MCR4) in the paraventricular nuclei (PVN) while inhibiting the ghrelin-NPY/AgRP neurons. These composite pathways involved in energy homeostasis have many neural/hormonal links which respond to varying physiological demands such as growth and pregnancy and to the environment. Ultimately body fat stores are defended at a level determined by an interaction of genetic, epigenetic, early developmental and environmental factors. Relevance to obesity is that the effect of decreasing levels of leptin and insulin with weight loss and dietary restriction trigger an increase in food intake via these mechanisms. The same applies with impaired central signalling that occurs with insulin and leptin resistance6-10,30 More detail can be found in many recent reviews.6-10,30 Energy homeostasis involves a two-way interchange of information between the brain, particularly the hypothalamus, and peripheral tissues. There are short term signals released by the digestive system that decrease food intake such as choleocystokinin (CCK) released in response to food consumption. Conversely, ghrelin, a potent stimulus for eating, is produced during the fasting state. The central effects on food consumption are integrated with longer term adiposity signals, such as leptin, released by adipose cells, and insulin, that reflect body energy stores. Reward pathways including the opioid, dopaminergic and cannabinoid system may modulate or override the hypothalamic energy homeostasis pathway, particularly with respect to the consumption of energy dense food and may make some inheritently more vulnerable to compulsive overeating.9,11 The important point we want to highlight is that a complex circuitry of physiological pathways regulate energy intake, metabolism, storage and basal energy output - and therefore body fat stores. Physiological factors as well as environmental factors are important. This is verified by the fact that drugs such as amphetamines, Rimonabant (a specific cannabinoid antagonist of CB-1 receptors, recently withdrawn as an anti-obesity agent after post marketing monitoring revealed adverse psychological effects) act directly on these central pathways in the brain (Figure 1) to depress appetite and can exert their effects even in an obesogenic environment. To date, the bioscience research has not been able to provide a simple pharmacological solution to a complex problem since side-effects and/or the development of tolerance limits their use. This is perhaps not surprising in view of the multifaceted nature of the physiological factors involved in energy intake, turnover and storage in the body. However, insights gained from the bioscience research have provided a deeper understanding for the limited long-term success of many intervention programmes. The role of early development and epigenetics Research into the developmental origins of adult disease and epigenetics is providing further insight, and revealing health concerns. Following on from the classical epidemiological studies by Barker and Osmond, much subsequent research in animal models and human populations has linked a compromised intra-uterine environment with an increased risk for central and visceral obesity, hypertension, raised fasting plasma glucose and triglycerides and decreased high density lipoprotein-cholesterola common definition of the metabolic syndrome.12,13 Insulin insensitivity, hyperinsulinaemia and salt-sensitivity hypertension, pro-inflammatory status, oxidative stress are also commonly found together with the metabolic syndrome and imply a high risk for type 2 diabetes mellitus and cardiovascular disease in adult life.14,15 The Oxford Round Table Forum shared concerns about an escalating obesity problem among previously nutritionally deprived communities around the world with nutritional transition. Of more relevance to communities with abundant processed food supplies is that maternal gestational diabetes and obesity likewise creates a significant increased risk for obesity in offspring, with metabolic compromise such as insulin resistance already apparent at birth.16 Recent research at the molecular level has identified permanent changes in gene expression (epigenetic changes) as mediators for these effects.17 Of particular concern is that these epigenetic changes may be carried through to the next generation of children born into an obesogenic environment. The metabolic syndrome: an anomaly of metabolism that pre-disposes to obesity and the associated health risks Key features of the metabolic syndrome are insulin resistance, a low grade chronic inflammatory state and visceral obesity.12,13 Peripheral insulin resistance is linked with obesity and markedly improves with weight loss. However, insulin resistance and other components of the metabolic syndrome,including an increased tendency towards abdominal obesity, may occur before the onset of obesity as a result of intra-uterine exposure to either a deprived or overabundant energy supply in animal models as well as from human data.14-17 As well as its peripheral effects, insulin also acts in the brain as an important satiety signal in conjunction with leptin and, since human obesity is commonly linked with both leptin and insulin resistance18,19 this may result in a vicious spiral of escalating weight gain, and problems with shedding the extra kilograms gained. There are other physiological factors that also operate to make some people more susceptible than others to obesity, and the metabolic syndrome including cortisol and the hypothalamic-pituitary axis (HPA),20 mitochondrial dysfunction,21 uncoupling proteins22, and sex hormones23 (see Figure 1, Table 1). This rapidly expanding body of basic research provides further support of the evidence that some people are inherently more vulnerable. What also emerges is that the increased propensity for central fat gain is part of the metabolic syndrome and may arise early in development. This highlights the importance of early screening and implementation of appropriate interventions for those at increased risk of the metabolic syndrome and becoming obese. For obesity-related health risks, fat distribution is the critical factor. It is visceral fat that is linked with the release of pro-inflammatory cytokines such as tumour necrosis factor (TNF 03b1) and interleukin-6 (IL-6), chronic inflammation and oxidative damage and the classic risk factors of hypertension and dyslipidaemia for cardiovascular disease, insulin resistance and type 2 diabetes mellitus as well as obesity-linked malignancies.24,25 Conversely, adiponectin is linked with anti-inflammatory, anti-oxidative, insulin-sensitising and anti-cancer properties and low levels of this protective cytokine are associated with the metabolic syndrome.26 It is interesting to note that Roux-en-Y gastric bypass surgery is able to reverse the metabolic effects of obesity virtually immediately, often before significant weight reduction.27 This is possibly due to enhanced nutrient sensing and stimulation of lower intestinal hormones such as GLP-1 or decreased production of ghrelin.27 However, energy deprivation in the obese prior to/at bypass surgery also contributes to rapid metabolic normalisation. The role of genetics The importance of genetic factors in obesity initially arose from twin and population studies and, more recently, from the human genome data. Cases of obesity linked to a single gene mutation have been identified in recent years, such as the FTO (fat mass and obesity associated gene)but human obesity is predominantly polygenic in nature.29-31 Currently more than 70 genes that may contribute to obesity have been identified, and genetic factors may account for 30-70% variability in BMI and waist/hip ratio, variations in energy homeostasis, eating behaviour, weight loss maintenance and ethnic differences in susceptibility to obesity. 29,31 It is the interplay of thesegenetic differences with socioeconomic and cultural differences and psychosocial factors that predisposes to obesity risk and re-affirms the value of early interventions. The bioscience: suggested directions for clinical practice Debates and presentations at the Round Table had several themes which could inform clinical practice: Obesity results from a chronic disruption of innate energy homeostasis mechanisms which may arise as a result of genetic, epigenetic or environmental factors, resulting in an increased risk for obesity for some people when faced with the same obesogenic environment as their leaner counterparts. The achievement and maintenance of a supposedly cideald BMI of 19-25 is not only elusive but an impossible challenge for some, Dieting, and 8diet induced behaviours, generally do not lead to lasting weight loss or health benefits,3-5,10,29 may predispose to weight regain and sensitise the brains reward circuitry and function,30 lead to an upward cogwheel 8resetting of energy homeostasis10 and may promote redistribution and increased visceral fat deposition with its related health risks.20,33 Peripheral hip and thigh fat is not just neutral but may be protective34 and it is essential to distinguish between weight loss and fat loss34 and health. Some sources consider long term successful outcomes can be seen with Bariatric surgery27but clearly this is not a general option, and has risks at surgery and often post surgery nutrition issues.28 In view of these considerations perhaps we would achieve better health for all if we were to modify our interventions and attitudes appropriately. Too often attempts to lose weight lead to frustration, guilt and ultimately failure and pre-occupation with food and an upward spiral of weight cycling. What is apparent is a need for early, realistic, achievable interventions with an emphasis on health rather than a narrow focus on weight loss. The protective effects of a healthy diet in conjunction with physical activity as part of a healthy lifestyle are seen even with quite modest effects in weight loss.35 Enabling people to do this in an obesogenic environment with cheap over-palatable food and which is not conducive to physical activity are major barriers. There has been some debate and confusion over what really constitutes chealthy eatingd by consumers, epidemiological and health workers as information available contains many contradictions. In NZ fat intake decreased from 37.5% to 35% of the kilojoules between 1989 to the 1997 in response to health messages to cut back fat. However, over the same time period, obesity levels increased from 11% to 17%36. Unsaturated fats, such as olive oil and omega-3, are healthy alternatives to saturated fats but just as energy dense. The only nutritional advantage that pasta has over white bread is its low glycemic index. Epidemiological studies that link higher intakes of individual nutrients such as carotenoids, dietary fibre, folic acid, and potassium with reduced health risks often miss the significant point that higher intakes of these nutrients are indicators of a higher intake of fruit, vegetables, whole grains and the significance of other health promoting substances found in these foods. The one certainty seems to be the value of a varied and generous intake of fruit and vegetables, whole grain cereals (in moderation and with consideration of other starchy staples), dairy foods, fish and modest servings of animal derived protein, and unsaturated fats instead of saturated and trans fat found in processed foods. It is important to eat foods that are not just energy dilute but provide generous supplies of many nutrients as well as antioxidants, cancer-protecting phytochemicals and dietary fibre and are satisfying and enjoyable. An example is the Mediterranean type diet, which has beneficial metabolic effects, established benefits for overall health and wellbeing and is conducive to longer term sustained weight loss.35 In contrast, dietary regimes are often nutritionally unbalanced and not adhered to in the long term and may have undesirable side effects.29,33,35 Therefore, for sustained long term health benefits, a more productive emphasis should be on healthy eating (rather than weight loss per se) as part of a healthy life style, and on public education that facilitates and promotes informed food choices that appeal37 ideally with wider community and food industry involvement. Debates at the Round Table about exercise noted that there was no evidence to show that exercise reliably caused weight loss but there is a great deal of evidence to show the beneficial effects of increased movement of any form with incremental benefits as exercise increases.35,38,39 This is an area where our current focus on weight loss may be counterproductive as many people begin an exercise programme to achieve weight loss and abandon it when weight loss does not occur. Health professionals could show leadership in promoting the intrinsic benefits of exercise entirely removed from a focus on weight loss and supporting persistence and enjoyment instead. Creating a clinical environment in which the person does not feel judged or criticised is critical to fostering attendance and participation. Another area of importance to clinical practice is advice about sleep habits. Multiple epidemiologic studies have shown an association between short sleep and higher BMI even when other confounders are controlled for.40-41 Studies of healthy volunteers in laboratory settings have shown that sleep restriction is associated with an adverse impact on glucose homeostasis and is also related to alterations in appetite and satiety. Conclusions What is apparent from a body of research over the last decade is that there are no short cuts or simple solutions to the obesity issue at the individual level and it is unrealistic to expect these. Obesity is a field in which leading researchers crepeatedly concede an alarming lack of knowledge about even the most fundamental questions while, often within the same article, making bold and unsupported generalisations about the causes and cures for obesityd (Gard, p.36).2 Such uncertainty was clearly evident at Round Table discussions and whilst many clinicians may be well aware of the scientific uncertainty it has not yet translated into more appropriate, sensitive public or clinical responses to those who live with obesity. At the community level there is much to be achieved. Community embedded processes which increase access to safe exercise and increase equitable access to good nutrition are valuable and vitally important, and need to be long term. It is unfortunate that we will not be able to assess the long term outcomes of the Healthy Eating Healthy Action initiatives due to changes in government policy. For individuals, we could move from a tendency to blame towards acknowledging that some may be disadvantaged because of biological factors. Simply concentrating on BMI focuses our attention away from inactivity and unhealthy dietary choices which are empirically recognised as a far more accurate predictor of disease than body weight per se. For many people the current cheap, processed highly palatable and energy dense food environment makes it more difficult to acquire, 8choose and eat healthier options. Regular physical activity is better for health than pure weight loss and is hard for many people, especially in an urban environment that discourages this. Dealing with obesity at a community or individual level needs supportive long-term commitment and investment better served by interventions that are realistic, achievable and with an overall focus on health in its fullest sense, and for people of any size.

Summary

Abstract

Aim

Method

Results

Conclusion

Author Information

Suzi Penny, Senior Lecturer, Health and Life Sciences, Institute of Food, Nutrition and Human Health, Massey University, Wellington; Jenny Carryer, Professor of Nursing, School of Health and Social Services, Massey University, Palmerston North

Acknowledgements

'- We thank Dr Rachel Page (Institute Food, Nutrition and Human Health, Massey University) for her comments and feedback.-

Correspondence

Suzi Penny, MSc (Distinction in Biochemistry), Senior Lecturer, Health and Life Sciences, Institute of Food, Nutrition and Human Health, Massey University, Private Bag 756, Wellington 6140, New Zealand

Correspondence Email

S.J.Penny@massey.ac.nz

Competing Interests

None

'-  Oxford Round Table Forum on Public Policy on Obesity. The affluent society and the quest for treatment. St Annes College, Oxford, Spring 2008. http://www.oxfordroundtable.com/index.php/view/Home-Main;http://forumonpublicpolicy.com/papers08spring.html#health--  Gard M. Understanding obesity by understanding desire. In: Malson H, Burns M, editors. Critical feminist approaches to eating disorders. United Kingdom: Routledge; 2009.--  Bessesen DH. Update on obesity. J Clin Endocrinol Metab. 2008;93(6):2027-2034--  Carryer J. Embodied largeness: a significant womens health issue. Nurs Inq. 2001;8(2):90-97.--  Penny S. Obesity: More complex than just a case of too much junk food? A case study. Proc Nutr Soc NZ. 2008;Dec.--  Farooqi IS, ORahilly S. Leptin: a pivotal regulator of human energy homeostasis. Am J Clin Nutr. 2009; 89(3):980S-984S.--  Valassi E, Scacchi M, Cavagnini F. Review: Neuroendocrine control of food intake. Nutr Metab Cardiovasc Dis. 2008;18:158-168.--  Neary MT, Batterham RL. Gut hormones: Implications for the treatment of obesity. Pharmacology & Therapeutics. 2009;124:44-56.--  Berthoud HR. Interactions between the ccognitived and cmetabolicd brain in the control of food intake. Physiology & Behaviour. 2007;91486-498.--  Levin BE. Symposium report: Why some of us get fat and what we can do about it. J Physiol. 2007;583:425-430.--  Taylor VH, Curtis M, Davis C. The obesity epidemic: the role of addiction. Can Med Ass J. 2010;182(4):327-328.--  Cornier MA, Dabelea D, Hernandez TL, et al. The metabolic syndrome. Endocr Rev. 2008;29:777-822.--  Alberti KGM, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome:A Joint Interim Statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society and the International Association for the Study of Obesity. Circulation 2009;120:1640-1645.--  Gluckman PD, Hanson MA, Cooper C, et al. Effect of in utero and early-life conditions on adult health and disease. New Engl J Med. 2008;359(1):61-73.--  Taylor PD, Poston L. Developmental programming of obesity in mammals. Exp Physiol. 2007;92(2):287-298.--  Catalano PM, Preseley L, Minium J, et al. Fetuses of obese mothers develop insulin resistance in utero. Diabetes Care. 2009;32:1076-1080.--  Waterland RA, Michels KB. Epigenetic epidemiology of the developmental origins hypothesis. Ann Rev Nutr. 2007;27:363-388.--  Morrison DC. Leptin resistance and the response to positive energy balance. Physiol Behav. 2008;94:660-663.--  Ahima RS. Revisiting leptins role in obesity and weight loss. J Clin Invest. 2008;118(7):2380-2383.--  Anagnostis P, Athyros VG, Tziomalos K, et al. The pathogenic role of cortisol in the metabolic syndrome: A hypothesis. J Clin Endocrinol Metab. 2009;94(8):2692-2701.--  Bhopal RS, Rafnsson SB. Could mitochondrial efficiency explain the susceptibility to adiposity, metabolic syndrome, diabetes and cardiovascular disease in South Asian populations? Int J Epi. 2009;38:1072-1081.--  Jia JJ, Zhang X, Ge R, et al. The polymorphisms of UCP2 and UCP3 genes associated with fat metabolism, obesity and diabetes. Obs Rev. 2009;10:519-526.--  Shi H, Seeley RJ, Clegg DJ. Review: Sexual differences in the control of energy homeostasis. Frontiers Neuroendrin. 2009;30:396-404.--  Barb D, Williams CJ, Neuwirth AK, et al. Adiponectin in relation to malignancies: a review of existing basic research and clinical evidence. Am J Clin Nutr. 2007;86(supple):858S-66S.--  Wozniak SE, Gee LL, Wachtel MS, et al. Adipose tissue: the new endocrine organ? A review article. Dig Dis Sci. 2009;54:1847-1856.--  Behre CJ. Adiponectin, obesity and atherosclerosis. Scan J Clin Lab Invest. 2007; 67:449-458--  Thaler PJ, Cummings DE. Mini-review: Hormonal and metabolic mechanisms of diabetes remission after gastrointestinal surgery. Endocrinology. 2009;150:2518-2525.--  Ziegler O, Sirveaux MA, Brunaud L, et al. Medical follow up after bariatric surgery: nutritional and drug issues. General recommendations for the prevention and treatment of nutritional deficiencies. Diabetes & Metabolism 2009;35:544-557.--  Hainer V, Zamrazilova H, Spalova J, et al. Mini-review: Role of hereditary factors in weight loss and its maintenance. Physiol Res. 2008;57 (Supple1):S1-S15.--  Figlewicz DP, Benoit SC. Insulin, leptin and food reward: update 2008. Am J Physiol Regul Integr Comp Physiol. 2008; 296:R9-R19.--  van Vliet JV, Hofker MH, van der Schouw YT, et al. Genetic variation in the hypothalamic pathways and its role in obesity. Obesity Rev. 2009;10:593-609.--  Fridlyand LE, Philipson LH. Cold climate genes and the prevalence of type 2 diabetes mellitus. Med Hypoth. 2006;67:1034-1041--  Jackman MR, Steig A, Higgins JA, et al. Weight regain after sustained weight reduction is accompanied by suppressed oxidation of dietary fat and adipocyte hyperplasia. Am J Physiol Regul Interg Comp Physiol. 2008;294:R1117-R1129.--  Lavie CJ, Milani RV, Ventura HO. Obesity and cardiovascular disease: Risk factor, paradox and impact of weight loss. J Am Coll Cardiol. 2009;53:1925-32--  Magkos F, Yannakoulia M, Chan JL, et al. Management of the metabolic syndrome and type 2 diabetes through life style modification. Ann Rev Nutr. 2009;29:223-56--  Russell DG, Parnell WR, Wilson NC et al. NZ Food: NZ People. Key results of the 1997 National Nutrition Survey. Ministry of Health, Wellington. 1999.--  The New Zealand Healthy Food Guide. www.healthyfood.co.nz--  Lee DC, Sui X, Blair SN. Does physical activity ameliorate the health hazards of obesity? Brit J of Sports Medicine. 2009;43(1):49-51.--  Fogelholm M. Obesity comorbidities: Physical activity, fitness and fatness: relations to mortality, morbidity and disease risk factors. A systematic review. Obesity Reviews. 2009;11:202-221.--  Patel SR, Hu FB. Short sleep duration and weight gain: a systematic review. Obesity (Silver Spring). 2008;16(3):643-653.--  Knutson KL. Associations between sleep loss and increased risk of obesity and diabetes. Ann NY Acad Sci. 2009;1129(1):287-304.--  Redinger RN. Fat storage and the biology of energy expenditure [review article]. Translational Res. 2009 Aug;154(2):52-60. Epub 2009 Jun 11.-

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Obesitythe challengehow effective are current strategies?Cheap readily accessible energy dense food in generous portions and a sedentary life style in conjunction with socioeconomic factors such as food insecurity have been the subject of much research and are certainly important contributing factors to obesity.1Frustratingly limited or lack of long term success, and weight regain after a period of weight loss, are predominant outcomes in most intervention programmes.2,3 Weight loss is presumed to be a simple matter of reducing intake and increasing energy expenditure highlighted in the public mind by frequent references to excessive consumption of cfastd or junk food. This, more than anything else, sets the scene for a high level of covert and sometimes overt blaming of fat people. However, this simplistic view does not explain why in all societies there are those who manage to stay lean while others in the same obesogenic environment do not.Some instead become locked into a demoralising cycle of dieting and weight regain while some acquire eating disorders.3-5 The proportion who struggle with their weight, are restrained eaters or have undiagnosed binge eating disorders compared to those who stay slim with very little effort or awareness is not known. What is apparent is that obesity cannot be explained by psychosocial factors alone and occurs in all social strata.The bioscience: new insights into factors that cause weight gain and regainKennedys proposal (over 50 years ago) that difficulty in maintaining a normal weight might be due to physiological factors, that determineand defendbody fat stores was received with a considerable amount of scepticism at the time. However, a vast amount of research involving animal models and human data has validated this core concept. An overview summary that illustrates the complexity of energy homeostasis and the many physiological factors that are involved is summarised in Figure 1 and Table 1. Table 1. Non-psychosocial factors that affect energy turnover and fat storage Genetic factors Genes that influence obesity risk Genes that affect weight loss and its maintenance Physiological responses to environmental factors Epigenetics Neural plasticity Transcription factors e.g. PPARs and PGC-1 03b1which are important in regulating energy metabolism by regulating gene expression in muscle, liver and adipose tissue in response to environmental factors such as diet and exercise. Neuroendocrine factors in the hypothalamic regulation of food intake Hypothalamic orexigenic peptides: neuropeptide Y (NPY) agouti-related peptide(AgRP) orexin, galanin melanin concentrating hormone (MCH ) Hypothalamic anorexic peptides: cocaine & amphetamine regulated transcript (CART) pro-opiomelanocortin (POMC) 03b1-melanin stimulating hormone(MSH ) corticotrophin releasing hormone (CRH) thyrotrophin releasing hormone (TRH) Neuroendocrine factors that modulate the hypothalamic regulation of food intake and/or affect energy turnover and fat storage GI tract hormones e.g. Choleocystokinin (CCK), grehlin, glucagon-like peptide 1 (GLP-1 ) Adipokines e.g. leptin, adinopectin Insulin- central satiety action and peripheral actions that promote glucose uptake and lipogenesis Opioid, dopaminergic, serotonergic and cannabinoid systems HPA axis and adrenal corticosteroid action Circadian clock Adrenergic stimulation Thyroid function Sex steroids Oxytocininsensitivity to its anorexic effect is important for weight gain during pregnancy Metabolic factors Raised blood glucose, lipids Nutrients, e.g. folate Oxidative stress Low grade inflammatory activation Oxidative metabolism Basal metabolic rate Body composition, e.g. low muscle/high central fat mass Mitochondrial function Thermogenesis Uncoupling proteins Transcription factors e.g. PPARs, SREBPs that regulate gene expression and fat metabolism in response to metabolic states Environmental factors Impacts of energy dense processed foods on physiological appetite regulation mechanism Low dietary fibresatiation factors High glycemic index carbohydrates High fat dietcauses leptin resistance Other nutrients, e.g. vitamins, antioxidants, phytochemicals Toxins, e.g. endocrine disrupters Side effects of medicationse.g. Atypical antipsychotics, De-Provera, Tricyclic antidepressants Prevailing temperature PPAR = Peroxisome proliferator -activated receptors the antidiabetic thiazolidinediones drugs such as such as ACTOS act as highly selective PPAR agonists; PGC-1 03b1 = PPAR gamma coactivator-1 03b1; SREBP = sterol regulatory element binding proteins Refs 6-23, 25, 26,2932, ,41, 42. Figure 1. Schematic representation of the hypothalamic regulation of the input side of energy homeostasis Note: Consumption of food results in the release of satiation signals that limit meal size such ascholeocystokinin(CCK), glucagon-like peptide 1(GLP-1 ) and vagal stimulation that act in the hypothalamus to reduce food intake. Conversely ghrelin released by gastric cells stimulates eating via activation of neuropeptide Y (NPY) and Agouti-related peptide (AgRP) neurons in the lateral hypothalamic area (LHA) and inhibits the pro-opiomelanocortin (POMC) and cocaine & amphetamine regulated transcript factor (CART) neurons in the arcuate nucleus (ARC). Ghrelin levels rise during fasting but also anticipated meal times and its suppression after eating depends on the kilojoules consumed. Leptin and insulin can reduce food intake by activating the POMC and CART neurons via 03b1-melanocyte stimulating hormone (MSH) acting on melanocortin receptors (MCR3 and MCR4) in the paraventricular nuclei (PVN) while inhibiting the ghrelin-NPY/AgRP neurons. These composite pathways involved in energy homeostasis have many neural/hormonal links which respond to varying physiological demands such as growth and pregnancy and to the environment. Ultimately body fat stores are defended at a level determined by an interaction of genetic, epigenetic, early developmental and environmental factors. Relevance to obesity is that the effect of decreasing levels of leptin and insulin with weight loss and dietary restriction trigger an increase in food intake via these mechanisms. The same applies with impaired central signalling that occurs with insulin and leptin resistance6-10,30 More detail can be found in many recent reviews.6-10,30 Energy homeostasis involves a two-way interchange of information between the brain, particularly the hypothalamus, and peripheral tissues. There are short term signals released by the digestive system that decrease food intake such as choleocystokinin (CCK) released in response to food consumption. Conversely, ghrelin, a potent stimulus for eating, is produced during the fasting state. The central effects on food consumption are integrated with longer term adiposity signals, such as leptin, released by adipose cells, and insulin, that reflect body energy stores. Reward pathways including the opioid, dopaminergic and cannabinoid system may modulate or override the hypothalamic energy homeostasis pathway, particularly with respect to the consumption of energy dense food and may make some inheritently more vulnerable to compulsive overeating.9,11 The important point we want to highlight is that a complex circuitry of physiological pathways regulate energy intake, metabolism, storage and basal energy output - and therefore body fat stores. Physiological factors as well as environmental factors are important. This is verified by the fact that drugs such as amphetamines, Rimonabant (a specific cannabinoid antagonist of CB-1 receptors, recently withdrawn as an anti-obesity agent after post marketing monitoring revealed adverse psychological effects) act directly on these central pathways in the brain (Figure 1) to depress appetite and can exert their effects even in an obesogenic environment. To date, the bioscience research has not been able to provide a simple pharmacological solution to a complex problem since side-effects and/or the development of tolerance limits their use. This is perhaps not surprising in view of the multifaceted nature of the physiological factors involved in energy intake, turnover and storage in the body. However, insights gained from the bioscience research have provided a deeper understanding for the limited long-term success of many intervention programmes. The role of early development and epigenetics Research into the developmental origins of adult disease and epigenetics is providing further insight, and revealing health concerns. Following on from the classical epidemiological studies by Barker and Osmond, much subsequent research in animal models and human populations has linked a compromised intra-uterine environment with an increased risk for central and visceral obesity, hypertension, raised fasting plasma glucose and triglycerides and decreased high density lipoprotein-cholesterola common definition of the metabolic syndrome.12,13 Insulin insensitivity, hyperinsulinaemia and salt-sensitivity hypertension, pro-inflammatory status, oxidative stress are also commonly found together with the metabolic syndrome and imply a high risk for type 2 diabetes mellitus and cardiovascular disease in adult life.14,15 The Oxford Round Table Forum shared concerns about an escalating obesity problem among previously nutritionally deprived communities around the world with nutritional transition. Of more relevance to communities with abundant processed food supplies is that maternal gestational diabetes and obesity likewise creates a significant increased risk for obesity in offspring, with metabolic compromise such as insulin resistance already apparent at birth.16 Recent research at the molecular level has identified permanent changes in gene expression (epigenetic changes) as mediators for these effects.17 Of particular concern is that these epigenetic changes may be carried through to the next generation of children born into an obesogenic environment. The metabolic syndrome: an anomaly of metabolism that pre-disposes to obesity and the associated health risks Key features of the metabolic syndrome are insulin resistance, a low grade chronic inflammatory state and visceral obesity.12,13 Peripheral insulin resistance is linked with obesity and markedly improves with weight loss. However, insulin resistance and other components of the metabolic syndrome,including an increased tendency towards abdominal obesity, may occur before the onset of obesity as a result of intra-uterine exposure to either a deprived or overabundant energy supply in animal models as well as from human data.14-17 As well as its peripheral effects, insulin also acts in the brain as an important satiety signal in conjunction with leptin and, since human obesity is commonly linked with both leptin and insulin resistance18,19 this may result in a vicious spiral of escalating weight gain, and problems with shedding the extra kilograms gained. There are other physiological factors that also operate to make some people more susceptible than others to obesity, and the metabolic syndrome including cortisol and the hypothalamic-pituitary axis (HPA),20 mitochondrial dysfunction,21 uncoupling proteins22, and sex hormones23 (see Figure 1, Table 1). This rapidly expanding body of basic research provides further support of the evidence that some people are inherently more vulnerable. What also emerges is that the increased propensity for central fat gain is part of the metabolic syndrome and may arise early in development. This highlights the importance of early screening and implementation of appropriate interventions for those at increased risk of the metabolic syndrome and becoming obese. For obesity-related health risks, fat distribution is the critical factor. It is visceral fat that is linked with the release of pro-inflammatory cytokines such as tumour necrosis factor (TNF 03b1) and interleukin-6 (IL-6), chronic inflammation and oxidative damage and the classic risk factors of hypertension and dyslipidaemia for cardiovascular disease, insulin resistance and type 2 diabetes mellitus as well as obesity-linked malignancies.24,25 Conversely, adiponectin is linked with anti-inflammatory, anti-oxidative, insulin-sensitising and anti-cancer properties and low levels of this protective cytokine are associated with the metabolic syndrome.26 It is interesting to note that Roux-en-Y gastric bypass surgery is able to reverse the metabolic effects of obesity virtually immediately, often before significant weight reduction.27 This is possibly due to enhanced nutrient sensing and stimulation of lower intestinal hormones such as GLP-1 or decreased production of ghrelin.27 However, energy deprivation in the obese prior to/at bypass surgery also contributes to rapid metabolic normalisation. The role of genetics The importance of genetic factors in obesity initially arose from twin and population studies and, more recently, from the human genome data. Cases of obesity linked to a single gene mutation have been identified in recent years, such as the FTO (fat mass and obesity associated gene)but human obesity is predominantly polygenic in nature.29-31 Currently more than 70 genes that may contribute to obesity have been identified, and genetic factors may account for 30-70% variability in BMI and waist/hip ratio, variations in energy homeostasis, eating behaviour, weight loss maintenance and ethnic differences in susceptibility to obesity. 29,31 It is the interplay of thesegenetic differences with socioeconomic and cultural differences and psychosocial factors that predisposes to obesity risk and re-affirms the value of early interventions. The bioscience: suggested directions for clinical practice Debates and presentations at the Round Table had several themes which could inform clinical practice: Obesity results from a chronic disruption of innate energy homeostasis mechanisms which may arise as a result of genetic, epigenetic or environmental factors, resulting in an increased risk for obesity for some people when faced with the same obesogenic environment as their leaner counterparts. The achievement and maintenance of a supposedly cideald BMI of 19-25 is not only elusive but an impossible challenge for some, Dieting, and 8diet induced behaviours, generally do not lead to lasting weight loss or health benefits,3-5,10,29 may predispose to weight regain and sensitise the brains reward circuitry and function,30 lead to an upward cogwheel 8resetting of energy homeostasis10 and may promote redistribution and increased visceral fat deposition with its related health risks.20,33 Peripheral hip and thigh fat is not just neutral but may be protective34 and it is essential to distinguish between weight loss and fat loss34 and health. Some sources consider long term successful outcomes can be seen with Bariatric surgery27but clearly this is not a general option, and has risks at surgery and often post surgery nutrition issues.28 In view of these considerations perhaps we would achieve better health for all if we were to modify our interventions and attitudes appropriately. Too often attempts to lose weight lead to frustration, guilt and ultimately failure and pre-occupation with food and an upward spiral of weight cycling. What is apparent is a need for early, realistic, achievable interventions with an emphasis on health rather than a narrow focus on weight loss. The protective effects of a healthy diet in conjunction with physical activity as part of a healthy lifestyle are seen even with quite modest effects in weight loss.35 Enabling people to do this in an obesogenic environment with cheap over-palatable food and which is not conducive to physical activity are major barriers. There has been some debate and confusion over what really constitutes chealthy eatingd by consumers, epidemiological and health workers as information available contains many contradictions. In NZ fat intake decreased from 37.5% to 35% of the kilojoules between 1989 to the 1997 in response to health messages to cut back fat. However, over the same time period, obesity levels increased from 11% to 17%36. Unsaturated fats, such as olive oil and omega-3, are healthy alternatives to saturated fats but just as energy dense. The only nutritional advantage that pasta has over white bread is its low glycemic index. Epidemiological studies that link higher intakes of individual nutrients such as carotenoids, dietary fibre, folic acid, and potassium with reduced health risks often miss the significant point that higher intakes of these nutrients are indicators of a higher intake of fruit, vegetables, whole grains and the significance of other health promoting substances found in these foods. The one certainty seems to be the value of a varied and generous intake of fruit and vegetables, whole grain cereals (in moderation and with consideration of other starchy staples), dairy foods, fish and modest servings of animal derived protein, and unsaturated fats instead of saturated and trans fat found in processed foods. It is important to eat foods that are not just energy dilute but provide generous supplies of many nutrients as well as antioxidants, cancer-protecting phytochemicals and dietary fibre and are satisfying and enjoyable. An example is the Mediterranean type diet, which has beneficial metabolic effects, established benefits for overall health and wellbeing and is conducive to longer term sustained weight loss.35 In contrast, dietary regimes are often nutritionally unbalanced and not adhered to in the long term and may have undesirable side effects.29,33,35 Therefore, for sustained long term health benefits, a more productive emphasis should be on healthy eating (rather than weight loss per se) as part of a healthy life style, and on public education that facilitates and promotes informed food choices that appeal37 ideally with wider community and food industry involvement. Debates at the Round Table about exercise noted that there was no evidence to show that exercise reliably caused weight loss but there is a great deal of evidence to show the beneficial effects of increased movement of any form with incremental benefits as exercise increases.35,38,39 This is an area where our current focus on weight loss may be counterproductive as many people begin an exercise programme to achieve weight loss and abandon it when weight loss does not occur. Health professionals could show leadership in promoting the intrinsic benefits of exercise entirely removed from a focus on weight loss and supporting persistence and enjoyment instead. Creating a clinical environment in which the person does not feel judged or criticised is critical to fostering attendance and participation. Another area of importance to clinical practice is advice about sleep habits. Multiple epidemiologic studies have shown an association between short sleep and higher BMI even when other confounders are controlled for.40-41 Studies of healthy volunteers in laboratory settings have shown that sleep restriction is associated with an adverse impact on glucose homeostasis and is also related to alterations in appetite and satiety. Conclusions What is apparent from a body of research over the last decade is that there are no short cuts or simple solutions to the obesity issue at the individual level and it is unrealistic to expect these. Obesity is a field in which leading researchers crepeatedly concede an alarming lack of knowledge about even the most fundamental questions while, often within the same article, making bold and unsupported generalisations about the causes and cures for obesityd (Gard, p.36).2 Such uncertainty was clearly evident at Round Table discussions and whilst many clinicians may be well aware of the scientific uncertainty it has not yet translated into more appropriate, sensitive public or clinical responses to those who live with obesity. At the community level there is much to be achieved. Community embedded processes which increase access to safe exercise and increase equitable access to good nutrition are valuable and vitally important, and need to be long term. It is unfortunate that we will not be able to assess the long term outcomes of the Healthy Eating Healthy Action initiatives due to changes in government policy. For individuals, we could move from a tendency to blame towards acknowledging that some may be disadvantaged because of biological factors. Simply concentrating on BMI focuses our attention away from inactivity and unhealthy dietary choices which are empirically recognised as a far more accurate predictor of disease than body weight per se. For many people the current cheap, processed highly palatable and energy dense food environment makes it more difficult to acquire, 8choose and eat healthier options. Regular physical activity is better for health than pure weight loss and is hard for many people, especially in an urban environment that discourages this. Dealing with obesity at a community or individual level needs supportive long-term commitment and investment better served by interventions that are realistic, achievable and with an overall focus on health in its fullest sense, and for people of any size.

Summary

Abstract

Aim

Method

Results

Conclusion

Author Information

Suzi Penny, Senior Lecturer, Health and Life Sciences, Institute of Food, Nutrition and Human Health, Massey University, Wellington; Jenny Carryer, Professor of Nursing, School of Health and Social Services, Massey University, Palmerston North

Acknowledgements

'- We thank Dr Rachel Page (Institute Food, Nutrition and Human Health, Massey University) for her comments and feedback.-

Correspondence

Suzi Penny, MSc (Distinction in Biochemistry), Senior Lecturer, Health and Life Sciences, Institute of Food, Nutrition and Human Health, Massey University, Private Bag 756, Wellington 6140, New Zealand

Correspondence Email

S.J.Penny@massey.ac.nz

Competing Interests

None

'-  Oxford Round Table Forum on Public Policy on Obesity. The affluent society and the quest for treatment. St Annes College, Oxford, Spring 2008. http://www.oxfordroundtable.com/index.php/view/Home-Main;http://forumonpublicpolicy.com/papers08spring.html#health--  Gard M. Understanding obesity by understanding desire. In: Malson H, Burns M, editors. Critical feminist approaches to eating disorders. United Kingdom: Routledge; 2009.--  Bessesen DH. Update on obesity. J Clin Endocrinol Metab. 2008;93(6):2027-2034--  Carryer J. Embodied largeness: a significant womens health issue. Nurs Inq. 2001;8(2):90-97.--  Penny S. Obesity: More complex than just a case of too much junk food? A case study. Proc Nutr Soc NZ. 2008;Dec.--  Farooqi IS, ORahilly S. Leptin: a pivotal regulator of human energy homeostasis. Am J Clin Nutr. 2009; 89(3):980S-984S.--  Valassi E, Scacchi M, Cavagnini F. Review: Neuroendocrine control of food intake. Nutr Metab Cardiovasc Dis. 2008;18:158-168.--  Neary MT, Batterham RL. Gut hormones: Implications for the treatment of obesity. Pharmacology & Therapeutics. 2009;124:44-56.--  Berthoud HR. Interactions between the ccognitived and cmetabolicd brain in the control of food intake. Physiology & Behaviour. 2007;91486-498.--  Levin BE. Symposium report: Why some of us get fat and what we can do about it. J Physiol. 2007;583:425-430.--  Taylor VH, Curtis M, Davis C. The obesity epidemic: the role of addiction. Can Med Ass J. 2010;182(4):327-328.--  Cornier MA, Dabelea D, Hernandez TL, et al. The metabolic syndrome. Endocr Rev. 2008;29:777-822.--  Alberti KGM, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome:A Joint Interim Statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society and the International Association for the Study of Obesity. Circulation 2009;120:1640-1645.--  Gluckman PD, Hanson MA, Cooper C, et al. Effect of in utero and early-life conditions on adult health and disease. New Engl J Med. 2008;359(1):61-73.--  Taylor PD, Poston L. Developmental programming of obesity in mammals. Exp Physiol. 2007;92(2):287-298.--  Catalano PM, Preseley L, Minium J, et al. Fetuses of obese mothers develop insulin resistance in utero. Diabetes Care. 2009;32:1076-1080.--  Waterland RA, Michels KB. Epigenetic epidemiology of the developmental origins hypothesis. Ann Rev Nutr. 2007;27:363-388.--  Morrison DC. Leptin resistance and the response to positive energy balance. Physiol Behav. 2008;94:660-663.--  Ahima RS. Revisiting leptins role in obesity and weight loss. J Clin Invest. 2008;118(7):2380-2383.--  Anagnostis P, Athyros VG, Tziomalos K, et al. The pathogenic role of cortisol in the metabolic syndrome: A hypothesis. J Clin Endocrinol Metab. 2009;94(8):2692-2701.--  Bhopal RS, Rafnsson SB. Could mitochondrial efficiency explain the susceptibility to adiposity, metabolic syndrome, diabetes and cardiovascular disease in South Asian populations? Int J Epi. 2009;38:1072-1081.--  Jia JJ, Zhang X, Ge R, et al. The polymorphisms of UCP2 and UCP3 genes associated with fat metabolism, obesity and diabetes. Obs Rev. 2009;10:519-526.--  Shi H, Seeley RJ, Clegg DJ. Review: Sexual differences in the control of energy homeostasis. Frontiers Neuroendrin. 2009;30:396-404.--  Barb D, Williams CJ, Neuwirth AK, et al. Adiponectin in relation to malignancies: a review of existing basic research and clinical evidence. Am J Clin Nutr. 2007;86(supple):858S-66S.--  Wozniak SE, Gee LL, Wachtel MS, et al. Adipose tissue: the new endocrine organ? A review article. Dig Dis Sci. 2009;54:1847-1856.--  Behre CJ. Adiponectin, obesity and atherosclerosis. Scan J Clin Lab Invest. 2007; 67:449-458--  Thaler PJ, Cummings DE. Mini-review: Hormonal and metabolic mechanisms of diabetes remission after gastrointestinal surgery. Endocrinology. 2009;150:2518-2525.--  Ziegler O, Sirveaux MA, Brunaud L, et al. Medical follow up after bariatric surgery: nutritional and drug issues. General recommendations for the prevention and treatment of nutritional deficiencies. Diabetes & Metabolism 2009;35:544-557.--  Hainer V, Zamrazilova H, Spalova J, et al. Mini-review: Role of hereditary factors in weight loss and its maintenance. Physiol Res. 2008;57 (Supple1):S1-S15.--  Figlewicz DP, Benoit SC. Insulin, leptin and food reward: update 2008. Am J Physiol Regul Integr Comp Physiol. 2008; 296:R9-R19.--  van Vliet JV, Hofker MH, van der Schouw YT, et al. Genetic variation in the hypothalamic pathways and its role in obesity. Obesity Rev. 2009;10:593-609.--  Fridlyand LE, Philipson LH. Cold climate genes and the prevalence of type 2 diabetes mellitus. Med Hypoth. 2006;67:1034-1041--  Jackman MR, Steig A, Higgins JA, et al. Weight regain after sustained weight reduction is accompanied by suppressed oxidation of dietary fat and adipocyte hyperplasia. Am J Physiol Regul Interg Comp Physiol. 2008;294:R1117-R1129.--  Lavie CJ, Milani RV, Ventura HO. Obesity and cardiovascular disease: Risk factor, paradox and impact of weight loss. J Am Coll Cardiol. 2009;53:1925-32--  Magkos F, Yannakoulia M, Chan JL, et al. Management of the metabolic syndrome and type 2 diabetes through life style modification. Ann Rev Nutr. 2009;29:223-56--  Russell DG, Parnell WR, Wilson NC et al. NZ Food: NZ People. Key results of the 1997 National Nutrition Survey. Ministry of Health, Wellington. 1999.--  The New Zealand Healthy Food Guide. www.healthyfood.co.nz--  Lee DC, Sui X, Blair SN. Does physical activity ameliorate the health hazards of obesity? Brit J of Sports Medicine. 2009;43(1):49-51.--  Fogelholm M. Obesity comorbidities: Physical activity, fitness and fatness: relations to mortality, morbidity and disease risk factors. A systematic review. Obesity Reviews. 2009;11:202-221.--  Patel SR, Hu FB. Short sleep duration and weight gain: a systematic review. Obesity (Silver Spring). 2008;16(3):643-653.--  Knutson KL. Associations between sleep loss and increased risk of obesity and diabetes. Ann NY Acad Sci. 2009;1129(1):287-304.--  Redinger RN. Fat storage and the biology of energy expenditure [review article]. Translational Res. 2009 Aug;154(2):52-60. Epub 2009 Jun 11.-

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Obesitythe challengehow effective are current strategies?Cheap readily accessible energy dense food in generous portions and a sedentary life style in conjunction with socioeconomic factors such as food insecurity have been the subject of much research and are certainly important contributing factors to obesity.1Frustratingly limited or lack of long term success, and weight regain after a period of weight loss, are predominant outcomes in most intervention programmes.2,3 Weight loss is presumed to be a simple matter of reducing intake and increasing energy expenditure highlighted in the public mind by frequent references to excessive consumption of cfastd or junk food. This, more than anything else, sets the scene for a high level of covert and sometimes overt blaming of fat people. However, this simplistic view does not explain why in all societies there are those who manage to stay lean while others in the same obesogenic environment do not.Some instead become locked into a demoralising cycle of dieting and weight regain while some acquire eating disorders.3-5 The proportion who struggle with their weight, are restrained eaters or have undiagnosed binge eating disorders compared to those who stay slim with very little effort or awareness is not known. What is apparent is that obesity cannot be explained by psychosocial factors alone and occurs in all social strata.The bioscience: new insights into factors that cause weight gain and regainKennedys proposal (over 50 years ago) that difficulty in maintaining a normal weight might be due to physiological factors, that determineand defendbody fat stores was received with a considerable amount of scepticism at the time. However, a vast amount of research involving animal models and human data has validated this core concept. An overview summary that illustrates the complexity of energy homeostasis and the many physiological factors that are involved is summarised in Figure 1 and Table 1. Table 1. Non-psychosocial factors that affect energy turnover and fat storage Genetic factors Genes that influence obesity risk Genes that affect weight loss and its maintenance Physiological responses to environmental factors Epigenetics Neural plasticity Transcription factors e.g. PPARs and PGC-1 03b1which are important in regulating energy metabolism by regulating gene expression in muscle, liver and adipose tissue in response to environmental factors such as diet and exercise. Neuroendocrine factors in the hypothalamic regulation of food intake Hypothalamic orexigenic peptides: neuropeptide Y (NPY) agouti-related peptide(AgRP) orexin, galanin melanin concentrating hormone (MCH ) Hypothalamic anorexic peptides: cocaine & amphetamine regulated transcript (CART) pro-opiomelanocortin (POMC) 03b1-melanin stimulating hormone(MSH ) corticotrophin releasing hormone (CRH) thyrotrophin releasing hormone (TRH) Neuroendocrine factors that modulate the hypothalamic regulation of food intake and/or affect energy turnover and fat storage GI tract hormones e.g. Choleocystokinin (CCK), grehlin, glucagon-like peptide 1 (GLP-1 ) Adipokines e.g. leptin, adinopectin Insulin- central satiety action and peripheral actions that promote glucose uptake and lipogenesis Opioid, dopaminergic, serotonergic and cannabinoid systems HPA axis and adrenal corticosteroid action Circadian clock Adrenergic stimulation Thyroid function Sex steroids Oxytocininsensitivity to its anorexic effect is important for weight gain during pregnancy Metabolic factors Raised blood glucose, lipids Nutrients, e.g. folate Oxidative stress Low grade inflammatory activation Oxidative metabolism Basal metabolic rate Body composition, e.g. low muscle/high central fat mass Mitochondrial function Thermogenesis Uncoupling proteins Transcription factors e.g. PPARs, SREBPs that regulate gene expression and fat metabolism in response to metabolic states Environmental factors Impacts of energy dense processed foods on physiological appetite regulation mechanism Low dietary fibresatiation factors High glycemic index carbohydrates High fat dietcauses leptin resistance Other nutrients, e.g. vitamins, antioxidants, phytochemicals Toxins, e.g. endocrine disrupters Side effects of medicationse.g. Atypical antipsychotics, De-Provera, Tricyclic antidepressants Prevailing temperature PPAR = Peroxisome proliferator -activated receptors the antidiabetic thiazolidinediones drugs such as such as ACTOS act as highly selective PPAR agonists; PGC-1 03b1 = PPAR gamma coactivator-1 03b1; SREBP = sterol regulatory element binding proteins Refs 6-23, 25, 26,2932, ,41, 42. Figure 1. Schematic representation of the hypothalamic regulation of the input side of energy homeostasis Note: Consumption of food results in the release of satiation signals that limit meal size such ascholeocystokinin(CCK), glucagon-like peptide 1(GLP-1 ) and vagal stimulation that act in the hypothalamus to reduce food intake. Conversely ghrelin released by gastric cells stimulates eating via activation of neuropeptide Y (NPY) and Agouti-related peptide (AgRP) neurons in the lateral hypothalamic area (LHA) and inhibits the pro-opiomelanocortin (POMC) and cocaine & amphetamine regulated transcript factor (CART) neurons in the arcuate nucleus (ARC). Ghrelin levels rise during fasting but also anticipated meal times and its suppression after eating depends on the kilojoules consumed. Leptin and insulin can reduce food intake by activating the POMC and CART neurons via 03b1-melanocyte stimulating hormone (MSH) acting on melanocortin receptors (MCR3 and MCR4) in the paraventricular nuclei (PVN) while inhibiting the ghrelin-NPY/AgRP neurons. These composite pathways involved in energy homeostasis have many neural/hormonal links which respond to varying physiological demands such as growth and pregnancy and to the environment. Ultimately body fat stores are defended at a level determined by an interaction of genetic, epigenetic, early developmental and environmental factors. Relevance to obesity is that the effect of decreasing levels of leptin and insulin with weight loss and dietary restriction trigger an increase in food intake via these mechanisms. The same applies with impaired central signalling that occurs with insulin and leptin resistance6-10,30 More detail can be found in many recent reviews.6-10,30 Energy homeostasis involves a two-way interchange of information between the brain, particularly the hypothalamus, and peripheral tissues. There are short term signals released by the digestive system that decrease food intake such as choleocystokinin (CCK) released in response to food consumption. Conversely, ghrelin, a potent stimulus for eating, is produced during the fasting state. The central effects on food consumption are integrated with longer term adiposity signals, such as leptin, released by adipose cells, and insulin, that reflect body energy stores. Reward pathways including the opioid, dopaminergic and cannabinoid system may modulate or override the hypothalamic energy homeostasis pathway, particularly with respect to the consumption of energy dense food and may make some inheritently more vulnerable to compulsive overeating.9,11 The important point we want to highlight is that a complex circuitry of physiological pathways regulate energy intake, metabolism, storage and basal energy output - and therefore body fat stores. Physiological factors as well as environmental factors are important. This is verified by the fact that drugs such as amphetamines, Rimonabant (a specific cannabinoid antagonist of CB-1 receptors, recently withdrawn as an anti-obesity agent after post marketing monitoring revealed adverse psychological effects) act directly on these central pathways in the brain (Figure 1) to depress appetite and can exert their effects even in an obesogenic environment. To date, the bioscience research has not been able to provide a simple pharmacological solution to a complex problem since side-effects and/or the development of tolerance limits their use. This is perhaps not surprising in view of the multifaceted nature of the physiological factors involved in energy intake, turnover and storage in the body. However, insights gained from the bioscience research have provided a deeper understanding for the limited long-term success of many intervention programmes. The role of early development and epigenetics Research into the developmental origins of adult disease and epigenetics is providing further insight, and revealing health concerns. Following on from the classical epidemiological studies by Barker and Osmond, much subsequent research in animal models and human populations has linked a compromised intra-uterine environment with an increased risk for central and visceral obesity, hypertension, raised fasting plasma glucose and triglycerides and decreased high density lipoprotein-cholesterola common definition of the metabolic syndrome.12,13 Insulin insensitivity, hyperinsulinaemia and salt-sensitivity hypertension, pro-inflammatory status, oxidative stress are also commonly found together with the metabolic syndrome and imply a high risk for type 2 diabetes mellitus and cardiovascular disease in adult life.14,15 The Oxford Round Table Forum shared concerns about an escalating obesity problem among previously nutritionally deprived communities around the world with nutritional transition. Of more relevance to communities with abundant processed food supplies is that maternal gestational diabetes and obesity likewise creates a significant increased risk for obesity in offspring, with metabolic compromise such as insulin resistance already apparent at birth.16 Recent research at the molecular level has identified permanent changes in gene expression (epigenetic changes) as mediators for these effects.17 Of particular concern is that these epigenetic changes may be carried through to the next generation of children born into an obesogenic environment. The metabolic syndrome: an anomaly of metabolism that pre-disposes to obesity and the associated health risks Key features of the metabolic syndrome are insulin resistance, a low grade chronic inflammatory state and visceral obesity.12,13 Peripheral insulin resistance is linked with obesity and markedly improves with weight loss. However, insulin resistance and other components of the metabolic syndrome,including an increased tendency towards abdominal obesity, may occur before the onset of obesity as a result of intra-uterine exposure to either a deprived or overabundant energy supply in animal models as well as from human data.14-17 As well as its peripheral effects, insulin also acts in the brain as an important satiety signal in conjunction with leptin and, since human obesity is commonly linked with both leptin and insulin resistance18,19 this may result in a vicious spiral of escalating weight gain, and problems with shedding the extra kilograms gained. There are other physiological factors that also operate to make some people more susceptible than others to obesity, and the metabolic syndrome including cortisol and the hypothalamic-pituitary axis (HPA),20 mitochondrial dysfunction,21 uncoupling proteins22, and sex hormones23 (see Figure 1, Table 1). This rapidly expanding body of basic research provides further support of the evidence that some people are inherently more vulnerable. What also emerges is that the increased propensity for central fat gain is part of the metabolic syndrome and may arise early in development. This highlights the importance of early screening and implementation of appropriate interventions for those at increased risk of the metabolic syndrome and becoming obese. For obesity-related health risks, fat distribution is the critical factor. It is visceral fat that is linked with the release of pro-inflammatory cytokines such as tumour necrosis factor (TNF 03b1) and interleukin-6 (IL-6), chronic inflammation and oxidative damage and the classic risk factors of hypertension and dyslipidaemia for cardiovascular disease, insulin resistance and type 2 diabetes mellitus as well as obesity-linked malignancies.24,25 Conversely, adiponectin is linked with anti-inflammatory, anti-oxidative, insulin-sensitising and anti-cancer properties and low levels of this protective cytokine are associated with the metabolic syndrome.26 It is interesting to note that Roux-en-Y gastric bypass surgery is able to reverse the metabolic effects of obesity virtually immediately, often before significant weight reduction.27 This is possibly due to enhanced nutrient sensing and stimulation of lower intestinal hormones such as GLP-1 or decreased production of ghrelin.27 However, energy deprivation in the obese prior to/at bypass surgery also contributes to rapid metabolic normalisation. The role of genetics The importance of genetic factors in obesity initially arose from twin and population studies and, more recently, from the human genome data. Cases of obesity linked to a single gene mutation have been identified in recent years, such as the FTO (fat mass and obesity associated gene)but human obesity is predominantly polygenic in nature.29-31 Currently more than 70 genes that may contribute to obesity have been identified, and genetic factors may account for 30-70% variability in BMI and waist/hip ratio, variations in energy homeostasis, eating behaviour, weight loss maintenance and ethnic differences in susceptibility to obesity. 29,31 It is the interplay of thesegenetic differences with socioeconomic and cultural differences and psychosocial factors that predisposes to obesity risk and re-affirms the value of early interventions. The bioscience: suggested directions for clinical practice Debates and presentations at the Round Table had several themes which could inform clinical practice: Obesity results from a chronic disruption of innate energy homeostasis mechanisms which may arise as a result of genetic, epigenetic or environmental factors, resulting in an increased risk for obesity for some people when faced with the same obesogenic environment as their leaner counterparts. The achievement and maintenance of a supposedly cideald BMI of 19-25 is not only elusive but an impossible challenge for some, Dieting, and 8diet induced behaviours, generally do not lead to lasting weight loss or health benefits,3-5,10,29 may predispose to weight regain and sensitise the brains reward circuitry and function,30 lead to an upward cogwheel 8resetting of energy homeostasis10 and may promote redistribution and increased visceral fat deposition with its related health risks.20,33 Peripheral hip and thigh fat is not just neutral but may be protective34 and it is essential to distinguish between weight loss and fat loss34 and health. Some sources consider long term successful outcomes can be seen with Bariatric surgery27but clearly this is not a general option, and has risks at surgery and often post surgery nutrition issues.28 In view of these considerations perhaps we would achieve better health for all if we were to modify our interventions and attitudes appropriately. Too often attempts to lose weight lead to frustration, guilt and ultimately failure and pre-occupation with food and an upward spiral of weight cycling. What is apparent is a need for early, realistic, achievable interventions with an emphasis on health rather than a narrow focus on weight loss. The protective effects of a healthy diet in conjunction with physical activity as part of a healthy lifestyle are seen even with quite modest effects in weight loss.35 Enabling people to do this in an obesogenic environment with cheap over-palatable food and which is not conducive to physical activity are major barriers. There has been some debate and confusion over what really constitutes chealthy eatingd by consumers, epidemiological and health workers as information available contains many contradictions. In NZ fat intake decreased from 37.5% to 35% of the kilojoules between 1989 to the 1997 in response to health messages to cut back fat. However, over the same time period, obesity levels increased from 11% to 17%36. Unsaturated fats, such as olive oil and omega-3, are healthy alternatives to saturated fats but just as energy dense. The only nutritional advantage that pasta has over white bread is its low glycemic index. Epidemiological studies that link higher intakes of individual nutrients such as carotenoids, dietary fibre, folic acid, and potassium with reduced health risks often miss the significant point that higher intakes of these nutrients are indicators of a higher intake of fruit, vegetables, whole grains and the significance of other health promoting substances found in these foods. The one certainty seems to be the value of a varied and generous intake of fruit and vegetables, whole grain cereals (in moderation and with consideration of other starchy staples), dairy foods, fish and modest servings of animal derived protein, and unsaturated fats instead of saturated and trans fat found in processed foods. It is important to eat foods that are not just energy dilute but provide generous supplies of many nutrients as well as antioxidants, cancer-protecting phytochemicals and dietary fibre and are satisfying and enjoyable. An example is the Mediterranean type diet, which has beneficial metabolic effects, established benefits for overall health and wellbeing and is conducive to longer term sustained weight loss.35 In contrast, dietary regimes are often nutritionally unbalanced and not adhered to in the long term and may have undesirable side effects.29,33,35 Therefore, for sustained long term health benefits, a more productive emphasis should be on healthy eating (rather than weight loss per se) as part of a healthy life style, and on public education that facilitates and promotes informed food choices that appeal37 ideally with wider community and food industry involvement. Debates at the Round Table about exercise noted that there was no evidence to show that exercise reliably caused weight loss but there is a great deal of evidence to show the beneficial effects of increased movement of any form with incremental benefits as exercise increases.35,38,39 This is an area where our current focus on weight loss may be counterproductive as many people begin an exercise programme to achieve weight loss and abandon it when weight loss does not occur. Health professionals could show leadership in promoting the intrinsic benefits of exercise entirely removed from a focus on weight loss and supporting persistence and enjoyment instead. Creating a clinical environment in which the person does not feel judged or criticised is critical to fostering attendance and participation. Another area of importance to clinical practice is advice about sleep habits. Multiple epidemiologic studies have shown an association between short sleep and higher BMI even when other confounders are controlled for.40-41 Studies of healthy volunteers in laboratory settings have shown that sleep restriction is associated with an adverse impact on glucose homeostasis and is also related to alterations in appetite and satiety. Conclusions What is apparent from a body of research over the last decade is that there are no short cuts or simple solutions to the obesity issue at the individual level and it is unrealistic to expect these. Obesity is a field in which leading researchers crepeatedly concede an alarming lack of knowledge about even the most fundamental questions while, often within the same article, making bold and unsupported generalisations about the causes and cures for obesityd (Gard, p.36).2 Such uncertainty was clearly evident at Round Table discussions and whilst many clinicians may be well aware of the scientific uncertainty it has not yet translated into more appropriate, sensitive public or clinical responses to those who live with obesity. At the community level there is much to be achieved. Community embedded processes which increase access to safe exercise and increase equitable access to good nutrition are valuable and vitally important, and need to be long term. It is unfortunate that we will not be able to assess the long term outcomes of the Healthy Eating Healthy Action initiatives due to changes in government policy. For individuals, we could move from a tendency to blame towards acknowledging that some may be disadvantaged because of biological factors. Simply concentrating on BMI focuses our attention away from inactivity and unhealthy dietary choices which are empirically recognised as a far more accurate predictor of disease than body weight per se. For many people the current cheap, processed highly palatable and energy dense food environment makes it more difficult to acquire, 8choose and eat healthier options. Regular physical activity is better for health than pure weight loss and is hard for many people, especially in an urban environment that discourages this. Dealing with obesity at a community or individual level needs supportive long-term commitment and investment better served by interventions that are realistic, achievable and with an overall focus on health in its fullest sense, and for people of any size.

Summary

Abstract

Aim

Method

Results

Conclusion

Author Information

Suzi Penny, Senior Lecturer, Health and Life Sciences, Institute of Food, Nutrition and Human Health, Massey University, Wellington; Jenny Carryer, Professor of Nursing, School of Health and Social Services, Massey University, Palmerston North

Acknowledgements

'- We thank Dr Rachel Page (Institute Food, Nutrition and Human Health, Massey University) for her comments and feedback.-

Correspondence

Suzi Penny, MSc (Distinction in Biochemistry), Senior Lecturer, Health and Life Sciences, Institute of Food, Nutrition and Human Health, Massey University, Private Bag 756, Wellington 6140, New Zealand

Correspondence Email

S.J.Penny@massey.ac.nz

Competing Interests

None

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