Hand book of obesity

George A. Bray (Editor), Claude Bouchard (Editor)0824709691, 9780824709693, 9780824759759

Table of contents :
Preface to the Second Edition……Page 2
Preface to the First Edition……Page 4
Contents……Page 6
Contributors……Page 10
1 Historical Framework for the Development of Ideas About Obesity……Page 16
2 Evaluation of Total and Regional Adiposity……Page 48
3 Ethnic and Geographic Influences on Body Composition……Page 96
4 Prevalence of Obesity in Adults: The Global Epidemic……Page 108
5 Fetal Origins of Obesity……Page 124
6 Pediatric Overweight: An Overview……Page 132
7 Obesity in the Elderly: Prevalence, Consequences, and Treatment……Page 150
8 Economic Costs of Obesity……Page 164
9 Genetics of Human Obesity……Page 172
10 Molecular Genetics of Rodent and Human Single Gene Mutations Affecting Body Composition……Page 216
11 Rodent Models of Obesity……Page 270
12 Primates in the Study of Aging-Associated Obesity……Page 298
13 Behavioral Neuroscience and Obesity……Page 316
14 Experimental Studies on the Control of Food Intake……Page 388
15 Diet Composition and the Control of Food Intake in Humans……Page 442
16 Central Integration of Peripheral Signals in the Regulation of Food Intake and Energy Balance: Role of Leptin and Insulin……Page 476
17 Development of White Adipose Tissue……Page 491
18 Lipolysis and Lipid Mobilization in Human Adipose Tissue Dominique Langin and Max Lafontan Obesity Research Unit, INSERM U586, Louis Bugnard Institute, Universite´ Paul Sabatier-Centre Hospı`talı`er Universitaire de Rangueil, Toulouse, France I INTRODUCTION Adipose tissue is the body’s largest energy reservoir. Energy is stored in fat cells as triacylglycerols (TG). Factors that control the storage and mobilization of TG in adipocytes are important regulators of fat accumulation in various fat areas (1). The major source for adipocyte TG comes from chylomicrons and very low density lipoproteins (VLDL). TG in the lipoprotein particles are hydrolyzed by lipoprotein lipase (LPL) located on the capillary walls of adipose tissue so that nonesterified fatty acids (NEFA) and monoacylgly-cerol are formed. NEFA are probably taken up by the fat cell through passive and active transport. Indeed, specific NEFA-transporting proteins have been described (2–4). Once taken up by the fat cells, NEFA are esterified to TG. The circulating albumin-bound NEFA can also be taken up by the fat cells and esterified to TG. Adipose tissue lipolysis, i.e., the catabolic process leading to the breakdown of triglycerides into NEFA and glycerol, is often considered as a simple and well-understood metabolic pathway. However, it is not firmly established what truly sets the rate of adipose tissue lipolysis. Newly released NEFA can be reesteri-fied in the adipocytes. Quantitative studies are lacking in vivo. Catecholamines and insulin represent the major regulators of lipolysis. However, the physiological role of a number of other lipolytic and antilipolytic agents remains to be elucidated. During lipolysis, intracellular TG undergo hydrolysis through the action of a neutral lipase located inside the fat cell, hormone-sensitive lipase (HSL). NEFA and glycerol leave the fat cells and are transported by the bloodstream to other tissues (mainly liver for glycerol; liver, skeletal muscle, and heart for NEFA). NEFA act as signaling molecules as well as metabolic substrates. In addition to their role in adipose tissue metabolism, they can regulate glucose utilization in muscle and are important signals to the liver and beta cells as well. Some of the NEFA that are formed during lipolysis do not, however, leave the fat cell and can be reesterified into intracellular TG. The glycerol formed during lip-olysis is not reutilized to a major extent by fat cells because they contain only minimal amounts of the enzyme glycerol kinase. In normal-weight man, the mean turnover rate of TG in the total fat mass is f100– 300 g TG per day. An imbalance between hydrol-ysis and synthesis of TG can be important for the development of obesity. Altered lipolysis could be an element leading to obesity and interindividual varia-tions in AT lipolysis are of importance for the rate of weight loss. Conversely, excessive lipolytic rates, in conjunction with impairment in NEFA utilization by muscle and liver, may be a major contributor to the metabolic abnormalities found in persons with android or upper-body obesity and lead to non-insulin-depend-ent diabetes mellitus (NIDDM). 515……Page 525
19 Lipodystrophy and Lipoatrophy Steven R. Smith Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana, U.S.A. I INTRODUCTION Excess adipose tissue is associated with metabolic dis-turbances and disease, i.e., the metabolic syndrome (1,2). Somewhat paradoxically, inadequate adipose tis-sue manifests itself in a similar fashion (3,4). This observation demonstrates that adipose tissue is required for normal metabolic function. The inherited and acquired lipodystrophies constitute a heterogeneous group of disorders that share the common feature of inadequate adipose tissue stores. Although the lipodystrophic disorders represent a variety of underlying pathophysiological states, their common sequelae are instructive, as they are likely to be similar to the metabolic complications associated with ‘‘garden-variety’’ obesity/metabolic syndrome X. Our understanding of the pathophysiology of these patients and parallel models of lipodystrophy in animals point toward the concept of an ‘‘optimal’’ adipose tissue mass that matches the energy requirements of the organism. In addition, these disorders illustrate the central role of adipose tissue to (1) sequester lipid, and (2) adipose tissue as an endocrine organ. This chapter is divided into three main sections. First, the characterized lipodystrophies and their sali-ent features will be briefly reviewed. Second, the common pathophysiological mechanisms will be dis-cussed in light of the available animal models. Last, based on the mechanisms by which inadequate adipose tissue leads to disease, potential therapeutic strategies are discussed. The following classification schema follows that of Garg (5), with reference to the schema presented by the Online Mendelian Inheritence in Man (OMIM) by McKusick (6). The reader is referred to the latter reference for a continual update of the rarer lipodys-trophy syndromes and a comprehensive bibliography: http://www.ncbi.nlm.nih.gov/Entrez/. II LIPODYSTROPHIES A Congenital Generalized Lipodystrophy (CGL) CGL, OMIM 269700, i.e., Berardinelli-Seip syndrome, is an autosomal-recessive disorder that manifests at birth as a complete absence of adipose tissue, hepato-megaly, and severe nonketotic insulin resistant diabetes. Additional features include acanthosis nigricans and an elevated basal metabolic rate. Mechanical fat in the hands, feet, orbit, scalp, and periarticular fat are usually preserved (3). B Familial Partial Lipodystrophy (FPL) FPL, OMIM 151660, familial partial lipodystrophy, an autosomal-dominant disorder, is differentiated from congenital generalized lipodystrophy, an autosomal-recessive disorder, by the timing of the onset (4). FPL 533……Page 543
20 Uncoupling Proteins Daniel Ricquier UPR 9078, Centre National de la Recherche Scientifique, Faculty of Medicine, Necker-Sick Children, Paris, France Leslie P. Kozak Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana, U.S.A. I INTRODUCTION The coupling of respiration to ADP phosphorylation in mitochondria represents the coupling of exergonic and endergonic processes. Actually, such a coupling is never complete and results in energy dissipation as heat. Apart from a role in thermogenesis, uncoupling of respiration limits ATP synthesis and allows NADH reoxidation. In the absence of uncoupling mechanisms, a high level of ATP would inhibit respiration and NADH reoxidation. Two types of mechanisms have been proposed to explain the molecular basis of respiration uncoupling. The first is based on a decreased efficiency of the respiratory chain or ‘‘slippage’’ of respiratory chains; the second one postulates the existence of proton leaks in the mitochondrial inner membrane. Analysis of thermogenic mechanisms in brown adipocytes has established that UCP1 in the inner mitochondrial mem-brane works as a regulatable proton leak and an uncou-pler that stimulates fatty acid oxidation (see below). The recent identification of homologues of UCP1 has extended this regulatory mechanism based on the pos-sible mitochondrial proton leaks to virtually all other tissues. Accordingly, this phenomenon of mitochon-drial proton leaks represents a widespread strategy for controlling substrate utilization, and energy partition-ing through changes in metabolic efficiency. II UCP1 A UCP1 in Energy Expenditure and Body Weight Regulation Pharmacological and genetic manipulations of exper-imental rodents suggest that nonshivering thermogen-esis is one of the most effective strategies for reducing adiposity in obese individuals. While there are many systems of thermogenesis that are theoretically capable of increasing energy expenditure, in fact, a body of evidence confirming that a specific mechanism for increasing thermogenesis is effective in reducing adiposity is available only for mitochondrial uncou-pling protein (UCPI)-dependent thermogenesis of brown adipose tissue. The previous edition of the Handbook of Obesity described the biology of brown adipose tissue, the biochemistry of UCP1, and the adrenergic signaling mechanisms that controlled the activation of nonshivering thermogenesis. Although the effectiveness of UCP1 in reducing adiposity in obese rodents is clear its relevance to obesity in humans has remained questionable because of the paucity of brown adipocytes in adult humans. Since the previous edition of the handbook was issued, important developments in mitochondrial uncoupling proteins and the regulation of brown adipocyte differ- 539……Page 549
21 Peroxisome Proliferator–Activated Receptor g and the Transcriptional Control of Adipogenesis and Metabolism Lluis Fajas and Johan Auwerx Institut de Ge´ne´tique et de Biologie Mole´culaire et Cellulaire, Illkirch, and Universite´ Louis Pasteur, Strasbourg, France I INTRODUCTION The peroxisome proliferator–activated receptor gamma (PPARg) is one of three PPARs, which together constitute a distinct subfamily of the nuclear receptor superfamily and which are all activated by naturally occurring fatty acids or fatty acid derivatives. PPARg heterodimerizes with retinoid X receptors (RXR) and alters the transcription of numerous target genes after binding to specific response elements or PPREs, which are found in several genes involved in fat metabolism. Coordinate regulation of genes involved in fat uptake and storage by PPARg underlies its effects on adipocyte differentiation. PPARg’s claim to fame is due to its pivotal roles in adipogenesis and its implication in insulin sensitization. A number of additional functions were attributed to PPARg, which suggests a more pleiotropic role affecting multiple fundamental pathways in the cell with wide-ranging biomedical implications. II THE PPAR; GENE, RNA, AND PROTEIN The human PPARg gene, which is mapped to a locus on chromosome 3p25, has nine exons and spans over 100 kb of genomic DNA (1). In contrast to mice, in which only two PPARg isoforms have been described so far (2), in man, three PPARg mRNA isoforms have been identified—PPARg1, g2(1), and g3 (3). Alternate transcription start sites and alternative splicing gen-erate these three PPARg mRNAs, which differ at their 5V ends. Consistent with the production of three PPARg mRNAs, there are three PPARg promoters, each with a specific and distinctive expression pattern, (1,3). Whereas the PPARg1 and g3 mRNAs give rise to an identical protein product, i.e., PPARg1, the PPARg2 mRNA encodes for the PPARg2 protein, which in man contains 28 additional amino acids encoded by the B exon. Little is known about the expression of PPARg during development in mammals (4). In adult animals, PPARg expression is relatively confined. Adipose tis-sue, large intestine, and hematopoietic cells express the highest levels of PPARg; kidney, liver, and small intes-tine have intermediate levels; whereas PPARg is barely detectable in muscle (1,5). Related to the subtype distribution, PPARg2 is much less abundant in all tissues relative to PPARgl, the predominant PPARg form. The only tissue expressing significant amounts of PPARg2 is adipose tissue, where PPARg2 mRNA makes up 30% of total PPARg mRNA (5). PPARg3 mRNA expression is restricted to macrophages and large intestine (3,6). In man, short-term changes in food intake do not affect the expression levels of PPARg (5), whereas 559……Page 569
22 Biology of Visceral Adipose Tissue Susan K. Fried University of Maryland and Baltimore Veterans Administration Medical Center, Baltimore, Maryland, U.S.A. Robert R. Ross Queen’s University, Kingston, Ontario, Canada I INTRODUCTION A Visceral Obesity and Health–A Brief Historical Perspective In humans and other mammals, fat is deposited within anatomically discrete depots that are located through-out the body. In humans, while most fat is present in subcutaneous depots, up to 20% of total body fat is deposited in adipose depots within the abdominal cavity (see Table 1). The pattern of fat distribution is a main determinant of variations in body shape (1–3). Vague first noted that that an upper body (android or male-type) fat distribution is associated with develop-ment of diabetes, atherosclerosis, and gout (4,5). Kis-sebah et al. (6,7) and Krotkiewski et al. (6), among others, confirmed and extended Vague’s hypothesis, finding evidence for correlations of upper-body obesity and enlarged abdominal subcutaneous fat cells to hypertension, insulin resistance, and hyperlipidemia in clinical studies. Epidemiological studies showed that upper-body fat distribution, measured by the ratio of waist to hip circumferences, was a significant determi-nant of diabetes, cardiovascular disease, and premature death in both men and women (3). These statistical associations were independent of overall obesity, as assessed by the body mass index. Thus, much research attention became focused on the phenomenon of abdominal obesity. With the application of imaging technology to the study of fat distribution, it became possible to better define fat distribution by distinguishing the relative sizes of intra-abdominal and subcutaneous fat com-partments. It was realized that increased waist circum-ference was a heterogeneous phenotype associated in some cases with high amounts of intra-abdominal fat, and in others with mostly subcutaneous abdominal fat. Many studies found that the size of intra-abdomi-nal fat stores as measured by computerized tomogra-phy (CT) or magnetic resonance imaging (MRI) was most closely linked with the metabolic complications of obesity (1,7–9). B The Portal Hypothesis The statistical association between abdominal obesity and health risk does not prove a causal relationship (10). Thus, investigators addressed potential mechanis-tic links between the size of specific fat depots and alter-ations in systemic metabolism. As noted by Bjo¨rntorp (10), there was accumulating evidence in the literature from 1960s and 1970s that fat cells from different fat depots exhibit marked differences in functional capaci- 589……Page 599
23 Resting Energy Expenditure, Thermic Effect of Food, and Total Energy Expenditure Yves Schutz and Eric Je´quier University of Lausanne, Lausanne, Switzerland I METHODS OF MEASURING ENERGY EXPENDITURE IN HUMANS A Introduction Three main methods are used to measure energy expen-diture in man: indirect calorimetry, direct calorimetry, and the doubly labeled water technique. These methods are based on different principles and do not measure the same type of energy. Indirect calorimetry is the best method to measure resting energy expenditure, the thermic effect of food and the energy expended for physical activity. It has the great advantage of being relatively simple; it can be used either with a ventilated hood system (for a resting subject), or with a respiration chamber, when a 24-hr measurement is needed. A first advantage of indirect calorimetry is the immediate response of oxygen con-sumption (measured by the method of respiratory gas exchange) in relation with the real oxygen consumption in the tissues and organs within the body. There is no delay in measuring oxygen consumption because the body has negligible O2 stores. A second advantage of indirect calorimetry in comparison with other methods is the possibility to assess nutrient oxidation rates, when oxygen consumption, CO2 production, and urinary nitrogen excretion are measured. Direct calorimetry is the method of choice for studies aiming at assessing thermoregulatory responses. The method consists in measuring heat losses, not heat production. In many circumstances, heat losses differ from heat production and there is a change in heat stored. For instance, after a meal, heat production begins to rise 20–30 min after the onset of eating, whereas heat loss increases only later on; the conse-quence of the different time courses of heat production and heat loss is a rise in body temperature. The method of direct calorimetry consists in the measurement of the heat dissipated by the body by radiation, convection, conduction, and evaporation (1). Under conditions of thermal equilibrium in a sub-ject at rest and in postabsorptive conditions, heat production, measured by indirect calorimetry, is iden-tical to heat dissipation, measured by direct calorimetry (Fig. 1). This is an obvious confirmation of the first law of thermodynamics—that the energy released by oxida-tive processes is ultimately transformed into heat (and external work during exercise). In steady-state condi-tions, the identity between heat production and heat loss in a resting subject (Fig. 1) corroborates the validity (for the whole body) of the method of indirect calorimetry. Doubly labeled water technique is the third method and is based on the difference in the rates of turnover of 2 H2O and H 2 18 O in body water. The subject is given a single oral dose of 2 H2 18 O to label body water with both isotopes 2 H and 18 O. A rapid exchange of 18 O occurs between water and carbon dioxide owing to the action of carbonic anhydrase. As a result, after 615……Page 625
24 Energy Expenditure in Physical Activity James O. Hill University of Colorado Health Sciences Center, Denver, Colorado, U.S.A. W. H. M. Saris University of Maastricht, Maastricht, The Netherlands James A. Levine Mayo Clinic, Rochester, Minnesota, U.S.A. I ENERGY EXPENDITURE DURING PHYSICAL ACTIVITY A Human Energy Balance Biological entities obey physical laws, and, in this regard, humans and other mammals obey the laws of thermodynamics. Body energy stores can only increase and obesity can only occur when food intake exceeds energy expenditure (or metabolic rate). Similarly, energy stores can only be depleted when energy expen-diture exceeds food intake. Thus, the balance between food intake and energy expenditure determines the body’s energy stores. The quantity of energy stored by the human body is impressive; lean individuals store 2–3 months of their energy needs in adipose tissue whereas obese persons can carry a year’s worth of their energy needs. The cumulative impact of energy imbalance over months and years can result in the development of obesity. The factors that regulate appetite and food intake are discussed elsewhere. In this chapter we will discuss the importance of physical activity as a compo-nent of energy expenditure. B Components of Energy Expenditure There are three principal components to energy expen-diture in humans: basal metabolic rate, thermic effect of food, and the energy expenditure of physical activity (activity thermogenesis). Basal metabolic rate is the energy expended when an individual is lying at complete rest, in the morning, after sleep, in the postabsorptive state. In individuals with sedentary occupations basal metabolic rate accounts forf60% of total daily energy expenditure. About 75% of the variability in basal metabolic rate is predicted by lean body mass within and across species (1,2). Resting energy expenditure, in general, is within 10% of basal metabolic rate and is measured in subjects at complete rest in the postabsorp-tive state. The second component of energy expenditure is the thermic effect of food (3–6). This is the increase in energy expenditure associated with the digestion, absorption, and storage of food and accounts for f10% of total daily energy expenditure; many believe there to be facultative (adaptive) as well as fixed com-ponents. The third component of energy expenditure is 631……Page 641
25 Endocrine Determinants of Obesity Jonathan H. Pinkney University of Liverpool, Liverpool, England Peter G. Kopelman Barts and the London Queen Mary’s School of Medicine and Dentistry, University of London, London, England I INTRODUCTION Obesity is a fundamental disorder of energy balance in which excessive energy stores accumulate in the form of fat in response to sustained high energy intake and/or low expenditure. While genetic factors influence obesity through endocrine mechanisms, the majority of endo-crine changes observed in obese subjects are consequen-ces of obesity. The endocrine mechanisms giving rise to disturbances of fat distribution, and by which obesity gives rise to its principal complications—diabetes, car-diovascular disease, and female reproductive dysfunc-tion— are becoming clear. In this chapter we consider the unusual primary endocrine causes of obesity, includ-ing recently described genetic syndromes, and then focus on the more common alterations in endocrine function that are characteristic of obesity—distur-bances in insulin secretion and action, adrenocortical function, sex steroid secretion, the growth hormone in-sulinlike growth factor and pituitary-thyroid axes. The evidence that these changes play a role in either the determination of corpulence or the perpetuation of the obese state is considered. II PRIMARY ENDOCRINE DISEASE AS A CAUSE OF OBESITY Diseases in which primary endocrine disturbances are the cause of obesity are unusual in clinical practice. This group of disorders (Table 1) includes structural lesions of the hypothalamus, of which craniopharyngioma, or its treatment with surgery or radiotherapy, is the com-monest. The mechanisms responsible for weight gain in this situation include hyperphagia, reduced resting me-tabolic rate, and autonomic imbalance leading to hy-perinsulinemia (1). Treatment, which reduces insulin secretion, promotes weight loss in a subset of such pa-tients (2). Patients with growth hormone (GH) defi-ciency secondary to pituitary/hypothalamic disease also have increased body fat and reduced muscle mass, and this is corrected by GH replacement (3–7). Genetic de-fects affecting the function of this brain region include Prader-Willi syndrome, until recently the commonest known monogenic form of obesity. Mutations in leptin, leptin receptor, pro-opiomelanocortin (POMC), and melanocortin-4 receptor (MC4R) have now been described in obese humans (8–11), but these are rare 655……Page 665
26 Endocrine Determinants of Fat Distribution Renato Pasquali, Valentina Vicennati, and Uberto Pagotto University of Bologna and S. Orsola-Malpighi General Hospital, Bologna, Italy I INTRODUCTION Obesity is a heterogeneous disorderwith wide variations in risks for complicating diseases. The recognition of the marked differences between excess fat localized in different parts of the body has markedly increased the knowledge of mechanisms by which metabolic and cardiovascular risk factors and diseases aggregate to specific phenotypes of obesity. At the same time, emerg-ing scientific interest has increased our understanding of the main metabolic and hormonal factors involved in the pathophysiology of different obesity phenotypes. This chapter will focus on the concept of adipose tissue as an endocrine organ, the regulation of the li-polytic/ lipogenetic balance, the physiology of hormone regulation of different adipose tissue depots, and the role of hormonal derangements in the pathophysiology of different obesity phenotypes, particularly the abdo-minal phenotype. II ADIPOSE TISSUE AS AN ENDOCRINE ORGAN Adipocytes are well known for their essential role as triglyceride depots, from which energy is called forth at times of need in the form of free fatty acids (FFAs) and glycerol. However, in the past few years, it has been definitively established that adipose tissue may also act as an endocrine organ. In fact, adipocytes express and secrete a number of peptidergic hormones and cyto-kines, which help to maintain homeostasis; vasoactive peptides, whose proteolytic products regulate vascular tone; and leptin, which plays a central role in regulating energy balance (1). Adipose tissue can also produce active steroid hormones, including estrogens and corti-sol, by conversion of androgen precursors and inactive glucocorticoids, respectively. Through such secreted products, adipocytes may deeply influence local adipo-cyte biology, as well as systemic metabolism at sites as diverse as brain, liver, muscle, pancreatic h-cells, go-nads, lymphoid organs, and systemic vasculature (2). Adipose tissue is also tightly regulated in its differ-entiation process and in its metabolic functions by many hormones. Each hormone has its own peculiar effect, according to the receptor expression pattern, to gender and age, and to the different adipose tissue sites. These effects are particularly related to regulating the balance between fat accumulation (lipogenesis) and breakdown (lipolysis). There are several differences in the balance between lipogenesis and lipolysis among adipose tissues located in subcutaneous or visceral sites. These effects mainly depend on the activity of lipoprotein lipase and hormone-sensitive lipase, respectively. III FUNCTIONS OF ADIPOSE TISSUE: LIPOGENESIS AND LIPOLYSIS A Lipoprotein Lipase: Lipogenesis Lipoprotein lipase (LPL) is an extrahepatic enzyme responsible for the hydrolysis of triglycerides into chy-lomicra and very low density lipoprotein (VLDL), and 671……Page 681
27 Sympathoadrenal System and Metabolism Eric Ravussin Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana, U.S.A. Ian Andrew Macdonald University of Nottingham Medical School, Nottingham, England I INTRODUCTION The sympathetic nervous system (SNS) is an impor-tant component of the autonomic nervous system, and thus plays a major role in the maintenance of body homeostasis. The SNS is of particular importance in the control of the cardiovascular system and of a number of metabolic processes including energy homeostasis. Alterations in SNS effects on metabolism have been implicated in the development and main-tenance of obesity, and the SNS is a potential ther-apeutic target in the treatment of obesity. This short review provides an overview of the anatomical and physiological aspects of the SNS, before considering the evidence showing a role for the SNS in the develop-ment or treatment of obesity. II ORGANIZATION AND STRUCTURE OF THE SNS The autonomic nervous system consists of the sympa-thetic nervous system, parasympathetic nervous system (PNS), and adrenal medulla. A number of anatomical differences distinguish the SNS and the parasym-pathetic nervous system, which are reviewed in detail by Astrup and Macdonald (1). The important struc-tural aspects of the SNS are that the preganglionic nerves arise from thoracic and lumbar regions of the spinal cord, and that the ganglia are close to the spinal cord. Thus, the SNS has long postganglionic nerves, which innervate almost all of the vital organs and tissues of the body. While most of these vital organs and tissues are also innervated by the parasympathetic nervous system, major exceptions are the blood vessels, sweat glands, and adipose tissue, which have only a sympathetic nerve supply. The adrenal medulla is effectively a sympathetic ganglion, but it releases hor-mones directly into the bloodstream instead of having a postganglionic nerve. There are many physiological and clinical situations in which activation of the SNS and adrenal medulla are dissociated, and it is more appropriate to consider them as the sympathoadrenal system than to include the adrenal medulla in the SNS. The other distinctive anatomical feature of sympa-thetic nerves is that they have varicosities along the length of nerve within the tissue that is innervated. Thus, each nerve releases neurotransmitters at a num-ber of sites. The SNS and PNS nerves, which arise from the spinal cord and supply the vital organs and tissues, represent the efferent part of the autonomic nervous system. Activation of these nerves usually occurs as part of reflex mechanisms that involve afferent signals 693……Page 703
28 Energy Expenditure and Substrate Oxidation Jean-Pierre Flatt University of Massachusetts Medical School, Worcester, Massachusetts, U.S.A. Angelo Tremblay Laval University, Sainte-Foy, Quebec, Canada I FACTORS DETERMINING TOTAL SUBSTRATE OXIDATION The rate of substrate oxidation varies considerably during the day, being dictated by the body’s need to regenerate the adenosine triphosphate (ATP) used in carrying out its metabolic functions, in digesting and storing nutrients, in moving, and in performing phys-ical tasks. The amount of heat generated is generally sufficient to allow maintenance of body temperature by regulation of heat dissipation, aided when necessary by measures seeking to maintain comfort through appro-priate clothing and control of environmental tempera-tures. Situations where substrate oxidation is activated for the sake of thermogenesis are avoided as much as possible. The energy expended in the resting state depends primarily on the size of the lean body mass, plus the metabolic costs for processing ingested nutrients. The energy expended for specific physical activities is highly reproducible and in many cases roughly pro-portional to body weight (1). Overall energy expendi-ture for weight maintaining adults is thus determined primarily by body size and by the intensity and duration of the physical activities undertaken. In sedentary individuals total daily energy expenditure (TEE) varies typically between 1.3 and 1.5 times the rate of resting energy expenditure (REE) extrapolated to 24 hr. A Efficiency of Oxidative Phosphorylation and P:O Ratio It is difficult to assess the efficiency of oxidative phos-phorylation and the P:O ratio in intact cells, because the ATP turnover due to the cell’s metabolic activities is not readily measurable. Pahud et al. (2) were nevertheless able to assess the efficiency of oxidative phosphoryla-tion in man by combining direct and indirect calorim-etry measurements in young men pedaling on a bicycle ergometer at different levels of work output. During sustained aerobic work, the mechanical work per-formed was equivalent to 27% of the energy contained in the increment in substrate oxidation elicited by ped-aling. During the first minutes of pedaling against a suddenly increased resistance, the mechanical work pro-duced (measured electrically with the bicycle ergome-ter) plus the energy appearing in the form of heat (measured by direct calorimetry and from the increase in the subjects’ body temperature) exceeded the energy liberated by substrate oxidation (determined by indirect calorimetry). This implies that preformed high-energy bonds (ATP and creatine-phosphate) were utilized to accomplish part of the mechanical work during this 705……Page 715
29 Skeletal Muscle and Obesity David E. Kelley University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A. Len Storlien University of Wollongong, Wollongong, New South Wales, Australia, and AstraZeneca, Mo¨lndal, Sweden I INTRODUCTION In obesity, there is increased nonadipose tissue as well as increased adiposity. The increase of nonadipose tissue entails an increase in skeletal muscle mass. Recent data indicate that obesity affects not only the quantity, but also the ‘‘quality’’ of skeletal muscle, and thiswill be one area of focus for this chapter. One manifestation of a change in the composition of skeletal muscle in obesity is an increased lipid content within and around muscle fibers. How this occurs is an important question. Al-tered composition of skeletal muscle may arise only as a consequence of having become obese, reflecting the general increase in adiposity in multiple organs. Yet, there are data that strongly suggest that changes in the physiology and biochemistry of skeletal muscle in obe-sity dispose to an accumulation of lipid within muscle. Indeed, these changes in muscle in fuel partitioning of lipid, between oxidation and storage of fat calories, may contribute to the pathogenesis of obesity and precede its development. This hypothesis could be of central impor-tance to our understanding of this chronic disease and therefore will be carefully considered in this chapter. A related theme of the chapter will be that skeletal muscle insulin resistance, a well-recognized metabolic complication of obesity, entails perturbations not only of glucose but also in fatty acid metabolism. In meta-bolic health, skeletal muscle physiology is characterized by the capacity to utilize either lipid or carbohydrate fuels, and to effectively transition between these fuels. We will review recent findings that indicate that in obesity, skeletal muscle manifests a loss of the capacity for transition between lipid and carbohydrate fuels. This inflexibility in fuel selection by skeletal muscle, as well as differences in fuel partitioning, is a key patho-physiological characteristic that contributes to an altered composition of muscle in obesity and to the in-sulin resistance of muscle. II NONINVASIVE STUDIES OF SKELETAL MUSCLE COMPOSITION IN OBESITY A Skeletal Muscle Quantity Adipose tissue mass is certainly increased in obesity, and contributes substantially to increased weight. How-ever, body composition analyses also suggest that there is an increased amount of nonadipose tissue compo-nents in obesity, including increased skeletal muscle mass. Two-compartment methods for estimating body composition, such as dual-energy x-ray absorptiometry (DXA) or underwater weighing, indicate that fat-free mass is increased in obesity. Part of the increase in fat- 733……Page 743
30 Nutrient Partitioning Samyah Shadid and Michael D. Jensen Mayo Clinic, Rochester, Minnesota, U.S.A. I INTRODUCTION A General Considerations on Nutrient Partitioning Nutrient partitioning can be defined as the process by which the organism selects fuels for storage (including protein synthesis) or oxidation. Understanding the reg-ulation of energy balance and nutrient partitioning can potentially facilitate the treatment of obesity. Although the factors that lead to an imbalance between energy/ fat intake and energy expenditure, and thus the devel-opment of obesity, remain incompletely understood, nutrient partitioning may be especially relevant to the development of obesity as it relates to the hypothesis of Flatt (1). The latter suggests that total food intake increases to meet carbohydrate needs. According to this theory, food intake is regulated, at least in part, to as-sure an adequate amount of carbohydrate. Consump-tion of a high-fat diet would require the intake of excess fat in order to satisfy carbohydrate needs and therefore lead to obesity under this scenario. The concept of a diet ‘‘relatively’’ deficient in carbohydrate becomes impor-tant in that dysregulation of substrate partitioning could potentially affect the body’s sense of what consti-tutes adequate carbohydrate intake. For example, if fat were preferentially shunted toward storage, more car-bohydrate would be required to meet oxidative needs, thereby preventing sufficient repletion of glycogen stores. This process is proposed to generate signals that stimulate appetite. Other examples where nutrient par-titioning relates to obesity and body fat content include the stimulation of lean tissue synthesis at the expense of fat calories by androgens and growth hormone, and (presumably) the reverse of this process by deficiencies of these hormones. A variety of physiological and cellular events play key roles in determining nutrient partitioning. After a general overview of these major determinants, the regu-lation of the major pathways of nutrient partitioning will be reviewed, followed by specific hormonal influ-ences on each pathway. The net effects of the major nu-trient partitioning hormones (insulin, growth hormone, testosterone and cortisol) on lipid, protein, and carbo-hydrate metabolism are summarized in Figures 1–3. B Nutrient Partitioning and Exercise When energy intake exceeds energy expenditure, the excess calories must be stored. Excess energy intake in sedentary, hormonally stable adults almost inevitably results in the expansion of adipose tissue triglyceride stores. Circumstances that promote lean tissue accre-tion, however, can allow excess energy to be stored as muscle and/or visceral proteins. The most common circumstance resulting in net lean tissue accretion with excess food intake is increased physical activity, usually in the form of resistance exercise training. The initiation of endurance exercise training in a previously sedentary 753……Page 763
31 Obesity and Mortality Rates Kevin R. Fontaine Johns Hopkins University, Baltimore, Maryland, U.S.A. David B. Allison The University of Alabama at Birmingham, Birmingham, Alabama, U.S.A. I INTRODUCTION ‘‘A certain amount of overweight has been looked upon with favor, our tendency being to consider a certain degree of hyper-nutri-tion to be desirable.’’ —O. H. Rogers (1901) ‘‘A sudden palpitation excited in the heart of a fat man has often proved as fatal as a bullet through the thorax.’’ —W. Wadd (1829) Since at least the mid-19th century there has been considerable interest and debate with regard to whether and how obesity is associated with mortality. Although a common view a century ago was that weights we would consider excessive today were innocuous and perhaps even desirable, case reports coupled with data from the life insurance industry suggested that excess weight and the central distribution of this weight were associated with shortened life expectancy (1). Over the past several decades, the question of the effect of variations in body weight on mortality has be-come increasingly important. This is in part because both relative body weight and rates of obesity have been dramatically and steadily increasing in the United States and most of the Western world (2–4). As agri-cultural and industrial technologies spread into the non-Western world, both the relative body weights and rates of obesity are increasing in those popula-tions as well (5). Given this, it is not surprising that body weight is of considerable interest to the scien-tific community. Indeed, the ‘‘problem’’ of obesity has become the subject of governmental policies, public education campaigns, and insurance policies, and has become a major target of the food and pharmaceutical industries. Despite efforts to address the rising rates of obesity, the effect of variations in body weight on mortality re-mains a controversial topic (6–9). Some studies (10–12) suggest that the relationship between measures of rela-tive body weight (e.g., body mass index [BMI]: kg/m 2 ) and longevity is decreasing, indicating essentially that one can never be too thin. On the other hand, some studies suggest that BMI has little important impact on longevity (13–15). Between these two extremes are studies that suggest that the relationship between BMI and mortality is U-shaped or J-shaped, indicating higher mortalities at the extremes of the BMI distri-bution (16–19). To complicate matters further, studies suggest that the BMI/mortality relationship may vary considerably as a function of demographic character-istics such as age, sex, and race (20–22). 767……Page 777
32 Etiology of the Metabolic Syndrome Per Bjo¨rntorp University of Go¨teborg, Go¨teborg, Sweden I INTRODUCTION One significant and rapidly developing area of obesity research is the etiology of the metabolic syndrome and its prevention and treatment. The syndrome exhibits the central, visceral subtype of obesity, which is an integral part of the syndrome and bears the most serious somatic hazards of obesity, while the peripheral, subcutaneous subtype is associated mainly with mechanical problems arising from the increased body weight. Historically, the clustering of the symptoms now called the metabolic syndrome has been observed and documented since the beginning of the 20th century. There is little consensus on the definition, although many different proposals have been advanced, partic-ularly after addition of new components to the core of the syndrome. Most authors agree on the inclusion of insulin resistance, abdominal obesity, dyslipidemia, and hypertension, since these established risk factors for cardiovascular disease, type 2 diabetes mellitus and stroke are the reason the metabolic syndrome is of major importance. Techniques for evaluation of the major components of the syndrome have changed little since the previous edition of the Handbook of Obesity (1998) (1), proba-bly because the methodology continues to be adequate. However, questions exist about certain simple anthro-pometric measurements; for example, the waist/hip cir-cumference ratio (WHR). It is a poor measurement of intra-abdominal, visceral fat mass, a major statistical determinant of most of the comorbidities, yet its statis-tical power is surprising. Possibly this measurement contains unrecognized information beyond intra-ab-dominal fat mass, such as a muscle component included in the hip circumference measurement. These issues are an area for more research. At the time of the first edition, research on endocrine perturbations focused on the disturbances of regulation of the hypothalamic-pituitary-adrenal (HPA) axis and its interference with the central gonadal and growth hormone axes. Major advances have occurred with the development of new techniques, which are sensitive and discriminating enough to reveal minor regulatory errors of daily life (2–4). Research has previously addressed the peripheral consequences of the endocrine perturbations (accumulation of intra-abdominal fat and insulin resist-ance) (5,6), perturbations in the capillary system and in the synthesis of myosins (1). Much progress has been made in these areas and in genetics since the previous edition. The original Handbook examined the period up to 1996–1997, so this chapter will focus on the following years, including generally integrated and specific aspects of these developments covered in several recent reviews (2–9). II DEFINITION OF THE METABOLIC SYNDROME A syndrome is a collection of symptoms typically occur-ring together. Such syndromes often originate from 787……Page 797
33 Obesity as a Risk Factor for Major Health Outcomes JoAnn E. Manson Harvard Medical School and Brigham & Women’s Hospital, Boston, Massachusetts, U.S.A. Patrick J. Skerrett Brigham & Women’s Hospital and Harvard Health Publications, Harvard Medical School, Boston, Massachusetts, U.S.A. Walter C. Willett Harvard School of Public Health, Boston, Massachusetts, U.S.A. I INTRODUCTION Until recently, excess weight was generally overlooked as a major risk factor for chronic disease. Now a rapidly expanding body of data is defining the impact of overweight and obesity on premature mortality, cardiovascular disease, type 2 diabetes mellitus, osteo-arthritis, gallbladder disease, some types of cancer, and other conditions (Fig. 1) (1,2). Models using data from the Third National Health and Nutrition Examination Survey (NHANES III), the Framingham Heart Study, and other sources have demonstrated a direct, dose-dependent relationship between increasing body mass index (BMI) and lifetime risk of various conditions (Table 1) (3–5). Data from the U.S. Behavioral Risk Factor Surveillance System indicate that obesity is associated with greater morbidity and poorer health-related quality of life than smoking or problem drink-ing (6), and a recent conservative estimate, derived from five long-term prospective cohort studies, suggests that overweight and obesity account for >280,000 deaths each year in the United States (7). The substan-tial morbidity and mortality associated with excess weight underscore the pressing need to improve the education of health professionals and the public about the hazards of overweight and obesity and to remove the barriers to healthy eating and increased physical activity. II MORTALITY While the precise shape of the body weight/mortal-ity curve remains controversial, there is little question that substantial excess adiposity increases mortality. A reanalysis of 12-year follow-up data of the American Cancer Society’s Cancer Prevention Study I cohort that excluded smokers and those with a history of cancer or cardiovascular disease at baseline (8), as well as a new analysis of a second Cancer Prevention cohort of more than 1 million adults with 14 years of follow-up (9), showed a clear pattern of increasing mortality with increasing weight (Fig. 2). Among healthy people who had never smoked, optimal mortality was found at a BMI of 23.5–24.9 for men and 22.0–23.4 for women. These data confirm similar observations from a 27-year 813……Page 823
34 Effects of Obesity on the Cardiovascular System Edward Saltzman Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University and Tufts–New England Medical Center, Boston, Massachusetts, U.S.A. Peter N. Benotti Valley Hospital, Ridgewood, New Jersey, U.S.A. I INTRODUCTION Cardiovascular disease is the leading cause of death in industrialized countries, and in the United States, car-diovascular disease accounts for f50% of all deaths (1). Obesity increases risk for coronary heart disease (CHD), congestive heart failure (CHF), arrhythmia, sudden death, and several other cardiovascular diseases (Table 1). Obesity promotes several traditional risk factors for cardiovascular disease, and in addition con-siderable attention has been devoted to defining the pathogenic role of excess weight that is independent of traditional risk factors. Obesity has recently been found to be associated with several nontraditional risk factors, such as disturbances in fibrinolysis, impaired endothelial function, and chronic low-grade inflammation. Regard-less of the mechanism, it is clear that obesity is associated with deleterious effects on the heart and circulatory system. In the sections below, the increased demands im-posed by obesity on the heart and circulation and the resultant cardiovascular adaptation are reviewed. This is followed by discussion of the contribution of obesity to pathologic conditions such as CHF, arrhythmia, CHD, and other cardiovascular syndromes. The bene-ficial effects of weight loss on specific conditions and overall cardiovascular mortality is also discussed where evidence exists. Finally, the association between weight loss medications and cardiac valve disease, as well as cardiovascular effects of other appetite suppressants, is presented. II EFFECTS OF OBESITY ON CARDIAC STRUCTURE AND FUNCTION Obesity is characterized by expansion of fat mass, as well as expansion of skeletal muscle, viscera, and skin, all of which increase oxygen consumption (2,3). Although metabolically active, adipose tissue oxygen consumption is lower than for lean tissue, hence total body oxygen consumption expressed per kilogram of body weight in the obese is lower than in leaner persons (3–5). Obesity is also accompanied by expansion of extracellular volume, which comprises the intravascular and interstitial fluid spaces. Total blood volume and plasma volume generally increase in proportion to the degree of overweight (4,6–8). For example, in compar-ison to lean control groups (BMI 22 kg/m 2 ), nonhyper-tensive obese subjects (BMI f36 kg/m 2 ) had 20–25% expansion of total blood volume, while the ratio of central to total blood volumes was comparatively unchanged (7,8). Expansion of blood volume leads to increased left ventricular filling, which in turn results in 825……Page 835
35 Obesity and Lipoprotein Metabolism Jean-Pierre Despre´s Quebec Heart Institute, Laval Hospital Research Center, Laval University, Sainte-Foy, Quebec, Canada Ronald M. Krauss Children’s Hospital Oakland Research Institute, Oakland, Lawrence Berkeley National Laboratory, and University of California, Berkeley, Berkeley, California, U.S.A. I DYSLIPIDEMIC PHENOTYPES IN CORONARY HEART DISEASE: BEYOND CHOLESTEROL The measurement of plasma lipid levels is now com-monly used to assess the risk of coronary heart disease (CHD). Several epidemiological studies have shown that there is a significant positive relationship between blood cholesterol levels and deaths associated with CHD (1–3). In the Multiple Risk Factor Intervention Trial (MRFIT), Stamler et al. (4) showed that in a sam-ple of 356,222 male subjects, increased blood cholesterol levels were associated with a progressive increase in CHD mortality. However, despite the fact that numer-ous studies have shown this relationship, Genest et al. (5) have reported that nearly 50% of patients having ischemic heart disease (IHD) have plasma cholesterol levels equal to or even lower than those of healthy subjects. Accordingly, Sniderman and Silberberg (6) empha-sized that although the mean blood cholesterol concen-tration in CHD patients is generally significantly higher than that of healthy subjects, there is a considerable overlap between CHD patients and healthy subjects. Thus, the clinical value of total cholesterol measure-ment alone is of limited use in distinguishing CHD pa-tients from healthy subjects. It was therefore suggested that additional determinations of blood lipid variables were needed to more accurately assess risk. Plasma cholesterol is a hydrophobic compound and is transported in the blood by lipoproteins. Lipopro-teins vary in size, composition, and density, and four main families can be identified: chylomicrons, very low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL) (Fig. 1). Chylomicrons are large particles found after a meal which are responsible for the transport of alimentary lipids. They are generally absent from the fasting plasma of healthy subjects. Triglyceride (TG) and cholesterol molecules of hepatic origin are secreted in VLDL par-ticles which are converted to LDL following hydroly-sis by the enzyme lipoprotein lipase (LPL). During the hydrolysis of chylomicrons and VLDL, excess surface component aggregates to form nascent HDL particles. Additional newly formed and immature HDL parti-cles originate from the intestine and the liver. A LDL Cholesterol: A Major Culprit in CHD Numerous prospective studies that have measured cho-lesterol in the lipoprotein fractions (VLDL, LDL, and HDL) have reported highly significant associations 845……Page 855
36 Obesity and Blood Pressure Regulation Albert P. Rocchini University of Michigan, Ann Arbor, Michigan, U.S.A. I INTRODUCTION Obesity is an independent risk factor for the develop-ment of both hypertension and cardiovascular disease. This chapter will summarize: techniques for measuring blood pressure in obese individuals and the effect of obesity on these measurements; the evidence that sub-stantiates that obesity is an independent risk factor for the development of hypertension; an explanation of how obesity may result in the development of hy-pertension; a brief summary of other cardiovascular abnormalities associated with obesity; and finally a brief summary of how to manage the hypertensive obese individual. II MEASUREMENT OF BLOOD PRESSURE IN OBESE INDIVIDUALS For years, physicians believed that the high blood pressure observed in many obese individuals was related to a measurement error. The indirect method of mea-suring blood pressure usually results in an overestima-tion of both systolic and diastolic blood pressure. The overestimation of blood pressure is due, in part, to the fact that pressure measured by the cuff and sphygmo-manometer is not just the force required to occlude the brachial artery but also includes the force required to compress the soft tissues of the arm. In the case of obesity, the increased subcutaneous fat present in the upper arm imposes a greater resistance to compression and therefore a higher cuff inflation pressure. Most of the effects of obesity on the indirect measurement of blood pressure can be corrected by using and appropri-ate size blood pressure cuff. Although, compared with intra-arterial measurements of blood pressure, the indi-rect method is less precise, nevertheless, when properly measured, elevated indirect blood pressure readings are a reliable method for diagnosing hypertension. The major errors encountered in the measurement of blood pressure include cuff size, type of instrumentation for measuring blood pressure, and observer errors. A Cuff Size The selection of an appropriate-size compression cuff is critical to obtaining accurate reading. The cuff consists of an inflatable bladder with a cloth cover. The dimen-sions of the inner bladder, not the size of the cover, determine cuff size (Fig. 1). The bladder must be the cor-rect width for the circumference at the mid point of the upper arm (Table 1). A bladder that is too small will cause a falsely high pressure. The bladder should be wide enough to cover f75% of the upper arm between the top of the shoulder and the olecranon. The length of the bladder also influences the accuracy of measure-ments. A bladder length that is roughly twice the width is ideal and should result in the cuff nearly encircling the arm. If a question arises as to which of two cuffs is appropriate, a cuff that is slightly wider and longer than 873……Page 883
37 Obesity and Diabetes Jeanine Albu and F. Xavier Pi-Sunyer Columbia University College of Physicians and Surgeons and St. Luke’s-Roosevelt Hospital Center, New York, New York, U.S.A. I ASSOCIATION BETWEEN OBESITY AND DIABETES Obesity is rare in insulin-dependent type 1 diabetes mellitus, but is common in type 2, non-insulin-depend-ent, diabetes mellitus (DM). About 85% of diabetics can be classified as type 2, and of these an average of 70% are overweight, ranging from a low of 50% to a high of 90%, depending on age, gender, and race (1). An initial observation that obesity and diabetes mellitus are associated was made by John (2) in 1929. Also, early on, it was observed that weight loss improves glucose control (3). West and Kalbfleisch (4), in the 1960s, in a series of population studies including many geographical areas, races, and cultures, noted a strong association between the prevalence of diabetes and overweight. They proposed that the largest environ-mental influence on the prevalence of diabetes in a population group was the degree of obesity present in that community (5). In some of these populations, diabetes was found to be as much as threefold higher in females than in males. Controlling for adiposity abolished these sex differences. In the Bedford diabetes survey of 1962, Fowler et al. (6) found that whereas in individuals 30 (males) or >28 (females). The literature is too heter-ogeneous to combine studies or to examine the relation-ship of obesity to respiratory function using continuous variables for each condition. Therefore, we will discuss studies that examined categorical effects (obese vs. non-obese subjects). Respiratory compliance is a measure that relates to the pressure changes that are required to increase lung volume and can be influenced by the mechanical proper-ties of both the lungs and the chest wall (14–16). One major problem in obesity is that increased weight press-ing on the thoracic cage and abdomen makes the chest wall stiff and noncompliant (14,15). In addition to in-creased adiposity around the thoracic cage, chest wall compliance may be decreased because the decreased total thoracic and pulmonary volume may pull the chest wall below its resting level to a flatter portion of its pres-sure- volume curve. In a study on sedated, paralyzed, postoperative morbidly obese patients, functional resid-ual capacity (FRC) was seen to be markedly low com-pared to normals, and respiratory compliance was found to be low owing to significant decrease in both lung and chest wall compliance (17). Total respiratory system resistance was also mark-edly increased, primarily owing to an increase in lung resistance. Oxygenation was impaired and correlated with total respiratory system compliance. PaCO2 was not different between obese and lean subjects and did not relate to compliance, resistance, or FRC. The same group later compared respiratory mechanics during 935……Page 945
40 Obesity, Arthritis, and Gout Anita Wluka and Flavia M. Cicuttini Monash University, Melbourne, Victoria, Australia Tim D. Spector Guy’s and St. Thomas’ Hospital NHS Trust, London, England I INTRODUCTION Musculoskeletal conditions affect 16% of all Americans (1). In 1988 it was estimated that the direct and indirect costs of these to the country were equivalent to 2.5% GNP (2). This was three times as great as the estimated cost in 1980. Musculoskeletal conditions are an im-portant cause of acute and chronic disability, being amongst the most common causes of work disability, because of their prevalence and severity (2). Indeed, in the workplace, the cost of musculoskeletal diseases were the highest and second-highest disease categories in workers with BMI between f27.5– 30 and >30, re-spectively (3). The most common musculoskeletal condition is osteoarthritis (OA), which affects 12.1% of Americans between the ages of 25 and 74 years (4). Its prevalence increases with age, so that the socioeconomic burden to society will grow with our aging population. Gout is the most common form of inflammatory arthritis in males over 40 years old. II OBESITY AND OSTEOARTHRITIS Osteoarthritis is a disorder of synovial joints character-ized by deterioration and abrasion of the joint cartilage and formation of new bone at the joint surfaces. Obesity is likely to be the most important preventable risk factor for knee OA. Overall, results to date suggest that the link between obesity and OA is more consistent in women and is strongest in OA of the knees and less conclusive in other joints. This has important implica-tions since OA is an enormous public health problem in developed countries as it is the commonest single cause of disability (5) and the major reason for hip and knee replacements (6). The combination of its effect on patients and the therapeutic procedures used produces a huge burden on society (7). Recently, efforts have been focused on potential risk factors for OA with a view to identifying possible preventive measures. The manage-ment of obesity is likely to be a key factor in the management of OA. A Association of Obesity and Osteoarthritis of the Knee Cross-sectional epidemiological studies have consis-tently shown a relationship between obesity and knee OA, which has generally been stronger in women than in men. The reported increased risks have ranged from two- to seven-fold for women in the top tertile of BMI compared to women in the bottom tertile (8–14) (Table 1). The earliest survey to mention this link 953……Page 963
41 Obesity, Pregnancy, and Infertility Stephan Ro¨ssner Huddinge University Hospital, Huddinge, Sweden I GENERAL HORMONAL BACKGROUND By definition obesity implies an excess of adipose tissue, which is not an inert storage room for triglycerides but actually the largest hormonally active gland of the body (1). Fat cells are known to convert androstenedione to estrone (2,3). Increased concentrations of estrone in obesity may interfere with the feedback system to the hypothalmohypophysial axis, increasing the levels of gonadotropins and androgens (4). As a consequence anovulation may occur. Furthermore, in obesity a re-duction in sex hormone–binding globulin (SHBG) con-centrations is seen, and the end result is an increased concentration of biologically active free androgens. Menstrual disturbances are frequent in obesity and may often be normalized after weight reduction (5–7). Several studies have demonstrated that with weight reduction various characteristics of the hormonal pro-file can be normalized. As early as the 1950s the relation-ship between obesity and menstrual disorders was reported (8). A particular clinical syndrome associated with obesity and anovulation is the polycystic ovarian syndrome (PCOS), characterized by anovulation, hy-perandrogenism, insulin resistance, and altered gonad-otropin secretion (9,10). Several investigations have analyzed the relationship between weight loss and men-strual function in PCOS, but often these designs have had clinical and methodological limitations. In some situations, appropriate endocrine characteristics have not been available, and in others no proper control group has been included. In the study of Guzick (11), on the other hand, a group of obese hyperandrogenic anovulatory women were studied in a prospective randomized controlled fashion before and after a weight loss of 16.2 kg. This weight loss resulted in a significant increase in SHBG, a significant reduction in non-SHBG testosterone levels, and resumed ovulation in two-thirds of these subjects. These changes appeared in spite of nonsignificant reduc-tions in fasting insulin concentrations and LH and FSH concentration characteristics. The positive effects of weight reduction in obese women with PCOS are underscored by a study of Hamilton-Fairley et al. (12). These authors suggest that all overweight women—whether with PCOS or not— should be advised to lose weight before attempted conception in order to improve their chances of a suc-cessful outcome, and furthermore that PCOS women requiring gonadotropin treatment should consider weight loss before treatment to improve their chances of a successful pregnancy. II OBESITY AFTER PREGNANCY It is common clinical experience that many overweight women report that each pregnancy has resulted in weight retention after delivery. Since pregnancy can in 967……Page 977
42 Physical Activity, Obesity, and Health Outcomes William J. Wilkinson and Steven N. Blair The Cooper Institute, Dallas, Texas, U.S.A. I INTRODUCTION As documented by recent national and international guidelines, obesity is a significant public health problem (1,2). The prevalence of overweight and obesity is increasing in many countries around the world. In the United States it is estimated that at least 55% of adults are overweight or obese (defined as a body mass index [BMI] z25 kg/m 2 ), and according to recent surveys, the prevalence of obesity (BMI z30 kg/m 2 ) in the United States increased from 12% to 19.8% between 1991 and 2000 (1,3,4). Low levels of energy expenditure from physical activity are likely a major contributing factor to the rapid increase in the prevalence of obesity (5–7). Although there are no direct data, it seems probable that a decline in energy expenditure has taken place due to obvious changes in occupational- and household-related physical activity, as well as urban environments that are increasingly less conducive to leisure-time physical activity. In the United States, the most recent data indicate that 29.2% of adults are inactive in their leisure time and 43.1% participate in some leisure-time activity but at levels too low to confer significant health benefits. Only 27.7% of U.S. adults are physically active at recom-mended levels (8,9). Compared with normal-weight and overweight adults, obese individuals are more likely to report being inactive (27.3%, 28%, and 37% respec-tively) (9). Cross-sectional and cohort studies suggest that differences in amounts of physical activity contrib-ute to differences in body weight and body fatness and play an important role in whether obesity develops (10– 13). Arecent ecological review of secular trends suggests that the prevalence of obesity is more strongly related to decreases in energy expenditure than to increases in energy intake (14). A large body of scientific evidence and consensus opinion indicates that physical activity is an essential element, along with dietary and behavioral modifica-tion, in the clinical strategy for weight management for patients who are overweight and obese (1,8,15). In recent years, professional and governmental bodies have provided expert consensus recommendations on physical activity for health promotion and disease prevention in all adults (8,16–18). The latest guidelines can be summarized as follows: All adults should increase their regular physical activity to a level appropriate to their capacities, needs, and interests. The long-term goal is to accumulate 30 min or more of moderate-intensity physical activity (i.e., brisk walking, leisurely cycling, swimming, recreational sports, home repair, and yard work) on most, preferably all, days of the week. People who currently meet these recommended minimal standards may derive additional health and fitness benefits by becoming more physically active or including more vigorous activity. The recommendation from the National Heart, Lung, and Blood Institute’s Clinical Guidelines on the Identification, Evaluation, and Treatment of Over-weight and Obesity in Adults for physical activity as 983……Page 993
43 Obesity and Quality of Life Donald A. Williamson Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana, U.S.A. Patrick M. O’Neil Medical University of South Carolina, Charleston, South Carolina, U.S.A. I OVERVIEW OF RESEARCH EVIDENCE Quality of life, particularly health-related quality of life, has been defined as the ‘‘physical, psychological, and social domains of health, seen as distinct areas that are influenced by a person’s experiences, beliefs, expecta-tions, and perceptions’’ (1). This definition makes it explicit that quality of life includes not only objective indicators but also subjective appraisals of well-being. Further, the growing interest in assessing quality of life reflects the recognition that health is much more than the absence of disease. Obesity is at once a chronic condition with numerous effects on physical health and functioning, a publicly apparent characteristic with pervasive social implica-tions, and a vexing health problem whose remediation or control requires long-term, often difficult behavioral changes. It is thus expected that obesity may affect quality of life in many ways. Agrowing body of research has examined the quality of life experienced by obese persons. Quality of life in obesity has been studied with questionnaires explicitly assessing a range of areas of life functioning, with assessment of specific psychiatric dis-orders or moods, and with examination of other indi-cators of life quality. We will approach this research from the point of view that different aspects of quality of life may be affected by obesity in different ways, and that various factors influence how obese individuals are affected. The present section describes measures of overall quality of life, mood and personality, eating behavior and disturbed eating, dietary restraint and overeating/ binge eating, and body image. Sections II–IV of this chapter provide a review of research findings pertain-ing to obesity and quality of life. Section V describes frequently used assessment methods that measure var-ious aspects of quality of life. When reading these sec-tions, the reader may wish to refer to the section on methods if there are questions about the reliability and validity of a particular measure that was used to assess the relationship between obesity and quality of life. A Obesity and Quality of Life 1 Overall Quality of Life Two questionnaires that have been frequently used in this research are the Impact of Weight on Quality of Life questionnaire (2) and the Medical Outcomes Study Short-Form Health Survey (SF-36) (3). They are de-scribed in more detail later in this chapter. Among a sample of treatment-seeking obese men and women, functioning in most areas of the Impact of Weight on Quality of Life questionnaire was worse with increas-ing body mass index (BMI). Women reported greater 1005……Page 1015
Index……Page 1033