Obesity is a Chronic Disease
The pathophysiology of obesity produces excess adiposity sufficient to impair health and results from an imbalance between caloric intake and energy expenditure in favor of fat accretion. In 2012, the American Association of Clinical Endocrinologists (AACE) published a position statement designating obesity as a disease.5 Subsequently, following a proposition submitted by AACE together with multiple other professional organizations, the American Medical Association (AMA) also recognized obesity as a chronic disease in June, 2013.11 Like many other chronic diseases, genetic factors constitute a substantial component of disease risk12 that can explain 50% to 60% of individual variation in body weight in monozygotic/dizygotic twin studies. Monogenic forms of the disease are rare, such as in families with leptin or leptin receptor mutations or deletion of the SNORD116 gene cluster in patients with Prader-Willi syndrome. Susceptibility to obesity in the majority of individuals results from the inheritance of multiple genes, with each allele conferring a very small relative risk for the disease. Genome-wide association studies have identified more than 100 susceptibility loci for obesity.13 Particularly strong association signals have been detected for the fat mass- and obesity-associated gene (FTO) and the melanocortin-4 receptor (MC4R) gene, but even these variants confer odds for obesity of less than 1.7.14,15 The multiple susceptibility genes interact with each other and with the environment, behavior, and biological factors to produce individual variation in the risks of obesity, as illustrated in Fig. 27–1. The development of excess adiposity is a complex process; however, those individuals who inherit larger subsets of obesity susceptibility genes will tend to be more overweight in any given environment.16,17 Progressive weight gain is not a lifestyle choice and cannot be viewed in terms of a simple thermodynamic equation of greater energy in than energy out. Rather, gene-environment interactions generate a human biological and behavioral interface unique to each individual that not only determines body weight but also explains individual variation in the net effect on body weight for any given amount of food intake or physical activity. To this point, among monozygotic twin pairs, the intra-twin changes in body weight are highly correlated in response to overfeeding18 and underfeeding19 of the same number of calories, such that if one member of the twin pair lost a greater or lesser amount of weight, so too did the corresponding twin. Thus, the genetic background and/or the common shared environment determined differences in the amount of weight gained or lost in response to an identical degree of caloric excess or deficit.20
Pathophysiology of obesity as a chronic disease.
Obesity fulfills the three essential criteria for a disease established by the AMA (report 4 A-05 of the AMA Council on Scientific Affairs), which are (1) characteristic signs or symptoms, (2) an impairment in normal functioning of some aspect of the body, and (3) a process that results in harm or morbidity. A defining sign of obesity is an excess of adipose tissue widely measured as BMI, calculated as weight in kilograms divided by height in meters squared (Table 27–1). There are two salient examples of pathophysiology that contribute to an understanding of the obese state: hypothalamic dysfunction and cardiometabolic risk.
TABLE 27–1.Classification of Overweight and Obesity by Body Mass Index and Waist Circumference ||Download (.pdf) TABLE 27–1. Classification of Overweight and Obesity by Body Mass Index and Waist Circumference
| ||Body Mass Index ||Waist |
|Classification ||Measurement (kg/m2) ||Comorbidity Risk ||Waist Circumference and Comorbidity Risk |
| || || || |
Men: ≤ 40 in
Women: ≤ 35 in
Men: > 40 in
Women: > 35 in
|Underweight ||< 18.5 ||Low but other problems || || |
|Normal Weight ||18.5–24.9 ||Average || || |
|Overweight ||25–29.9 ||Increased ||Increased ||High |
|Obese class I ||30–34.9 ||Moderate ||High ||Very high |
|Obese class II ||35–39.9 ||Severe ||Very high ||Very high |
|Obese class III ||≥ 40 ||Very severe ||Extremely high ||Extremely high |
Defects in Hypothalamic Regulation of Appetite
Homeostatic dysregulation in the hypothalamus adversely affects appetite and satiety as they respond to peripheral hormones that register fuel storage and availability. With obesity, these mechanisms drive an increase in appetite producing a positive energy balance, which generates and maintains a higher body weight.21,22 By way of illustration, this pathophysiology is fully operational in response to weight loss when compensatory changes in hypothalamic processes result in increased hunger and energy storage, driving weight regain back to the previous high level of body weight.21 As shown in Fig. 27–2, following a weight-loss intervention, secretion of ghrelin from the stomach is increased above baseline both before and after meals. Ghrelin stimulates neuropeptide Y (NPY) and Agouti-related peptide neurons in the arcuate nucleus of the hypothalamus, causing release of NPY, which activates orexigenic neural pathways leading to an increase in appetite. At the same time, hormones from the gastrointestinal tract and pancreas (eg, leptin, cholecystokinin, glucagon-like peptide-1, amylin, and peptide YY) are reduced below baseline levels.21 These latter hormones circulate to the hypothalamus and stimulate proopiomelanocortin-expressing neurons in the arcuate nucleus to produce α-melanocyte-stimulating hormone (MSH). The α-MSH binds upstream MC4R receptors to activate anorexigenic neural pathways, resulting in suppression of appetite. The fall in these satiety-producing hormones has an additional effect to stimulate appetite. Furthermore, in response to weight loss, resting energy expenditure rates are decreased, and the energy that muscles use for any given amount of work is also decreased (ie, increased muscle energy efficiency). These energetic changes also promote weight regain.23 Finally, psychological food preferences become oriented to food of greater caloric density with high fat and sugar content.
The pathophysiology of obesity protects against weight loss and maintains a high body weight. CCK, cholecystokinin; PYY, peptide YY.
All of these factors promote weight regain and help to maintain a degree of excess adiposity that is harmful to health. In this sense, obesity protects obesity in that hypothalamic set points protect the obese state and resist efforts to reduce adiposity. This makes it challenging for people to maintain a healthy weight. To maintain weight loss, individuals must adhere to therapeutic behaviors or take weight-loss medications that oppose these pathophysiological adaptations (ie, recalcitrant set points) as well as other factors favoring weight regain.
Dysfunctional Adipose Tissue and the Cardiometabolic Disease Process
The second dysfunctional aspect of the obese state is adipose tissue itself and the role it plays affecting other organ systems. The BMI is used to estimate overall adiposity; however, an important consideration is the distribution of body fat, which can have significant implications for disease risk. With increases in body weight, accumulation of intra-abdominal fat is central to the pathophysiology of cardiometabolic disease.24 Cardiometabolic disease risk represents a spectrum of disease manifestations due to common underlying pathophysiological mechanisms that begins with insulin resistance, progresses to the clinically identifiable high risk states of metabolic syndrome (MetS) and prediabetes, and finally to type 2 diabetes mellitus (T2D), cardiovascular disease (CVD), or both in individual patients.25 Based on animal models, primarily murine, and human studies, fat accumulation in visceral adipose tissue is accompanied by an influx of macrophages, the production of proinflammatory cytokines (eg, interleukin-6 [IL-6]), adipocyte insulin resistance, and the dysregulated secretion of adipokines such as adiponectin and resistin.26,27,28,29 Altered levels of circulating adipokines affect metabolism in various organs (eg, liver, muscle, vascular wall), and this helps produce the MetS trait complex. For example, serum adiponectin levels are decreased, which exacerbates systemic insulin resistance and promotes atherogenesis through loss of adiponectin’s effect to suppress foam cell formation.30
Another aspect of dysfunctional fat is the diminished ability to store lipid. This causes a redistribution of fat to the intra-abdominal compartment and the accummulation of lipid within muscle cells and hepatocyes, which further exacerbates insulin resistance at the level of these organs and contributes to abnormal glucose tolerance. Generalized obesity can exacerbate insulin resistance by augmenting lipid accumulation in muscle, liver, and the visceral compartment, and thus it further impels progression of cardiometabolic disease toward the end-stage manifestations of overt T2D and CVD.31 Obesity alone, however, is not a prerequisite for cardiometabolic disease, and is not sufficient as a cause of such disease because even lean individuals can be insulin resistant, and obese indivuals can be insulin sensitive with no manifestations of MetS.25 Nevertheless, weight loss in overweight/obese individuals with insulin resistance and cardiometabolic disease represents highly effective therapy. These principles and the spectrum of cardiometabolic disease are illustrated in Fig. 27–3.
The spectrum of cardiometabolic disease. Insulin resistance represents the initial lesion beginning early in life. This includes insulin resistance in adipocytes and defective capability for lipid storage, with accumulation of lipid in muscle and liver cells and in the intra-abdominal depot. There is the eventual transition to the clinically identifiable high-risk states of prediabetes and metabolic syndrome. These individuals are then at high risk for developing type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD) events, or both. Thus, the operant pathophysiological mechanisms give rise to both metabolic and vascular disease components.
Obesity, Circadian Rhythms, Sleep, and Cardiometabolic Risk
Lifestyle plays a central role in the expression of the obese state comprising not only dietary patterns, physical activity, and stress, but other factors as well, including sleep hygiene and the emerging science of chronobiology.32 Hierarchical regulatory levels ultimately determine circadian changes in appetite, energy consumption, adipocyte function, and body composition. These grossly consist of (1) photic entrainment by the retinal-hypothalamic pathway, (2) oscillators in the suprachiasmatic nuclei of the hypothalamus (master clock), (3) neuronal and hormonal (eg, glucocorticoid) coordination of peripheral clocks (eg, gastrointestinal, pulmonary, and fat), (4) transcription-translation feedback loops involving clock genes (eg, Clock, Bmal1, Per1-3, Cry1-2, Chrono, Rev-erbα, and Rorα), and many downstream clock-controlled genes.32 Food intake also entrains circadian rhythmicity via nutrients (eg, glucose, amino acids, sodium, ethanol, caffeine, thiamin, and retinoic acid), hormones (eg, glucagon, leptin, and ghrelin), cellular energy signals, and various transcription factors.32 Chronodisruptors that are associated with obesity include frequent flying, shift work, disturbed eating patterns, and certain macronutrient distributions (eg, high fat).32 Considering the increased risk of myocardial infarction from 6:00 a.m. to noon, it is not surprising that there may be chronobiological mechanisms mediating the association of obesity with CVD.33
Potential targeted interventions addressing chronodisruptor-related weight gain include healthy dietary patterns, structured and consistent sleep-wake cycles, decreasing artificial light exposures, and improved sleep hygiene, with pharmacological modalities currently under investigation.32,34 More specifically, disrupted sleep during critical weight gain periods in young adulthood, as well as short sleep durations (< 6–9 hours/night) and other causes of sleep debt (eg, television/computer screen time and long commuting hours), affect appetite and energy balance (via hormones, such as insulin, cortisol, ghrelin, leptin, NPY, and orexin). Poor sleep hygiene is associated with obesity, T2D, CVD, and total mortality, and it should be targeted therapeutically.35,36,37,38,39,40,41
Obesity markedly augments risk of obstructive sleep apnea, which interrupts normal sleep with periods of hypoxia. This establishes a vicious cycle whereby progressive weight gain exacerbates sleep apnea and sleep apnea promotes further weight gain.38,42 Obstructive sleep apnea adversely affects psychological health, causing fatigue and depression, metabolic health by predisposing to metabolic syndrome and T2DM, and cardiovascular health as an independent risk factor for refractory hypertension, stroke, and CVD.43,44,45,46,47 The therapeutic options for obstructive sleep apnea include continuous positive airway pressure therapy and weight loss.48,49 Severity of sleep apnea is quantified by the apnea-hypopnea index (AHI), which reflects the average number of apneic/hypopneic episodes per hour during a polysomnography study.45 Weight loss, whether achieved by lifestyle therapy49 or obesity medications,49 can dramatically improve both AHI scores and symptomatology; however, therapeutic benefits are most predictably achieved with at least 10% weight loss.48,50