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Supplements Impact of Obesity Interventions on Managed Care
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Obesity: Definition, Comorbidities, Causes, and Burden
Caroline M. Apovian, MD, FACP, FACN
The Role of Managed Care Organizations in Obesity Management
Kenneth L. Schaecher, MD, FACP, CPC
Impact of Obesity Interventions on Managed Care
Impact of Obesity Interventions on Managed Care

Obesity: Definition, Comorbidities, Causes, and Burden

Caroline M. Apovian, MD, FACP, FACN
Genetic influences on BMI appear to be strongly correlated.27 Researchers assessed identical twins reared together and apart, as well as fraternal twins reared together and apart. Intrapair correlations for BMI of identical twins reared apart were 0.70 for men and 0.66 for women, demonstrating that genetic influences were independent of environmental influences.27 A comparison of body fat in a cohort of adult twins who were reared apart versus a control group of twins reared together showed that body fat is strongly associated with genetic factors.28 About 60% of individual differences in body fat were attributed to genetics, but because the correlation is less than 100%, the environment must also influence body fat percentage. A study of monozygotic and dizygotic twins examined the heritability estimates for fat measures and found that these measures were about the same for both sexes, although slightly higher in men.29 The genetic variance range for BMI and body fat percentage was 0.58 to 0.63; for total skin folds, 0.48 to 0.69; and for waist circumference, 0.61 for men and 0.48 for women. Therefore, genetics appear to determine who will become obese, and the environment appears to determine the extent of obesity.28,29

Gut Microbiome

The body’s microbiome the bacteria, viruses, archaea, and eukaryotic microbes residing in and on the body have the potential to impact our physiology in several ways, including contributing to metabolic function.30 Studies have demonstrated that the gut microbiome can increase dietary energy harvest, and an “obese microbiome” results in greater total body fat than a “lean microbiome.”31 Clinical trials are needed to assess replacing or altering the gut microbiome to treat obesity and its complications.


Chronodisruption is associated with the development of obesity, prediabetes, diabetes, and lipid disorders.32,33 Chronodisruption can be induced by shift work, sleep deprivation, or shifting the normal eating time to night hours.

Relationship Between Hormones and Weight

The regulation of food intake is managed by neural and hormonal signals between the gut and central nervous system (CNS). Hormones, such as glucagon-like peptide (GLP), oxyntomodulin (OXM), leptin, peptide tyrosine-tyrosine (PYY), and cholecystokinin (CCK), signal to important areas in the CNS involved in appetite control.34,35 Blood concentrations of these hormones increase after a meal; the concentrations are proportional to the caloric intake and composition of a meal.34

Glucagon-like Peptide

Several biologically active peptides are produced from proglucagon.35 These include GLP and OXM. GLP stimu-lates insulin release and inhibits glucagon release in a glucose-dependent manner. Nonglycemic effects include weight loss. Independent of weight loss, potential effects include cardiovascular, neurologic, and renal benefits, along with changes in taste perception. Currently, a GLP-1 receptor agonist is approved for the treatment of obesity.36


OXM regulates the secretion of gastric acid and intestinal hydro-minerals. It is also needed for the control of food intake and energy expenditure. In the CNS, OXM suppresses hunger and reduces food intake. In addition, it increases energy expenditure and inhibits the orexigenic signal carried by ghrelin. In all, these features make OXM a good target for the development of an anti-obesity drug.35

Peptide Tyrosine-Tyrosine

PYY regulates food intake in lean and obese persons. The exact mechanism of its anorectic effects are unclear. High concentrations of circulating PYY are found in patients with anorexia nervosa, and low concentrations are observed in those with obesity. In addition, PYY may increase energy expenditure by increasing postprandial thermogenesis, resting metabolic rate, and 24-hour respiratory quotient.34


CCK-induced hunger suppression mainly occurs via the CCK 1 receptor. CCK does not appear to impact gastric emptying; CCK likely acts peripherally because it is unable to cross into the CNS. It appears to reduce food intake via the vagus nerve; however, the mechanism is unclear. CCK and leptin may have a synergistic effect on food intake inhibition.34 Leptin Leptin is responsible for the communication in the brain of energy availability and storage; the hypothalamus responds to these signals by controlling behavior and metabolic responses. Leptin can suppress appetite and increase energy expenditure, resulting in weight loss.37 However, when leptin signaling is not functioning properly, it can result in weight gain. Leptin resistance was associated with obesity (odds ratio [OR]: 4.12; 95% CI, 3.29-5.16), while normal weight was associated with the absence of leptin resistance (OR: 0.13; 95% CI, 0.01-0.20). Leptin resistance and obesity are possibly heritable traits. One hypothesis is that people who are obese are resistant to endogenous leptin signaling. Patients who were obese were reported to have significantly higher serum leptin concentrations than patients who were considered to be of normal weight (mean serum leptin concentration 31.3 ± 24.1 ng/mL in participants who were obese vs 7.5 ± 9.3 ng/mL in participants who were considered of normal weight, P <.001).38 In addition, there was a strong cor-relation between serum leptin concentration and body fat percentage (r = 0.85, P <.001), BMI (r = 0.66, P <.001), fasting serum insulin concentration (r = 0.57, P <.001), and age (r = 0.26, P <.001).39


Adiponectin appears to assist in the modulation of glucose and lipid metabolism in insulin-sensitive tissues. It increases sensitivity to insulin, reduces hepatic glucose production, and stimulates fatty acid oxida-tion. Plasma adiponectin concentrations are decreased with insulin resistance (such as in type 2 diabetes [T2D]). Obesity is associated with adiponectin deficiency, which makes this hormone a possible target for therapeutic interventions.40


Ghrelin is a potent orexigenic hormone that stimulates food intake. Its levels are elevated 1 to 2 hours before a meal and are decreased soon after. Exogenous ghrelin is associated with increased food intake, reduced resting energy expenditure, and catabolism in adipose tissue.40

Obesity and Associated Conditions

Conditions Associated With Weight Gain

Hypothyroidism, Cushing’s syndrome, polycystic ovary syndrome (PCOS), and certain neurologic prob-lems are associated with excessive weight.41


With hypothyroidism affecting weight and obesity affecting thyroid function, the interrelationship between hypothyroidism and obesity is a complex one.42 Thyroid hormones are linked to body composition because they are integral in basal metabolism and thermogenesis; they also affect glucose and lipid metabolism, fat oxidation, and food intake.43 As stated above, an increase in thyroid-stimulating hormone (TSH) levels has been seen with an increase in BMI, suggesting that obesity has an impact on the hypothalamic-pituitary–thyroid axis,  leading to changes in thyroid function tests similar to the abnormalities seen in primary hypothyroidism.44-46 However, weight gain associated with hypothyroidism is often a result of fluid retention; studies of body composi-tion before and after treatment for hypothyroidism have shown that weight loss was the result of a decrease in lean body mass and not in fat mass.47

Cushing’s Syndrome

Cushing’s syndrome, which is a condition caused by long-term exposure to excessive glucocorticoids, is a rare disease that affects an estimated 10 to 15 people per million in the United States.48 Patients with obe-sity who experience mild hypercortisolism, diabetes, and hypertension may have Cushing’s syndrome.49 Clinical features include sudden weight gain and central obesity.50 A screening of patients who were obese (N = 150) showed that 9.33% had Cushing’s syndrome. Unless the patient exhibits other clinical features such as poorly controlled hypertension, hypokalemia unresponsive to treatment, diabetes, or rapidly progressing osteoporosis, clinicians often do not screen patients with obesity for Cushing’s syndrome. Tiryakioglu and colleagues reported that a screening program for patients with obesity resulted in the identification of 14 cases of Cushing’s syndrome in 150 patients with obesity, suggesting that patients with obesity should routinely be screened for Cushing’s.51

Polycystic Ovary Syndrome

PCOS is characterized by irregular menstrual periods, excess hair growth, infertility, severe acne, oily skin, ovarian cysts, patches of thickened dark skin, and obesity.52 According to the American College of Obstetrics and Gynecology, approximately 80% of women with PCOS are obese, with prevalence rates 6- to 7-fold higher in morbidly obese women than in controls.52,53 Increased body fat is associated with increased androgen levels and increased metabolic risk, so it is recommended that women with PCOS be screened for increased adipos-ity.54 Losing weight can have a positive effect on hor-mone balance in these women. A small study evaluated the response of PCOS symptoms and hormone levels to weight loss in women who were morbidly obese. Premenopausal women undergoing bariatric surgery were screened, and 17 out of 36 were found to have PCOS. At 1-year follow-up, mean weight loss was 41 ± 9 kg (95% CI, 36-47 kg; P <.001). Women had less hirsutism and normalization of total and free testosterone, androstenedione, and dehydroepiandrosterone concentrations. A restora- tion of insulin sensitivity and increase in circulating sex hormone-binding globulin were also observed.53

Comorbid Conditions With Obesity as a Risk Factor

Patients with obesity are at increased risk of morbidity from dyslipidemia, T2D, hypertension, coronary heart disease, stroke, gallbladder disease, respiratory problems, sleep apnea, osteoarthritis, and some cancers.1 Compared with adults of normal weight, adults with a BMI of 40 kg/m2 or higher had an increased risk of diabetes (OR, 7.37; 95% CI, 6.39-8.50), hypertension (OR, 6.38; 95% CI, 5.67-7.17), hyperlipidemia (OR, 1.88; 95% CI, 1.67-2.13), asthma (OR, 2.72; 95% CI, 2.38-3.12), arthritis (OR, 4.41; 95% CI, 3.91-4.97), and fair or poor health (OR, 4.19; 95% CI, 3.68-4.76).55 A study (N = 300) examining the mean values and heritability of 3 global and 11 regional obesity measures in siblings with or without hypertension sug-gested a genetic link between hypertension and obesity.56 On average, siblings with hypertension were more obese and had more centrally distributed body fat. A pooled analysis of 20 studies reported that heart disease was the most common underlying cause of death in patients with class III obesity (BMI 40.0-59.9 kg/m2), followed by can-cer and diabetes. There was a 2.57-fold (95% CI, 2.41-2.74) increased risk of death in people with a BMI of 40.0 to 59.9 kg/m2 versus 18.5 to 24.9 kg/m2. In addition, people with a BMI of 40 to 59 kg/m2 live 6.5 to 13.7 years less than those with a BMI of 18.5 to 24.9 kg/m2 57

Rheumatoid Arthritis

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