MID-LIFE OBESITY

Helping middle-aged patients lose weight

By Michael Hamilton, MD, and Jennifer Lovejoy, PhD

Providing patients with the basic information they need to reduce their caloric intake and increase activity levels may not be as challenging as doing a complex diagnostic work-up or performing an intricate surgical procedure. But the clinical results can be just as rewarding.

Weight gain and its effect on health have become major public health concerns in the United States—and a personal obsession for many Americans. As testimony to the severity of this national epidemic, the American Cancer Society recently launched its "Great American Weigh In" campaign to make the public aware of just how much of a risk factor obesity is in the pathogenesis of cancer. By ACS estimates, one third of cancer deaths could be prevented each year through healthier diets, more active lifestyles, and maintenance of proper weight. Many other national health-related organizations have issued similar warnings, linking weight to a long list of chronic disorders.

For women, the issue of obesity is especially important because of the health consequences of weight gain as they age. We'll focus our discussion here on the middle years, between 40 and 55, a time during which most women experience the changes of perimenopause and menopause. While the strategies for achieving a healthier weight have changed little during the last 20 years, our understanding of the mechanisms that regulate weight has advanced significantly, giving current strategies and treatments a firmer foundation in the biological and behavioral sciences.

How weight and body fat distribution change in mid-life

Women often worry that their transition through menopause will be accompanied by significant weight gain, but research shows that on average menopause is associated with only a modest 1 to 2 kg increase in weight.¹ But that statistic is somewhat misleading because a significant number of women gain more. In a 3-year longitudinal study of 485 perimenopausal women between 42 to 50, although the average weight gain was 2.25 kg, one in five gained 4.5 kg or more.²

During menopause there is also a change in body fat distribution, with a shift in fat distribution from the lower to the upper body and the visceral area.¹ In addition to menopause, age itself is a factor in the redistribution of body fat. For instance, in a 7-year longitudinal study, women who were on average 35 years old at baseline had a 30% increase in visceral fat, even in the absence of significant weight gain.³

Obesity's physical, emotional, and social consequences

As we mentioned earlier, overweight (BMI 25–30 kg/m²) and obesity (BMI >30 kg/m²) increase the risk for many health problems, including insulin resistance, diabetes mellitus, hypertension, dyslipidemia, hyperuricemia, endothelial dysfunction, a prothrombotic state (increased plasminogen activator inhibitor-1 [PAI-1]), coronary heart disease, sleep apnea, cholelithiasis, osteoarthritis, urinary stress incontinence, thrombophlebitis, irregular menses, infertility, polycystic ovary syndrome, and breast, uterine, and colon cancer. Of course, age, ethnicity, body fat distribution, physical activity, diet, use of alcohol and nicotine, and heredity will influence whether and to what extent these disorders will develop.

Overweight and obesity may contribute to these various disorders by at least three proposed mechanisms: (1) the physical effects of excess adipose tissue, (2) the secretory effects of enlarged adipose cells, and (3) the deposition of fat in visceral fat depots and "ectopic" non-adipose tissues, which leads to insulin resistance and hyperinsulinemia. For a more detailed discussion of how these mechanisms play their part, see "How does obesity contribute to chronic disease?".

While studies suggest that obese persons are no more likely to suffer from psychiatric disorders than normal weight persons, obese persons are more inclined to have a self-disparaging image of their bodies.⁴ Similarly, obese persons are more likely to face disapproval and discrimination.^5,6 Even at a young age, overweight and obese teens have fewer social opportunities as they move to adulthood, when compared to their leaner peers.⁷ Thus it's important to remember that overweight women have probably been ridiculed or embarrassed because of their weight, even within the "safety" of a health-care setting. That's why it is essential for physicians and their staffs to examine their attitudes toward persons who are overweight, and work to become more sensitive to their feelings.

Assessing risks, setting goals, choosing treatment options

As Table 1 reveals, weight increases with age until about age 60. Although a 10-year study of women between 30 and 55 found an average weight gain of only 4.4 lb, 12% of white women and 17% of African-American women experienced a weight gain greater than 22 lb (10 kg).⁸ The prevalence of BMI categories above 30 kg/m² in 40- to 49-year-old women and 50- to 59-year-old women has also increased significantly since 1960 (Table 2), roughly a 60% increase in both age groups, with lower-income and minority women being disproportionately affected.⁹

TABLE 1
Prevalence (%) of different BMI levels by age groups:
United States, 1988–1994 NHANES III

TABLE 2
Prevalence (%) of obesity in women ages 40–49 and 50-59:
United States, 1960–1994

Therefore, in spite of evidence that the healthiest BMI for middle aged women is between 19 and 24 kg/m², significant numbers of women are entering midlife above that range.^10,11 Carefully conducted weight loss trials also indicate that average weight loss is only in the range of 10% to 15% from initial weight. So in practical terms, management of weight in women at mid-life will involve two populations: one normal in weight (BMI <25 kg/m²) comprising 52% of the population of women aged 40 to 49 and in whom we should encourage weight maintenance; and a second group, comprising 48% of the population, that is already overweight or obese and may not lose more than 10% to 15% from initial weight, even with the best weight loss program.

The intensity of any therapeutic intervention should depend on the patient's and her family's history of risk factors, the longevity of family members, her body fat distribution and lifestyle, especially smoking and physical activity. Thus, we are more concerned about a woman with a BMI of 26 kg/m² and central obesity (a waist circumference of 35 inches or more) who smokes, is sedentary, and whose parents have diabetes and coronary heart disease, than we are about a woman with a BMI of 32 kg/m² who does not smoke, is physically active, whose parents lived into their 80s and 90s, and who has a lower body distribution of fat.¹² One should also be aware that weight loss may decrease bone mineral density (BMD), but that this loss appears to be attenuated by physical activity.¹³ Therefore, an assessment of osteoporosis risk is wise before starting a weight loss program so that preventive and monitoring measures can be planned.

Choosing the right therapeutic approach

Losing an initial 10% to 15% of one's weight may be less than most women hope for, but it has been shown to lower their health risks, and just as importantly, it's a realistic and achievable goal.^14-16 The strategies used to achieve this goal are simple: controlling caloric intake and adopting a physically active lifestyle. For patients who are significantly obese and who are not successful in adopting healthier nutrition and physical activity habits, medications are available. Sibutramine is a centrally acting agent that decreases satiety and reduces hunger. Orlistat is a lipase inhibitor that reduces the absorption of dietary fat.

As a general rule, medications are indicated only in those with a BMI greater than 30 kg/m², but may be prescribed for patients with a BMI as low as 27 kg/m² if obesity-related diseases that affect cardiovascular health or quality of life are present. Gastric restriction surgery or gastric bypass is indicated in patients with a BMI greater than 40 kg/m² or as low as 35 kg/m² in the presence of obesity-related conditions. Surgery is the most effective treatment for patients with such severe obesity and should be discussed as a possible option with appropriate patients.¹⁷

Diet therapy. The elements of a healthy diet in perimenopausal women at midlife are essentially the same as for women of all ages. However, preventing and controlling the dysmetabolic syndrome, coronary heart disease, and osteoporosis are more important for women in their 40s and 50s, especially those with a family history of health problems.

The Food Pyramid put forth by federal nutrition experts describes what we believe to be the healthiest diet, but you should keep some modifications in mind: (1) the base of the pyramid should strongly emphasize unrefined complex carbohydrates, (2) vegetable sources of protein, particularly soy, offer an advantage over animal protein, (3) calcium from natural sources should be a major component of the diet in women of all ages but particularly so for women nearing menopause, especially if there are risk factors for osteoporosis. A calcium supplement may be needed to achieve an intake of at least 1,200 to 1,500 mg daily. Some authorities recommend a multivitamin daily, even for those whose diet is varied and well balanced.¹⁸

Because so many women nearing menopause are concerned about gaining weight, and because almost half of all women in this age group are either overweight or obese, we've outlined a few basics concerning nutrition and weight control here:

• To maintain weight, consume no more calories than are expended throughout the day. To lose weight, consume less calories than are expended during the day. For a very rough estimate of daily caloric requirements, multiply a patient's weight in pounds by 10 kcal/lb, always keeping in mind that this estimate will be too low for someone who is normal weight or relatively muscular and lean. Alternatively, you can estimate caloric needs by using the WHO basal metabolic rate equations and then factoring in activity level (see Table 3).

TABLE 3
Estimating energy needs

• As a general rule, don't restrict calories by more than 500 to 1,000. Although a well-balanced and varied diet will be the healthiest, it's wise to add a multivitamin and a calcium supplement to even the most carefully selected menu because some nutritional requirements may not be met when food intake is decreased. As mentioned, weight loss can decrease BMD. Although obesity decreases the risk of osteoporosis, the potential loss of BMD must be weighed against the benefits of weight loss. Again, physical activity attenuates the loss of BMD with weight loss.¹³

• Meal replacements can also be effective, both for acute weight loss and weight maintenance. One study showed that replacing two meals and two snacks daily with a commercially available liquid meal and snack bar for an initial 3 months, followed by a 24-month maintenance phase using replacements for just one meal and one snack daily, resulted in the maintenance of an 11.3% loss from initial weight, compared to a 5.9% loss in the control group assigned to conventional meals.¹⁹

• Although high-fat, low-carbohydrate diets have become popular again, there is no consistent evidence that the proportion of macronutrients in the diet makes any difference with respect to weight maintenance or loss.²⁰ A 1,000 kcal diet consisting of roughly nine tablespoons of olive oil, for instance, should result in about the same weight loss as a 1,000 kcal diet consisting of six to seven cups of cooked rice. However, many patients who do go on low-carbohydrate, higher-fat and protein diets report dramatic weight losses, at least initially. Such losses can probably be attributed to a substantial decrease in caloric intake resulting from the elimination of carbohydrates, which normally comprise 50% of caloric intake, as well as the satiating effect of animal protein that is generally allowed in liberal amounts on these diets.²¹

Some evidence suggests that long-term use of a low-carbohydrate, higher-fat diet may increase cardiovascular risk, but it's important to realize that there's also controversy surrounding the health effects of high-carbohydrate diets. Some low-fat, high-carbohydrate diets have been shown to increase triglycerides and reduce HDL levels, particularly in patients who are insulin resistant and are neither gaining nor losing weight.^22,23 A low-fat diet rich in complex carbohydrates is perfectly appropriate during weight loss, but during weight maintenance, it may be preferable to follow the generally recommended 30% fat diet, low in saturated fats with a relative increase in monounsaturated fats, along with a liberal intake of unrefined complex carbohydrates and fiber in the form of whole grains, vegetables, and fruits.²⁴

• Lifestyles have changed for many working families who increasingly depend on foods prepared outside the home. The US Department of Labor Bureau of Labor Statistics has found that the food budget spent on eating out increased from 27% to 38% between 1974 and 1994.²⁵ In this study, those who ate out 6 to 13 times per week ate more calories (2,057 kcal vs. 1,769 kcal), more fat (80 g vs. 61 g) but only slightly more carbohydrate and protein, when compared to those who ate out less than five times per week. While it may be next to impossible to get many patients to eat out less frequently, educating patients to make healthier selections, both in the choice of restaurants and menu items, may help limit the damage from the large portions and energy- dense selections that restaurants offer.

Physical activity. While no one questions the fact that women with higher BMIs consume more calories than those with lower BMIs, they may not consume that many more. For example, a 40-year-old woman who is sedentary and weighs 300 lb requires a caloric intake of approximately 2,600 kcals each day in order to maintain a stable weight. A woman who weighs 150 lb requires approximately 1,850 kcal, a difference in food intake equivalent to a quarter-pound burger, small fries, and a soft drink.

Many experts believe that the increasing prevalence of overweight and obesity is primarily due to a decrease in physical activity over the past decades. For example, it has been estimated that in Britain since 1970, daily energy expenditure from physical activity has fallen by 800 kcal.²⁶ Anyone over the age of 30 can probably recall several activities of daily life that now require less effort to accomplish than they once did. Seventy-five years ago, when women were generally responsible for maintaining the home, washing was done by hand with a washing board; clothes were twisted until nearly dry, and finally carried to the clothesline to be hung. These were fairly strenuous tasks estimated to burn 1,500 kcal for a week's worth of household clothes.²⁷ Today, washing the same amount with a washer and dryer probably expends no more than 270 kcal.

When encouraging a patient to adopt a program of physical activity, remind her not to limit it to formal exercise but to also increase the amount of energy expended on the activities of daily life, like walking, climbing stairs, carrying bags, and, in general, refusing the physical assistance of others with things she can do herself.

One advantage of physical activity is that, in addition to increasing caloric expenditure, it minimizes the loss of lean tissue that normally occurs with weight loss (the weight loss generated by reduced food intake results in about a 75% drop in fat tissue and a 25% reduction in lean tissue).

While physical activity alone has only a modest impact on weight loss, physical activity appears to be essential in maintaining weight loss.²⁸ And studies have shown that the benefits of exercise can be attained in shorter segments, that is, exercising three times per day in 10-minute sessions instead of exercising 30 minutes once per day.²⁹ Therefore, the exercise prescription can be adapted to the patient's lifestyle and level of conditioning.³⁰

Aerobic activities will have the greatest impact on cardiovascular health, but in terms of weight loss, the total calories expended determine the effect on weight. Physical activities carried out with less intensity over a longer period of time will burn approximately the same number of calories as the same activity at a higher intensity over a shorter period of time. Walking one mile, for example, will burn approximately the same number of calories as jogging one mile (about 100 kcals, depending on body weight).

Resistance exercises build lean tissue and can help attenuate the normal loss of lean tissue that occurs with weight loss. For those over the age of 50, resistance training can help to maintain lean body mass, which normally decreases after that age.³¹ Resistance training can also improve quality of life for people over 60, who are generally less interested in running a marathon than continuing to enjoy the activities of daily life. Resistance exercises also reduce the risk of osteoporosis.

From a behavioral viewpoint, the specific type of physical activity chosen is less important than settling on an activity the patient enjoys and will do on a consistent basis.

The experience of people in the National Weight Control Registry provides testimony to the fact that it is possible to lose weight and keep it off long-term.²⁸ In a study of 3,000 subjects who have maintained an average weight loss of 66 lb for over 5 years, the major ingredients of success were: (1) following a diet low in fat (24% of total calories from fat), (2) daily self-monitoring of body weight and food intake, and (3) consistent physical activity. Keep in mind that the level of physical activity reported was considerably higher than the 30 minutes a day recommended to the general public. Women reported expending 2,545 kcal per week in physical activity (equivalent to walking about 25 miles). Walking was an important physical activity in over 75% of subjects. Twenty-four percent of men and 20% of women reported weight lifting. Subjects reported that considerable effort was required to maintain weight loss, but that after 2 years of maintenance, these efforts seemed easier to sustain. Almost half reported being overweight as children, 46% reported they had one obese parent, and 26% had two obese parents.

Managing stress. Every clinician knows that the best-intentioned nutrition and exercise regimes often fail in the face of stressful events, no matter how seemingly minor. Stress can encourage patients to eat too much because it provides emotional arousal and relief, especially in those who overeat in response to stress.

Studies indicate, however, that physiological and hormonal mechanisms also play an important role. Glucocorticoids have been associated with increased food intake and clinicians are certainly familiar with the appetite-stimulating effects of steroid therapy.³² In a recent study of women aged 30 to 45, caloric intake was greatest in those who had the greatest increase in cortisol secretion in response to a standard mental stress or, compared to women who were low-cortisol reactors in response to the same stressor.³³ On control days, however, (days without an administered stress stimulus) high- and low-cortisol reactors ate approximately the same number of calories.

In another study on the effect of mental stress on food intake, those whose response to stress was greatest (as determined by blood pressure, heart rate, and mood) ate more sweet and fatty foods.³⁴ Because so many women work outside the home today, stress levels resulting from the dual responsibilities of home and work are greatly increased. One study of workplace stress showed that periods of high stress, as defined by longer working hours, were associated with a higher intake of saturated fat and sugar. Furthermore, restrained eaters (those who habitually try to limit their food intake) were more likely to overeat in response to work stress.³⁵

The effect of stress on physical activity is also intuitively apparent. While some respond to stress by increasing their level of physical activity, it is probably more common that most will become less physically active during periods of stress, in spite of the fact that physical activity has been shown to reduce stress.

Stress management has become a huge industry in the US, as evidenced by bookstore shelves heavy with self-help books, weekend seminars on coping with just about every situation or condition of human existence, and counseling from a wide variety of well-trained and capable therapists. For some, these avenues are readily available, but many women have no access because of economic, social, or cultural barriers. Nevertheless, referring patients to appropriate community resources when available, along with practical advice about lifestyle sends a message: Nutrition, physical activity, and how one manages one's life are important to health and quality of life, and therefore worth talking about, even for a busy clinician.

Summing up the treatment options

Because almost half of all women entering mid-life are either overweight or obese and because as many as 20% of women may gain 10 or more pounds during this period, it's important to bring this topic up as your patients approach middle age. The primary goal for all women should be to maintain a stable weight and for those who are overweight or obese to lose 10% to 15% of initial body weight.

Lifestyle strategies to accomplish these goals are simple but difficult to implement and maintain because of changing societal patterns of physical activity and food intake, which combine to encourage weight gain. Nevertheless, clinicians must continue to inform their patients about the elements of a healthy lifestyle and to help them to adopt even small changes in their daily patterns of eating and physical activity. When these measures fail, currently available anti-obesity drugs can lead to modest weight losses that are meaningful in terms of health benefit. Surgery is the most effective treatment for severe obesity.

Key points

REFERENCES

1. Tchernof A, Poehlman ET. Effects of the menopause transition on body fatness and body fat distribution. Obes Res. 1998;6:246-254.

2. Wing RR, Matthews KA, Kuller LH, et al. Weight gain at the time of menopause. Arch Intern Med. 1991;151:97-102.

3. Lemieux S, Prud'homme D, Nadeau A, et al. Seven-year changes in body fat and visceral adipose tissue in women. Association with indexes of plasma glucose-insulin homeostasis. Diabetes Care. 1996;19:9839-91.

4. Stunkard AJ, Wadden TA. Psychological aspects of severe obesity. Am J Clin Nutr. 1992;55:524S-532S.

5. Hill AJ, Silver EK. Fat, friendless and unhealthy: 9-year old children's perception of body shape stereotypes. Int J Obes Relat Metab Disord. 1995;19:423-430.

6. Puhl R, Brownell KD. Bias, discrimination, and obesity. Obes Res. 2001;9:788-805.

7. Gortmaker SL, Must A, Perrin JM, et al. Social and economic consequences of overweight in adolescence and young adulthood. N Engl J Med. 1993;329:1008-1012.

8. Williamson DF, Kahn HS, Byers T. The 10-y incidence of obesity and major weight gain in black and white US women aged 30-55 y. Am J Clin Nutr. 1991;53:1515S-1518S.

9. Flegal KM, Carroll MD, Kuczmarski RJ, et al. Overweight and obesity in the United States: prevalence and trends, 1960-1994. Int J Obes Relat Metab Disord. 1998;22:39-47.

10. Brown WJ, Dobson AJ, Mishra G. What is a healthy weight for middle aged women? Int J Obes Relat Metab Disord. 1998;22:520-528.

11. Stevens J. Impact of age on associations between weight and mortality. Nutr Rev. 2000;58:129-37.

12. Seidell JC, Perusse L, Despres JP, et al. Waist and hip circumferences have independent and opposite effects on cardiovascular disease risk factors: the Quebec Family Study. Am J Clin Nutr. 2001;74:315-321.

13. Salamone LM, Cauley JA, Black DM, et al. Effect of a lifestyle intervention on bone mineral density in premenopausal women: a randomized trial. Am J Clin Nutr. 1999;70:97-103.

14. Foster GD, Wadden TA, Vogt RA, et al. What is a reasonable weight loss? Patients' expectations and evaluations of obesity treatment outcomes. J Consult Clin Psychol. 1997;65:79-85.

15. Blackburn G. Effect of degree of weight loss on health benefits. Obes Res.1995;3(suppl 2):211S-216S.

16. Thomas PR, ed. Weighing the Options: criteria for evaluating weight-management programs. Washington, DC: National Academy Press; 1995.

17. The Practical Guide. Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. National Institutes of Health. National Heart, Lung, and Blood Institute, North American Association for the Study of Obesity. NIH Publ. No. 00-4084, 2000.

18. Willett WC, Stampfer MJ. Clinical practice. What vitamins should I be taking, doctor? N Engl J Med. 2001;345:1819-1824.

19. Ditschuneit HH, Flechtner-Mors M, Johnson TD, et al. Metabolic and weight-loss effects of a long-term dietary intervention in obese patients. Am J Clin Nutr. 1999;69:198-204.

20. Leibel RL, Hirsch J, Appel BE, et al. Energy intake required to maintain body weight is not affected by wide variation in diet composition. Am J Clin Nutr. 1992;55:350-355.

21. Freedman MR, King J, Kennedy E. Popular diets: a scientific review. Obes Res. 2001;9(suppl 1):1S-40S.

22. Parks EJ, Hellerstein MK. Carbohydrate-induced hypertriacylglycerolemia: historical perspective and review of biological mechanisms. Am J Clin Nutr. 2000;71:412-433.

23. Baum CL, Brown M. Low-fat, high-carbohydrate diets and atherogenic risk. Nutr Rev. 2000;58:148-151.

24. Lovejoy JC, Lefevre M, Bray GA, et al. Beneficial effect of a low-fat diet on health risk factors is mediated by weight-loss in middle age men. Obes Res. 2000;8:56S.

25. Clemens LH, Slawson DL, Klesges RC. The effect of eating out on quality of diet in premenopausal women. J Am Diet Assoc. 1999;99:442-444.

26. James WP. A public health approach to the problem of obesity. Int J Obes Relat Metab Disord. 1995;19(suppl 3):S37-S45.

27. Martinez JA. Body-weight regulation: causes of obesity. Proc Nutr Soc. 2000;59:337-345.

28. Wing RR, Hill JO. Successful weight loss maintenance. Annu Rev Nutr. 2001;21:323-41.

29. Schmidt WD, Biwer CJ, Kalscheuer LK. Effects of long versus short bout exercise on fitness and weight loss in overweight females. J Am Coll Nutr. 2001;20:494-501.

30. Physical activity and cardiovascular health. NIH Consensus Development Panel on Physical Activity and Cardiovascular Health. JAMA. 1996;276:241-246.

31. Douchi T, Yamamoto S, Nakamura S, et al. The effect of menopause on regional and total body lean mass. Maturitas. 1998;29:247-252.

32. Cavagnini F, Croci M, Putignano P, et al. Glucocorticoids and neuroendocrine function. Int J Obes Relat Metab Disord. 2000;24(suppl 2):S77-S79.

33. Epel E, Lapidus R, McEwen B, et al. Stress may add bite to appetite in women: a laboratory study of stress-induced cortisol and eating behavior. Psychoneuroendocrinology. 2001;26:37-49.

34. Oliver G, Wardle J, Gibson EL. Stress and food choice: a laboratory study. Psychosom Med. 2000;62:853-865.

35. Wardle J, Steptoe A, Oliver G, et al. Stress, dietary restraint and food intake. J Psychosom Res. 2000;48: 195-202.

Dr. Hamilton is Associate Professor, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, La.

Dr Lovejoy is Manship Associate Professor and Chief, Women's Nutrition Research Program, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, La.

How does obesity contribute to chronic disease?

The physical effects of adiposity. Certain obesity-related disorders seem to clearly be the results of the physical effects of excess adipose tissue and weight. Sleep apnea due to upper airway obstruction, for instance, has been linked to excess pharyngeal soft tissue; osteoarthritis in weight-bearing joints can likewise result from excess body weight. The increased intra-abdominal pressure that results from central adiposity can also impede venous and lymphatic return from the legs, contributing to venous insufficiency and stasis ulcers in the legs. Increased intra-abdominal pressure is also thought to contribute to gastroesophageal reflux, urinary stress incontinence, hypoventilation, and even systemic hypertension.¹

Secretory effects of adipose cells. In addition to storing energy as triglycerides, adipose tissue has endocrine-like functions, secreting proteins with signaling actions that affect adjacent as well as distant tissues, including skeletal muscle, liver, and brain. Among the proteins secreted by fat cells are leptin, plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor (TNF) alpha, angiotensinogen, and interleukin 6.

Many of these signaling proteins are involved in maintaining energy balance and normal physiological function, but several of these proteins, if present in excess, may contribute to the complications of obesity, particularly in persons with large hypertrophic fat cells. For example, white adipose cells secrete two important proinflammatory cytokines, TNF-alpha and interleukin-6. Both cytokines can potentially increase the risk of cardiovascular disease; TNF-alpha may also mediate the development of insulin resistance and interleukin-6 is carried by the circulation to the liver, where it stimulates the production of C-reactive protein (CRP), a marker of inflammation that predicts coronary heart disease.^2,3

Angiotensinogen and PAI-1 may increase the threat of cardiovascular disease through their actions on blood pressure and homeostasis, respectively. Resistin, a newly identified protein produced by fat cells, may induce insulin resistance.⁴

Fat deposition in visceral fat depots and "ectopic" non-adipose tissues. The diseases of major concern in patients with overweight and obesity are those that increase the risk of cardiovascular disease: diabetes, hypertension, dyslipidemia (low HDL-C and elevated triglycerides), and biochemical changes that lead to a proinflammatory and prothrombotic state, often referred to as the metabolic syndrome and now assigned a separate billing code ICD 277.7.

One widely held theory posits that the flow of free fatty acids (FFA) from visceral fat stores to and through the liver via the portal system increases hepatic insulin resistance and impairs the liver's ability to clear plasma insulin, resulting in excess insulin finding its way into the systemic circulation.⁵ This, combined with increased pancreatic production of insulin needed to overcome insulin resistance, leads to hyperinsulinemia. Hyperinsulinemia progresses to diabetes when the pancreas is unable to meet the demand for insulin. At this point, a state of relative insulin deficiency leads to elevated fasting and post-prandial blood sugar levels, that is, frank diabetes.

Hyperinsulinemia appears to be a risk factor for hypertension and dyslipidemia but the role of hyperinsulinemia in the development of hypertension is still unclear. One hypothesis linking hyperinsulinemia to hypertension is based on animal studies showing that insulin increases sympathetic tone and renal sodium reabsorption. The clinical relevance of these animal studies to humans has been questioned.⁶

Recent studies indicate that increased levels of free fatty acids, commonly seen with obesity, may also play an important role in blood pressure regulation through an effect on vasoconstriction and vasorelaxation (elevated blood levels of free fatty acids increase vasoconstriction and impair vasorelaxation.)⁷

The effect of hyperinsulinemia on the lipid profile is complex but contributes to the typical lipid profile often seen in overweight and obese patients: a low HDL, moderately elevated triglycerides, and normal or moderately elevated LDL and total cholesterol levels.⁸ LDL particles in obese persons are generally small and dense and possibly more atherogenic than the fluffier, lighter, triglyceride-rich LDL particles seen in leaner people.

Arguing against the central importance of visceral fat in the development of insulin resistance, other studies suggest that total body fat and a newly appreciated layer of deep subcutaneous abdominal fat are more closely related to insulin resistance than visceral fat.⁹ In addition, evidence from a variety of sources has led to an emerging concept regarding the role of adipose tissue in carbohydrate metabolism: adipose tissue as guardian of insulin sensitivity. This concept is supported by the observation that patients with a deficiency or absence of adipose tissue, that is, lipodystrophy, develop insulin resistance, diabetes, and dyslipidemia.^10,11 Some investigators postulate that because these patients do not have a storage site of sufficient capacity for FFAs, namely adipose tissue, any "overflow" of circulating FFAs is deposited within the cells of non-adipose tissues like muscle, liver, and possibly the pancreas, resulting in insulin resistance.

Supporting this concept is the observation that surgical implantation of adipose tissue into lipoatrophic mice that are diabetic reverses the diabetes and restores insulin sensitivity.¹² Studies also show that large fat cells are associated with insulin resistance, whereas small fat cells are associated with insulin sensitivity, and that treatment with thiazoladinediones in animals leads to the development of new smaller fat cells and clinically, in humans, to weight gain but improved insulin sensitivity and glycemic control.^13,14

This suggests that patients who develop insulin resistance and diabetes are those who, once their fat cells are filled to capacity, are unable to recruit additional fat cells to store excess calories, leading to the deposition of fat in "ectopic" sites such as muscle and liver, and the development of insulin resistance and diabetes.¹⁵ This sequence of events might explain why some who are only moderately overweight have severe diabetes while others who are significantly obese are spared.

REFERENCES

1. Sugerman HJ. Effects of increased intra-abdominal pressure in severe obesity. Surg Clin North Am. 2001;81:1063-1075, vi.

2. Mohamed-Ali V, Pinkney JH, Coppack SW. Adipose tissue as an endocrine and paracrine organ. Int J Obes Relat Metab Disord. 1998;22:1145-1158.

3. Lagrand WK, Visser CA, Hermens WT, et al. C-reactive protein as a cardiovascular risk factor: more than an epiphenomenon? Circulation. 1999;100:96-102.

4. Steppan CM, Bailey ST, Bhat S, et al. The hormone resistin links obesity to diabetes. Nature. 2001;409:307-312.

5. Grundy SM. Metabolic complications of obesity. Endocrine. 2000;13:155-165.

6. Brands MW, Hall JE, Keen HL. Is insulin resistance linked to hypertension? Clin Exp Pharmacol Physiol. 1998;25:70-76.

7. Sheehan MT, Jensen MD. Metabolic complications of obesity. Pathophysiologic considerations. Med Clin North Am. 2000;84:363-385, vi.

8. Despres JP, Krauss RM. Obesity and Lipoprotein Metabolism. In: Bray GA, Bouchard C, James WP, eds. Handbook of Obesity. New York, NY: Marcel Dekker; 1998:651-675.

9. Smith SR, Lovejoy JC, Greenway F, et al. Contributions of total body fat, abdominal subcutaneous adipose tissue compartments, and visceral adipose tissue to the metabolic complications of obesity. Metabolism. 2001;50:425-435.

10. Hubler A, Abendroth K, Keiner T, et al. Dysregulation of insulin-like growth factors in a case of generalized acquired lipoatrophic diabetes mellitus (Lawrence Syndrome) connected with autoantibodies against adipocyte membranes. Exp Clin Endocrinol Diabetes. 1998;106:79-84.

11. Robbins DC, Horton ES, Tulp O, et al. Familial partial lipodystrophy: complications of obesity in the non-obese? Metabolism. 1982;31:445-452.

12. Gavrilova O, Marcus-Samuels B, Graham D, et al. Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. J Clin Invest. 2000;105:271-278.

13. Weyer C, Foley JE, Bogardus C, et al. Enlarged subcutaneous abdominal adipocyte size, but not obesity itself, predicts type II diabetes independent of insulin resistance. Diabetologia. 2000;43:1498-1506.

14. de Souza CJ, Eckhardt M, Gagen K, et al. Effects of pioglitazone on adipose tissue remodeling within the setting of obesity and insulin resistance. Diabetes. 2001;50:1863-1871.

15. Smith SR, Ravussin E. Emerging paradigms for understanding fatness and diabetes risk. Current Diabetes Reports. 2002;2:223-230.

 

Michael Hamilton. Helping middle-aged patients lose weight. Contemporary Ob/Gyn Apr. 1, 2003;48:84-99.