In this article, we will examine whether women differ from men in their metabolic response to excess fat and whether energy restriction achieves the same outcome in men and women. Finally the very important issue of weight maintenance and whether women are more successful than men at maintaining weight will be examined.
ETIOLOGY OF OBESITY IN WOMEN
The exact etiology of obesity in either men or women is not clear and for any individual the contribution of increased energy intake or decreased activity may vary widely although most authors would accept that dietary change is probably the most significant factor. Nevertheless whatever the cause, treatment will need to include both long-term energy restriction and increased activity levels and a constant focus on weight to avoid regain. There is a vast literature on the possible environmental causes of obesity and this section will be able to cover only a small fraction of it. There is nothing in the etiology that is unique to women. Although fat has often been the target of many interventions there probably has been little or no increase in fat intake over the last 20 years. However, it is clear that there has been an increase in carbohydrate-rich foods. For instance in Australia, in children, there has been an increase between 1985 and 1995 in the consumption of energy-dense foods, such as: Cakes and biscuits (46% increase); Soft drinks (30%–50% increase); Confectionary (40%–56% increase); Sugar products and dishes (60%–136% increase); In the United States, National Health and Nutrition Examination Survey (NHANES) data (1971–2000) has shown an increase in the percentage of energy from carbohydrate by about 6.2%–6.6% (absolute), with a decrease in the percentage energy from fat and an increase in total energy intake. For men, average energy intake increased from 2450 to 2618 kcal (p < 0.01), and for women, from 1542 to 1877 kcal (p > 0.01). The increase in energy intake is attributable primarily to an increase in carbohydrate intake, with a 62.4 g increase among women (p < 0.01) and a 67.7 g increase among men (p < 0.01). Total fat intake in grams increased among women by 6.5 g (p < 0.01) and decreased among men by 5.3 g (p < 0.01).
Soft drinks have been a major cause of the increase in carbohydrate in the United States, with a 135% increase in consumption from 1977 to 2001 years. This increase has been associated with an increase in body mass index (BMI) in frequent consumers but not all data is consistent, especially in Europe where a very large survey in 138,000 ten to sixteen year olds showed no relationship between BMI and soft drink intake. A recent systematic review concluded that the association was strong enough to recommend public health action. Global dietary quality in terms of high fibre, high whole grain, lower fat, and sugar is associated with weight status. The Swedish Mammography study followed 33,840 women for 9 years. Normal weight and overweight women increased their weight while obese women decreased their weight. A higher score on a healthy eating scale predicted a better weight outcome in all groups and obese women lost up to 4 kg. In the Pound of Prevention study in 826 women and 214 men over 3 years, weight gain was related to the level of fat in the diet and to the level of physical activity, especially high intensity activity. In the Framingham Offspring Study of 2245 men and women, a higher dietary quality (according to standard dietary guidelines) predicted a lower weight gain by about 2–5 lb over 8 years. In 74,091 nurses, high fiber, whole grain foods were associated with a 1.4 kg less weight gain over 12 years. Women in the highest quintile of intake had a 50% reduction in the risk of major weight gain (>25 kg) compared with the lowest quintile. A high refined grain intake was positively associated with weight gain. Similar but less dramatic findings were shown in male physicians, in whom even refined breakfast cereals were associated with protection from weight gain. Breakfast cereal consumption was predictive of lower BMI in adolescent girls and in the NHANES III cohort although in a later NHANES cohort this was seen only in women. In a large cohort from Denmark, protein intake, especially from animal protein, was significantly inversely associated with 5 year changes in waist circumference.
BODY COMPOSITION AND SEX FAT
Women have a higher rate of obesity (BMI > 30) than men, but in addition, at the same BMI, the fat to lean ratio in women is about 0.9 (varying from 0.6 to 1.1) while in men it is about 0.5 (varying from 0.4 to 0.6). However, much of this additional fat, at least in premenopausal women, is subcutaneous fat in the gluteal and thigh regions, where it may exert protective effects. At the same BMI, men have the same or an increased absolute amount of midriff fat by DEXA and thus may be more insulin resistant despite their larger lean mass. This sexual dimorphism is seen already in 5–7 year olds where boys have higher waist to hip ratios due to less gluteal adiposity. As women age, they have a greater increase in fat mass (26% increase per decade compared with 17% in men) and waist circumference (4% per decade compared with 2% in men). However, in Japanese subjects, males gain 2.6 times more visceral fat than premenopausal women and about the same amount as postmenopausal women. Leg fat decreased with age.
LEPTIN AND FAT
The other major difference between men and women is in plasma leptin levels, which are significantly higher in women even after adjustment for the increased fat mass. Although plasma leptin is correlated with fat mass in men and women, the level is 3 times higher in women for a given fat mass. In response to caloric reduction and a similar decrease in percent fat mass, women have a decline in plasma leptin that is twice as great as in men. In addition, in this study, the decrease in leptin per kilogram of fat mass was greater in women than in men (0.37 þ= 0.34 vs. 0.04 þ= 0.06 ng=mL=kg; p < 0.01). After weight loss, the change in leptin concentrations correlated positively with the change in fat mass in men (r¼0.60; p < 0.01), but not in women (r¼0.31; p¼0.17). The loss in fat mass correlated negatively with baseline leptin levels in women (r¼0.47; p < 0.05), but not in men (r¼0.03). Dietary fat content has no effect on plasma leptin levels. Although in men and women leptin is closely associated with BMI and percent fat equally (r¼0.82–0.88), hyperleptinemia is associated with insulin resistance (r¼0.57; p < 0.0001) and high waist to hip ratio (WHR) (r¼0.75; p < 0.0001) only in men. On the other hand, during the hyperinsulinemic euglycemic clamp studies, hyperinsulinemia acutely increased leptin concentrations (20%) only in women. While absolute and relative reductions in body weight and body fat are similar, men mobilize more intra-abdominal fat than women, and women lose more subcutaneous fat.
The greater reduction in intra-abdominal fat seen in men is accompanied by a more marked improvement in the metabolic risk profile. Subcutaneous fat thickness shows a stronger association with leptin levels in males than in females, whereas no association is found with preperitoneal fat thickness (as measured by ultrasound). Leptin and the ratio of subcutaneous to preperitoneal fat are significantly related only in men. WHR values are not correlated with leptin concentrations in either sex. Leptin mRNA is expressed to a much greater degree in subcutaneous fat compared with omental fat and the ratio of expression between the two is much greater in women (5.5-fold) compared with men (1.9-fold) and a relationship could be observed in women between leptin mRNA and BMI. Leptin secretion rates in women are 2–3-fold higher from subcutaneous compared with omental fat and the subcutaneous secretion rate was the major predictor of plasma leptin levels. Subcutaneous cells were ~50% bigger than those in omental fat. Estrogen stimulates leptin mRNA production and leptin release.
LEPTIN AND ENERGY METABOLISM
Bobbioni-Harsch et al. found that a high leptin level was a marker of low rates of resting energy expenditure (REE) when body weight is stable and a marker of a decrease in REE and fat oxidation during a hypocaloric diet. However, leptin, ghrelin, and adiponectin do not predict long-term weight changes in 60–91 year olds over an 18 year period. Leptin was not associated with weight gain over 8 years in young men and women although Savoye et al. found that high basal leptin levels accounted for 18% of the variance in weight gain over 2.5 years in children aged 7–8 yearsandin boys andgirls aged 6–9overa12monthperiod. Inrats,thereareclear differences in physiology between malesandfemales, with femalerats increasing their food intake by40% after a12 hfast compared with only 10% in male rats. Theincrease in plasma ghrelin was 2-fold greater with fasting in female rats, suggesting this was driving the increased food intake. In response to an inflammatory stimulus (LPS), food intake was reduced equally as was ghrelin but leptin rose by 230% in female rats compared with 33% in male rats. This finding suggests again that ghrelin was a major determinant of food intake and that the changes in leptin played no role.
FAT CELL PHYSIOLOGY
In women, estrogen downregulates b-adrenergic receptors and upregulates a-receptors, thus reducing lipolysis rates in fat compared with men. Differences between omental and subcutaneous fat have been conflicting but Tchernof et al. clarified some of the conflict in a study in a large group of 55 women. Compared with adipocytes from the omental fat, subcutaneous adipocytes are larger, have higher LPL activity, and are more lipolytic on a per cell basis, reflecting the fact that this is the major fat storage organ in women. 17-b estradiol strongly stimulates mRNA expression for Type I 11-b-hydroxysteroid dehydrogenase (HSD1) in preadipocytes and potentially stimulates cortisol production from cortisone but decreases P450 aromatase expression by half, thus potentially reducing estrogen production from testosterone. In men, it has no effect on HSD1 but stimulates aromatase mRNA 2.4-fold. Androgens increase the expression of mRNA for both enzymes in men by 2.5–5-fold. Leptin stimulates the expression of mRNA for both enzymes in men but decreases expression in women but the physiological impact of these observations is not clear.
BODY COMPOSITION, METABOLIC SYNDROME, AND SEX
The association of obesity with the metabolic syndrome is very clear, in fact in the International Diabetes Federation definition, visceral obesity is part of the definition. Whether the metabolic syndrome is expressed differently in women is not clear. In a population of 1974 men and women in Turkey, 40% of women and 29% of men had the metabolic syndrome as defined by the criteria of the National Cholesterol Education Program guidelines (three or more of fasting glucose >6.1, BP > 135=85, TG > 1.7, HDL < 1.0 (M) or 1.3 (W) or waist circumference >88 or 102 cm). Women with the metabolic syndrome, regardless of the presence of obesity, were twice as likely to develop a disturbance in glucose metabolism (either impaired fasting glucose or frank diabetes) over a 4 year follow-up period compared with women without the metabolic syndrome or obesity. This relationship was not seen in men. In men, CVD events were predicted by the presence of the metabolic syndrome, regardless of the presence of obesity, but abnormal glucose metabolism was not a predictor. The converse was seen in women. In the United States, between NHANES III(1988–1994)andNHANES1999–2000 studies, there was a statistically significant increase in prevalence of the metabolic syndrome in women but not in men. Young women aged 20–39 years had a 76% increase in the incidence of metabolic syndrome compared with a 5% increase in men driven by a marked increase in obesity in this age group. In the French MONICA (Multinational monitoring of trends and determinants in cardiovascular disease) cohort, the predictors of the metabolic syndrome were examined in 3508 men and women aged 35–64. In women, metabolic syndrome was associated more with BMI, waist girth, and low HDL cholesterol while systolic and diastolic BP and apolipoprotein B were more associated in men. Fasting insulin, glucose, triglyceride, and LDL cholesterol were not different between sexes. Thus, women need higher levels of obesity to achieve the same degree of insulin resistance and metabolic disturbance as men.
The relationship of visceral and peripheral fat to the metabolic syndrome is discussed in a review by Wajchenburg in 2000. Lower intakes of carbohydrate are associated with lower rates of the metabolic syndrome in men (odds ratio of 0.44 compared with a high carbohydrate intake) but not in women while in women only a moderate alcohol intake was protective (odds ratio 0.76). In a German cohort study from Augsburg, elevated fasting glucose was more common in men (9.9%) compared with women (4.4%). Women in this and other studies have higher 2 h glucose levels for the same level of fasting glucose compared with men. Thus women appear to have a disturbance in insulin release while men have higher levels of insulin resistance probably related to increased visceral fat. The development of diabetes increases the risk of cardiovascular disease in women. From eight prospective studies, the multivariate-adjusted summary odds ratio for CHD mortality due to diabetes was 2.3 but this difference disappeared after adjustment for classic CHD risk factors. A later meta-analysis suggested the risk of fatal coronary disease in women with diabetes was 50% greater than that in men.
POLYCYSTIC OVARY SYNDROME
Polycystic ovary syndrome (PCOS), a syndrome of insulin resistance, disturbed menstrual function, infertility and hyperandrogenism, is closely associated with obesity, which worsens its clinical expression. There is no similar syndrome in men although obesity in men lowers testosterone, increases free estradiol, and worsens sexual and reproductive function. Intra-abdominal fat in normal healthy women expresses Type 3 17-b-hydroxysteroid dehydrogenase (17-b-HSD), the enzyme that catalyzes the conversion of androstenedione to testosterone in the testis and exceeded the level of aromatase. The converse was found in subcutaneous abdominal adipose tissue. Androstenedione in vitro was converted to testosterone with minimal conversion to estrone. Thus visceral fat accumulation contributes an androgenic burden in women. Lifestyle modification can clearly benefit women with PCOS although there is no evidence that any one dietary strategy is beneficial.
ANDROGENS AND CARDIOVASCULAR RISK
Low sex hormone binding globulin (SHBG) and high free androgen index (FAI) are strongly related to elevated cardiovascular risk factors. In the Women’s Health Initiative Study, lower SHBG and higher FAI levels were noted among postmenopausal women who developed CVD events, but this was not independent of BMI and other cardiovascular risk factors. Estradiol levels were not associated with risk of CVD in hormone replacement therapy users or nonusers.
C-reactive protein (CRP) is a sensitive inflammatory marker that predicts future cardiovascular events but is also related to obesity and falls with weight loss. Women generally have higher levels of CRP than men, reflecting their increased fat mass. There may be a sex related difference in the relationship between CRP and the metabolic syndrome. In the Mexico City Diabetes Study of 515 men and 729 women, 14% of women and 16% ofmen developed the metabolic syndrome over6 years.For women in the highest tertile of CRP, the odds ratio of developing the metabolic syndrome was 4 and diabetes was 5.5, with little effect of adjustment for BMI or the Homeostatic Model Assessmentscore.This relationship was not seen in men. Similarly,CRP was more strongly associated with components of the metabolic syndrome in women than in men in a Japanese population. In the Framingham cohort, age-adjusted CRP levels in subjects with the metabolic syndrome (24% of the population) were higher in women than in men (7.8 vs. 4.6 mg=L).
WEIGHT CONTROL BEHAVIORS, DIET, AND GENDER
Women are far more likely than men to report a history of dieting (8-fold greater) and to participate in organized weight loss programs (11-fold greater than men). Exercise was the most frequently reported specific weight loss practice (66% of women and 53% of men), followed by decreasing fat intake (62% of women and 48% of men). In a large twin study in Finland, individuals who had engaged in intentional weight loss exhibited markedly more restricting, overeating, and alternating restricting or overeating than those in the no intentional weight loss group. Snacking and eating in the evening were characteristic of women with at least two weight loss attempts. Eating in response to visual and emotional cues was very pronounced in women who had attempted to lose weight but this was much less so in men. Interestingly, engaging in intentional weight loss was much more heritable in women than in men (66% vs. 38%). Female twins also have higher heritability of BMI than men (0.61 vs. 0.46 for Danish twins aged 46–59). Social status of women has an effect, with women with low employment grade in the Whitehall II study of London civil servants being twice as likely as men in this same work strata to consume unhealthy diets compared with higher status men and women. High disinhibition and low restraint in female Whitehall civil servants are directly associated with BMI, while in US women aged 55–69, disinhibition was the major predictor of BMI and weight gain although somewhat modified by restraint. In the Quebec Family Study, women had significantly higher cognitive dietary restraint and disinhibition scores than did men (p < 0.0001). In both genders, disinhibition and susceptibility to hunger was higher in obese subjects than in overweight and nonobese subjects (p < 0.05).
Low Fat Diets
Low fat diets have been advocated for weight loss for many years and have been based on several well-established principles. Low fat diets have a lower energy density than high fat diets. Since humans respond mostly to volume of food eaten rather than calories, this should lead to a lower energy intake. Lower fat diets also have higher fiber content and this may also enhance satiety. Some minor degree of faecal loss of energy occurs with high carbohydrate diets, especially those with a high fiber or high resistant starch level. In a review by Avenell et al. they found that low fat diets reduced weight by an average of 3.6 kg for up to 3 years while four studies found that low fat diets are associated with lower rates of diabetes and reduced antihypertensive medication for up to 3 years. There were no sex effects in these studies. So although there is good evidence that low fat diets work for some people many people cannot maintain them long term and so new and different solutions have been sought.
Very Low Carbohydrate Diets
A complete contrast to the low fat, high carbohydrate diet is the low carbohydrate diet, which has been in use for over 100 years but was popularized by Atkins many years ago. Surprisingly trials have only appeared over the last 3–4 years evaluating the effects of the Atkins diet. These are very uniform in their findings, with a better weight loss of about 3.3 kg at 6 months, but no difference from low fat diets at 12 months. The diets worked by reducing caloric intake by removing a very wide range of carbohydrate-rich foods, but as compliance to this fairly severe regime drifted, so did the weight. Although triglyceride levels dropped more and HDL cholesterol levels were maintained on the Atkins diet, LDL cholesterol rose by about 2%–3%. There is no data beyond 12 months on Atkins diets. There are modified forms of the Atkins diet, which endeavor to replace some of the saturated fat with unsaturated fat (e.g., the South Beach Diet) but there is no trial data. One would expect similar weight loss but better LDL results compared with Atkins.
High Protein, Moderate Carbohydrate Diets
This is the compromise position diet and there are many variants, e.g., the Zone diet, the Protein Power diet, CSIRO (Commonwealth Scientific and Industrial Research Organisation) diet. Only the CSIRO diet has been extensively studied in large groups of people but its results have been confirmed by other investigators with smaller numbers of patients. In general, protein as a percentage of energy is doubled from 15% to 30%. People with elevated triglyceride levels gain particular benefits, at least at 3 months, with greater weight, fat, and central fat loss. There have now been several meta-analyses done and in one Krieger et al. examined 87 short-term studies and found that protein intakes of >1.05 g=kg of actual rather than desirable body weight were associated with 0.6 kg better retention of lean mass. In studies of 12 weeks or more in duration, this increased to 5.6 and 1.7 kg, respectively. Thus a low carbohydrate, high protein diet is associated with better fat loss and sometimes less lean mass loss. In this meta-analysis there were no sex effects. We have performed a meta-analysis (unpublished) of our published data on high protein diets for short-term weight loss and found that there were no sex effects. We found that in participants with a baseline fasting triglyceride >1.7 mmol=L, there was greater total and abdominal fat loss.
An alternative approach for weight loss is to use meal replacements like Optifast to replace 1, 2, or 3 meals. Total meal replacement can certainly lead to dramatic weight loss of 20 kg or more but in the long term the amount of weight lost is the same when more gradual approaches are taken. The best long-term data has shown that a 10% weight loss can be maintained up to 5 years with the use of 1 meal replacement=day increasing to 2 if weight regain occurs. It is a strategy that works very well for some people. There are a relatively limited number of studies using meal replacements to achieve weight loss.
Six studies have been included in a recent meta-analysis of randomized controlled trials. This meta-analysis found that a diet plan that includes meal replacements to replace 1 or more meals achieved more weight loss, ~2.5 kg more at 3 months, than a reduced energy food based diet plan. Four randomized controlled studies support the view that meal replacements may be advantageous in weight loss programs whereas two studies do not.
Adverse Outcomes from Different Diets
There is no risk from eating high fibre and high carbohydrate weight loss diets but the high protein diets have several risks attributed to them.. Those with normal renal function had no such decline. Thus until evidence to the contrary is shown then care should be shown in those with renal impairment. high protein diets have been shown to reduce the risk of fractures. High meat diets have been shown to be associated with increased colorectal cancer, but in the biggest study of all, the European Prospective Investigation into Cancer and Nutrition study from Europe, this was true only for processed meat. Nevertheless, studies from the United States have also implicated red meat alone with an increased risk of colorectal cancer (but significant only in the rectosigmoid and rectum). The increased risk is of the order of 30%–40% in the highest quintile. The risk can be reduced substantially by weight loss and exercise, eating chicken and fish; eating more than 28 g fiber=day removes the effect of meat altogether. So in terms of this diet, replacing processed meat with fish or chicken at lunch or ensuring fiber intake is high is the best strategy. The Atkins diet has been portrayed as prone to many adverse outcomes but the evidence is very limited. Certainly constipation is a problem and fiber supplements may be required. Ketogenic diets can cause renal stones (about 6% incidence over 5 years) in children but not in adults. Although in theory, this seems unlikely as a very restricted diet is actually not maintained over the long term. Although data relating deliberate weight loss with beneficial outcomes is not clear and there is a vast and controversial literature on this subject, recent reports at the International Congress on Obesity in 2006 showed benefit on cardiovascular events and mortality from surgically induced weight loss. Certainly bariatric surgery can lead to clinical improvement or resolution in 64%–100% of patients with diabetes mellitus, 62%–69% of patients with hypertension, 85% of patients with obstructive sleep apnea, 60%–100% of patients with dyslipidemia, and up to 90% of patients with nonalcoholic fatty liver disease.
LEAN MASS LOSS WITH WEIGHT LOSS AND SEX
With energy restriction, both fat and lean mass loss occur but Sartorio et al. demonstrated that with aerobic and resistance exercise, women appeared to be better at preventing this loss of lean mass (at least over 3 weeks). High protein weight loss diets may also be better at preserving lean mass in women. Part of the reason may be the much greater fat free mass (FFM) in obese men compared with obese women. Thus, women have much lower limb power per unit body mass but not per unit FFM. Similar findings are seen in obese adolescents. However, other investigators have seen no difference between men and women in loss of visceral, subcutaneous, or lean mass in response to dietary restriction although less visceral fat loss (either as an absolute amount or as a percentage) is sometimes seen in women. Weight loss can lead to bone loss even with exercise and calcium supplementation and bone density has been inversely related to the number of times premenopausal women have been on a weight loss diet and in those women with high cognitive dietary restraint and a weight of <71 kg.
The National Weight Loss register in the United States contains 4800 individuals who have lost at least 13.6 kg and maintained this loss for at least a year. It was set up in 1995 to understand what behavior is required for successful weight maintenance. Approximately 20% of overweight individuals are successful at long-term weight loss when defined as losing at least 10% of initial body weight and maintaining the loss for at least 1 year. Individuals in the weight loss register maintained their body weight by a few simple strategies: eating a low fat diet with very limited variety in energy-dense high calorie foods, eating breakfast almost every day, weighing themselves regularly and engaging in high levels of physical activity (about 1 h=day), watching little television, and maintaining a consistent food pattern across week days and weekends. A subset of the register (n¼2708, enrolled between 1995 and 2003) who had lost an average of 33 kg and maintained a 13.6 kg loss for 5.8 years before enrolment had measurements of diet and physical activity at enrolment and 1 year later. Individuals who enrolled later in the study had higher levels offat intake (29.8%) than those who enrolled earlier, and energy from carbohydrate was proportionately decreased. Physical activity was lower in later years. The use of low carbohydrate diets had increased about 3-fold in 17% of participants in 2003. Weight regain over 1 year was related to higher levels of caloric intake, fast food consumption, and fat intake and lower levels of physical activity. There were no apparent sex effects. In overfeeding studies in normal weight men and women (n¼48), the energy cost of the weight gain was the same in both sex at 33.7 kJ=kg, and 43.6% of the gain was lean body mass. In our study of weight maintenance at 1 year after losing weight on either a high protein or a high carbohydrate diet, it was found that women who could maintain a protein intake of 90 g=day or more (about 30% of the cohort) maintained a weight loss of 4 kg more than those who had lower protein intakes. Wing et al. examined a self-regulation weight maintenance program delivered either face to face or over the internet in 314 participants who had lost a mean of 19.3 kg in the 2 previous years. Weight gain over 18 months was 2.5 kg in the face to face group, 4.9 kg in the control group (p¼0.05 for difference between these 2 groups), and 4.7 kg in the internet group. The proportion of individuals who regained 2.3 kg or more was significantly higher in the control group (72.4%) than either the face to face (45.7%) or the internet group (54.8%) (p < 0.01 for both). The intervention programs daily self-weighing and self-regulation.
Although body composition clearly differs between men and women, with women having more total and subcutaneous fat and men having more visceral fat and lean tissue, the response to energy restriction, regardless of macronutrient composition, is very similar in terms of percentage weight loss. There is limited evidence that women might sometimes lose less visceral fat than do men and may reduce absolute lean mass loss with exercise or high protein diets. Although leptin levels are clearly different in women and relate differently to weight loss in men and women, the implications of this finding in terms of weight maintenance are not clear. Although rates of the metabolic syndrome and diabetes are similar in men and women, diabetes probably has a greater impact in women for cardiovascular risk. Again there are well described differences in fat cell physiology between men and women but this does not appear to be of clinical relevance at present.
Whether there are weight maintenance strategies that are particularly beneficial to women is not clear and has not really been prospectively examined. It is also not clear if the health benefit of weight loss, surgical or otherwise, is different between men and women and much larger cohorts need to be studied. Thus at least 10,000 men and women who have had obesity surgery need to be examined to see if there are gender differences in the reduction in fat mass, hypertension, Type 2 diabetes, cardiovascular disease, and death over a 10 year period.