Helen at 59 years of age with a height of 170 cm and a weight of 136 kg has a BMI of 49 kg/m² which classifies her as being seriously obese. She is a health professional and well aware of the health risks associated with her excess weight. She is also a woman living in a society where a slim body is perceived as an essential requirement for feminine beauty and fashion. Over the years Helen has tried most non-fat diets as well as various drugs in her attempts to lose weight. Instead there has been a relentless increase in weight from 82 kg after the birth of her two children when she was 21 years old (a BMI of 28.5 kg/m²) to her current weight and BMI which persists in spite of her healthy diet and not excessive kilojoules intake [1]. Helen is not alone; there are many other women who can testify to similar long term battles against excess weight gain [2,3]. Too often for some, attempts to lose weight leads to frustration, guilt and ultimately failure and a pre-occupation with food and dieting that may for some lead on to eating disorders. Women are not only more vulnerable to these psychological pressures [4], but also their intrinsic physiological make up makes them more prone to weight gain.

Cheap energy dense food in generous portions that is too easily accessible and a sedentary life style in conjunction with socioeconomic factors such as food insecurity and lack of nutritional understanding are certainly important contributing factors to weight gain. But the question remains why, in any community, there are some who find it easier to remain slim, in spite of sharing the same obesogenic environment while others like Helen, a health conscious well informed professional, become increasingly obese. An accumulating body of emerging research in neuroscience and molecular biosciences confirms what many women know well from personal experience - that slimness is not simply a matter of willpower and diet and easily obtainable by all. The objective of this paper is to provide a broad-based literature search on current research in genetics, early development, environmental factors, gender and physiological pathways that regulate energy turnover and discuss how these may affect body fat storage in the body and biological vulnerability to obesity.

Energy homeostasis involves complex sophisticated neurohormonal pathways that regulate energy balance and ensure adequate energy stores to meet increased demands for growth in children and it is particularly significant for women during pregnancy and lactation. This can be seen in the rapid increase in fat deposition that occurs particularly in critical periods during the human life span: prior to and during pregnancy and in the baby, prior to birth, during the first 6 months of life and prior to weaning [5]. The existence of these energy regulating mechanisms is also seen in the remarkable constancy of human weight, often over many years (and without calorie counting!) for some, and in the resistance to weight change that so often frustrates the attempts for others like Helen when trying to lose weight. The concept of such regulatory mechanisms was postulated over 50 years ago by Kennedy [6] as the ‘set point’ hypothesis where the body would defend its fat stores as a physiological response to attempts at weight reduction by calorie restriction. However, though received with a considerable amount of skepticism at the time, it has been extensively confirmed starting with Coleman’s early pioneering experiments with genetically obese mice that led to the identification of leptin and its recognition as a controller of body fat stores, through modulating food intake and energy output [7-9]. Much subsequent research has established the existence of multifaceted neurophysiological energy regulating systems that operates in animal models as well as humans [10,11]. It involves a complex interplay via numerous different neural/hormonal signaling systems that operate between peripheral tissues and key centers in the brain particularly the hypothalamus (Figure 1). In the hypothalamus these different incoming messages and signals are integrated and trigger either an increase in food intake (linked with energy storage and conservation by or exigenic signals such as ghrelin) or a decrease/cessation of food intake (mediated via anorexic/satiety signals such as leptin, insulin and Cholecystokinin (CCK). These basic energy homeostasis pathways are modulated by physiological factors such as pregnancy and environmental factors such as nutrition [11-14] as well as parts of the brain such as the reward pathways [15-17]. Though less defined at this stage there is also growing evidence that other innate biological differences may occur that make some people more susceptible than others to obesity. These include differences in hypothalamic-pituitary axis (HPA) axis function [18] or in basal energy expenditure for example as a result of mitochondrial function [19] or uncoupling proteins and non-shivering thermogenesis [20-22].

Figure 1: Simplified overview of neurohormonal pathways involved in energy homeostasis.

In terms of understanding the implications for human obesity, the relevant point to note is that multiple complex interacting pathways regulate energy stores that have evolved because survival and perpetuation of the human race are absolutely dependant on an energy supply. Also their overall effect is to maintain and defend body energy stores [11].

Because of their biological role in child-bearing, women are physiologically programmed to store more fat compared to men [5] and in women both total body fat and circulating leptin levels are significantly higher compared to men [23]. Pregnancy and lactation put high demands on energy requirements and leptin (mediating its effect in the hypothalamus via gonadotropin releasing hormone) serves as an important signal that their energy stores are adequate to maintain a pregnancy if they become pregnant [24]. This is the physiological reason behind the well known observation that very low fat stores for example in the highly trained female athlete or extreme thinness may cause absent or irregular menstrual cycles. Leptin is released into the blood stream by fat cells and during pregnancy increasing fat stores will result in a corresponding increase in plasma leptin levels. However, pregnancy is marked by a state of leptin resistance, as the anorexic effect of leptin is blunted or over-ridden during pregnancy [25,26] predisposing to fat accumulation.

As well, in women, energy homeostasis is markedly modified by fluctuating levels of ovarian hormones, with the onset of menstruation, pregnancy and lactation and post menarche [5,27-29]. The action of progesterone, produced in the second half of the menstrual cycle, and in large amounts during pregnancy is to increase food intake and energy storage [30]. It is a physiological adaptation to ensure there are adequate energy stores to meet the demands of pregnancy and lactation. It is also the likely reason for the weight gain some women experience on progesterone hormonal contraception. Oestradiol has the opposite effect to progesterone, reducing meal size, and increasing leptin sensitivity in the brain [30,31]. During pregnancy the relatively low levels of oestradiol in proportion to levels of progesterone further augments the increase in appetite. Low levels of oestradiol may also be a contributing factor to susceptibility to weight gain in postmenopausal women. Oxytocin has also been implicated in regard to energy homeostasis in women and in the non-pregnant state acts centrally in the brain to reduce food intake [32,33]. During pregnancy, attenuation of oxytocin action on the uterus until term prevents premature labour and functions to maintain the pregnancy. At the same time, inhibition of its action in the hypothalamus is another physiological factor that contributes to increased food intake during pregnancy and vulnerability to weight gain. Prolactin, in women significantly elevated with lactation, has also been linked with increased hyperphagia in a dose dependent manner and involves direct actions of prolactin in the hypothalamus [34]. There is a physiological rationale that a hormone that plays an important role in lactation would also act to ensure adequate energy supplies for the metabolic demands of lactation. What emerges is that energy homeostasis pathways are plastic, and that the ‘set point’ changes, overall in an upward direction, and that, particularly in women, their inherent hormonal milieu is a powerful determinant for fat accumulation and deposition.

For many individuals, relatively stable body weight is maintained in spite of the usual day by day variations in food consumption and activity as a result of these energy homeostasis mechanisms [35,36]. However what has become apparent is that the ‘set point’ or level of defended body energy stored can vary significantly between individuals. Table 1 summarises the biological factors such as genetic, environmental, epigenetic and prenatal/perinatal [37-39] that are relevant to food intake, energy turnover and fat deposition in a woman. For some the outcome is an increased susceptibility to weight gain, advantageous in the past, but which creates strain where modern obesogenic lifestyles are juxtaposed alongside a culture that promotes leanness as the ideal [2,3,40,41].

Table 1: Summary of biological factors that affect food intake, energy turnover and fat relevant to women.

The importance of genetic factors, initially identified from earlier twin and population based studies, has been substantially confirmed in large scale genetic epidemiology studies in animal and human studies [38,42-44]. Though specific genes have been identified, such as the FTO (fat mass and obesity associated gene) [33], (human obesity is predominantly polygenic in nature [44]. Recent research has also provided some evidence that genetics may be an important determinant in long-term successful weight loss [45]. The critique that human genes have not changed significantly over recent decades fails to recognize that expression of genes that confer vulnerability such as propensity to weight gain will only become apparent in an obesogenic environment. This critique has also been countered by the rapidly emerging field on the significance of epigenetics in long term gene expression as outlined in the following section.

The importance of early environmental factors arose from the initial observations by Barker and Osmond [46,47] that low birth weight in full term babies was linked with an increased risk for obesity and cardiovascular disease as adults. This has been confirmed in much subsequent research in animal models and different human populations, which showed that compromised intrauterine nutrition or low protein, particularly in the first trimester, was linked with an increased risk for obesity, cardiovascular disease, hypertension and type 2 diabetes mellitus and hypertension in adult life [12,48-51]. This provided a basis for the ‘thrifty phenotype’ hypothesis where the developing foetus in response to early environmental factors, specifically protein or calorie restriction, makes long term adaptations (becomes ‘programmed’) that promote energy conservation and fat storage. At the other end of the spectrum, maternal gestational diabetes and in utero over nutrition increases vulnerability to the development of obesity in later life of the unborn child [39,52-54]. At a cellular level both under-nutrition and over-nutrition have been linked with a resetting of energy homeostasis mechanisms that persist into adulthood and involve epigenetic changes. Epigenetic changes are long term changes in the regulation of gene expression (as distinct from changes in the actual DNA coding in the gene) that occur in response to environmental factors. They are important in determining the phenotype during early development of the child and therefore at the individual level, but also may be passed on to the next generation [13,14].

In regard to health, the traditional perception of obesity as the cause for health risks for type 2 diabetes, high blood pressure and cardiovascular disease has also been shown to be more complex due to a growing understanding of the metabolic syndrome. Increasingly the metabolic syndrome is emerging as a multifaceted metabolic disorder where, as well as insulin resistance, hypertension and physiological changes that increase cardiovascular disease risk, there is also an increased susceptibility to weight gain [55]. A common feature is leptin resistance (and hence resistance to its weight reducing effects) and a low-grade chronic inflammatory state [51,56]. An important point that is often overlooked is that it is visceral fat, an “apple shape” pattern of fat distribution that is particularly associated with the classic health risk features of the metabolic syndrome [57,58]. Conversely, hip and thigh fat, a “pear shape” pattern of fat distribution, more typically found in women is not just neutral but may be protective [59].

Problems with conception are commonly blamed on obesity but this is also more complex. Relevant in this context is that polycystic ovary syndrome (PCOS), which is linked with reduced fertility, has also been shown to display all the characteristic manifestations of the metabolic syndrome such as hypertension, blood lipoproteins that increase cardiovascular risks, insulin resistance and type 2 diabetes and abdominal fat [60-63] and as a likely deduction, possible early developmental origins [56,59] with apropensity to gain weight and reduced fertility akin to those well established for the metabolic syndrome. In women with PCOS, the hyperinsulinemia linked with peripheral insulin resistance and altered adipokines are associated with increased ovarian androgen secretion leading to arrest of follicle growth and an ovulation [63] and specifically loss of intra-abdominal fat (as distinct from weight loss per se) was positively correlated with return of ovulation.

In spite of a myriad of dietary strategies and a thriving weight loss industry, what has become obvious over two decades of research is that for the majority the dietary based weight loss interventions for obesity fail in achieving long term weight loss [64-68]. It has been estimated that more than 90% of those who lose weight by dieting interventions regain it in 3-5 years. Rather than merely being ineffective long term, dieting and ‘diet’ induced behaviors have been linked with weight regain, weight cycling and negative psychological consequences as summarized in Table 2. Behavioral studies that identified associations, but unable to clearly establish cause and effect, have been extended by the emerging understanding of the complex multifaceted neurophysiological mechanisms that determine energy balance, storage and turnover current research in energy homeostasis outlined in previous sections [15,44,70,71]. The impact of calorie restriction on these innate neurohormonal pathways has been extensively studied in animal models. With a decrease in energy intake, especially acute restriction, leptin levels decrease independent of fat stores which generates an inevitable powerful or exigenic drive (Figure 1). This provides a biological basis for the weight regain commonly observed. An established feature of energy restriction is a decrease in the Basal Metabolic Rate (BMR). Since for most individuals the BMR contributes 50-60% of total daily energy expenditure this is another factor predisposing to weight regain.

Table 2: Negative impacts reported in behavioral research associated with dieting and dieting related behaviours*

At a basic metabolic biochemical level this decrease in BMR can be partly accounted for calorie-restriction associated loss of muscle mass, especially in the absence of exercise, but, based on animal models, the decrease in leptin may also be a factor in the reduced metabolic rate. Thus an accumulating body of neurohormonal/physiological research serves to confirm the behavioral studies, namely that low energy dietary interventions for obesity may predispose to weight regain, weight cycling and increased weight as a result of an upward cogwheel ‘resetting’ of the energy homeostasis mechanisms [36]. In terms of obesity linked health concerns, significant energy restriction may promote fat redistribution and increased visceral fat deposition with its related health risks [57,70].

Neuroscience research is also providing some insights into the psychological factors associated with obesity. Penny and Carryer [71] proposed a potential role for leptin in emotional processing based on rat studies that demonstrated leptin to have an antidepressant action and the localization and neuronal activation in response to leptin administration of leptin receptors in limbic structures in the brain particularly the hippocampus. This location is quite distinct from leptin’s action on energy homeostasis via neurons located in the hypothalamus. In their experiments standard animal model tests used for determining the action of pharmacological antidepressants, chronic stress was linked with increased cortisol and low leptin levels. In contrast to pharmacological antidepressants whose therapeutic effects generally are not apparent until after 2-3 weeks, leptin had a rapid antidepressant action. A possible deduction from their research is that low leptin levels associated with strict dietary regimes may underlie the dieting related mood changes reported in behavioral studies. Leptin has also been linked with depression with some studies reporting direct correlation between leptin levels on depression while in others there was an inverse relationship [72]. The apparently contradictory results may reflect methodological issues as suggested by Labad et al. [72] but an alternative explanation may be a blunted response to leptin due to central leptin resistance. Relative leptin resistance has been associated with both the metabolic syndrome (which is linked with type 2 diabetes, abdominal obesity and cardiovascular disease) and women, and in both these groups increased proneness to depression has been reported. Preoccupation with food at the physiological level, may be an outcome of the sensitization of the brain’s reward circuitry and function since this part of the brain is associated with addictive type behaviors [15-17].

Epidemiological studies, cross sectional and longitudinal, have shown that there is an inverse relationship between physical activity and weight gain in both men and women [73-77]. Energy balance is the most important factor in weight regulation. Excess storage of fat occurs due to greater energy intake than energy expenditure for a period of time. Reduced energy intake (calorie restriction as mentioned in the previous section) can lead to weight loss. Another way to promote weight loss is by increasing energy expenditure e.g. physical activity.

Exercise has become an important intervention for weight loss. Both aerobic and resistance training appear to have different health benefits [13,78-84]. Aerobic exercise seems to improve metabolic activity [85], insulin sensitivity [83] and cardiovascular fitness [3,78] whilst resistance training has been shown to improve body composition [80], lipolysis and muscle mass [85].

Moderate intensity exercise for prolonged period is recommended for treatment of obesity; however more evidence is evolving supporting differences between men and women for loss of weight in response to exercise and amount of physical activity required for maintenance of weight. This means that “one size” or “one exercise” does not suit all. Men do appear to lose more weight in response to exercise [86,87]. A randomized trial comparing the effects of different durations and intensities of exercise on 12 month weight loss in sedentary overweight women found that approximately 10% weight loss occurred with higher amounts of exercise but it was not significantly different to the 8% weight loss with lesser amount of exercise [88]. A randomized control trial [89] comparing effect of 12 weeks of moderate-intensity exercise in young obese men and women, demonstrated significant decreases in body mass and significant increases in resting metabolic rate and VO₂ max for both men and women. Women in the control group (non exercise) had significant increases in body mass which was not observed in the control group for men indicating different biological responses to exercise or lack of exercise between men and women. A recent study [85] investigated the acute impact of moderate-intensity and vigorousintensity exercise bouts on daily physical activity energy expenditure in postmenopausal women. It was found that women expended more energy on physical activities outside of prescribed exercise on days they did not perform in the center-based exercise, especially if the prescribed exercise was vigorous-intensity. This means that greater weight loss will be achieved if women involved in exercise programs maintain their levels of activity outside of the prescribed exercise session. Women appear to “compensate” i.e. increase energy intake, if they do not maintain their levels of activity which ultimately reduces their ability to lose weight. The Midwest Exercise Trial 1 (MET1), evaluated weight loss to 16 months of exercise (45 min/day, 5 days/ week, 75% heart-rate-reserve) in overweight/obese, sedentary men and women without energy restriction [90]. They found that men lost weight and women did not. The gender differences in weight loss were associated with higher energy expenditure in men compared to women, however they could not conclude that weight loss was due to gender differences. The results from the MET1 study has led to the development of a randomized control trial designated MET2 [91]. MET2 has been designed specifically to examine gender differences in weight response to exercise prescribed at the same level of energy expenditure without diet restriction. This exercise intervention may finally provide results that will clarify if men and women differ in response to exercise and if they do then this will definitely have an impact on how exercise will be prescribed for women wanting to lose weight.

Prejudice against women who are perceived as ‘fat’ or obese can disadvantage them at many levels [92] and weight stigmatization has increased significantly over recent years [93]. This has been fuelled by large numbers of clinical studies where higher BMIs were associated with a greater risk for type 2 diabetes mellitus, cardiovascular disease and other health risks. Parallel to this is the persisting notion that obesity is due to over-eating, laziness and lack of will power. Therefore obese people are not only blamed for their own weight but also held personally responsible for health consequences. The copious amount of scientific evidence, in genetics, epigenetic, neuroscience and metabolic biochemistry that strongly challenge these assumptions has not been so well dispersed. An important reason may be that these different strands of research, particularly in view of their diversity, complexity and evolving nature, are not so readily understood or accessed by those who do not work in these specialist areas. It highlights the need for raising awareness and communicating this more effectively to the non-specialist. Namely, that the simplistic application of an energy balance equation to explain both cause and answer for obesity has been well and truly displaced by the large rapidly expanding body of research in these different bioscience areas. That intrinsic biology is the key determinant of body size rather than personal shortcomings and with it a sense of frustration, personal failure or blame, a common perception all too often re-enforced by health professionals in the name of health promotion [3]. That inherent biological factors, of how energy regulatory mechanism are set, reset or disrupted from a complex interaction of genetic, epigenetic, early development with environmental factors, are powerful determinants of body weight. As a direct result of their gender, in women energy homeostasis mechanisms are further reset promoting fat storage and in response to hormonal changes such as puberty, pregnancy and lactation. It serves to explain why for some women the achievement and maintenance of a lean body is an impossible challenge and why dieting regimes generally do not lead to lasting weight loss and conversely may predispose to weight regain [15,44].

However, the awareness, understanding and acknowledgement of the relevant biology does not contradict the confirmed health benefits that come from healthy well balanced nutrition in conjunction with enjoyable regular physical activity. What it does do is to highlight the need for a clear distinction between health and body size alongside realistic doable goals that emphasize wellbeing and mental and physical health in its widest sense rather than a pre-occupation with BMI. For women in her role as mother it is important that she has awareness that her diet during pregnancy may have long term implications for her child, the need for early intervention for gestational diabetes [94], good nutrition and the well-established benefits of breastfeeding. However just as important, especially for her daughters, is a role model that affirms that it is personality, enjoying life, healthy food, physical activity done for pleasure and not weight loss that determines positive outcomes in life, not body size and a negative spiral of pre-occupation with food and weight loss regimes. Campaigners in the western world protest at girls being force-fed for marriage in Mauritania where the opposite prevailing cultural norm sees fatness as the ideal in terms of feminine beauty and health [95]. Is this really so significantly different from the pre-occupation with slimness in western cultures and the pressures faced by those whose genetic and biological endowment does not favor a lean body build? What is needed is a positive affirmation and focus on health and wellbeing for everybody, at any body size!