Genetic (Loos and Bouchard, 2003), epigenetic (Gluckman and Hanson, 2008), environmental (Romao and Roth, 2008), and mainly dietary (Sclafani and Springer, 1976; Seidell, 1998; Mendoza et al., 2007) causes of the metabolic syndrome exert their effects principally through the modulation of the expression of proteins (enzymes, transporters, regulatory agents). These agents carry out their functions only within short periods of time because of their relatively fast turnover, since a short life is one of the basic premises of any regulatory agent. In the same way, wearing out, saturation, and exhaustion of metabolic pathways and control systems could not either extend too much far away in time from the actual active life of the agents implicated, i.e., the half-lives of proteins, or the life-span of the cells affected. In short, if the development of obesity (or other metabolic syndrome-related disease) depends on excessive energy or fat intake and the wearing out of the systems controlling fat deposition (Virtue and Vidal-Puig, 2009), then, it should be expected that the metabolic syndrome-induced derangements should appear shortly after the initiation of the inflammatory processes and regulatory systems’ alteration. However, the expected changes usually do not occur shortly after exposure to triggering agents. Often a number of years elapse before the symptoms of the metabolic syndrome appear and the cluster of related diseases fully develops (Gustafsson et al., 2011). In addition, the metabolic syndrome tends to appear more often and/or earlier in adult males than in females (Regitz-Zagrosek et al., 2007; Hong et al., 2009; Gustafsson et al., 2011), the differences in incidence decreasing sharply after menopause (Janssen et al., 2008). There are sex-related differences, but the regulatory mechanisms and metabolic pathways affected are the same. Then, why are there so marked sex-related differences in the incidence of the metabolic syndrome? And also, why does this delay in its full manifestation occurs?

There is also a growing incidence of infantile obesity (Bua et al., 2007; Patton et al., 2011), i.e., an accelerated presentation of metabolic syndrome diseases fairly shortly after exposure to environmental (i.e., diet, sedentary behavior) obesogenic conditions (Butte, 2009; Tamayo et al., 2010; Bleich et al., 2011; Guinhouya et al., 2011). Why the delay between triggering factors and disease manifestation is much shorter in children than in adults?

We cannot directly attribute the differences to genetic factors (usually shared), neither to the nature of pathogenic mechanisms: usually lack of exercise (Rey-López et al., 2008; Mitchell et al., 2009), social tensions and stress (Moschonis et al., 2010; Tamayo et al., 2010; Gundersen et al., 2011), and mainly, excess dietary energy and predominance of lipids in the diet (Kohen-Avramoglu et al., 2003; Zimmermann and Aeberli, 2008). The proinflammatory mechanisms are shared too (Valle et al., 2005; Kowalska et al., 2008; Rizvi, 2009; Maury and Brichard, 2010). In addition, the sex differences are practically inexistent in children (Dubose et al., 2006), but tend to become manifest already in adolescents (Duncan et al., 2004), a harbinger of the adult appearance of the metabolic syndrome.

The mechanisms explaining the metabolic alterations observed in the diseases of the metabolic syndrome cluster, when known, seldom refer to the delay in the process of presentation of the syndrome. This raises a number of key questions which are critical for our understanding of the (adult) metabolic syndrome, its roots, maintenance, development, and eventual treatment.

There is an enormous body of information on these issues, but there is also a huge void in place of serious integrative analysis of a disease that has been intuitively considered a unique pathognomic entity (Bruce and Byrne, 2009) even before serious studies on its pathogenicity began. The center of study is progressively descending into detail to the molecular level (Nicolson, 2007; Maury and Brichard, 2010), usually forfeiting the integration of these data within the context of a living being, and adding complexity and background noise to any contextual analysis of the situation (Miranda et al., 2005).

The mechanisms so far presented to explain the pathogenicity of the metabolic syndrome should induce significant changes in a very short period of time, since:

The dilated timing of development of most cases of the metabolic syndrome in adults fits fairly well with the patterns of change, over the long-term, of androgens and estrogens (as well as of the postulated estrone-derived ponderostat signal), and are far away from the rapid change associated with peptide hormones, catecholamines, and most metabolic regulative signals. Steroid hormones are also synthesized in the brain, and freely cross the blood–brain barrier (Pardridge and Mietus, 1979; Baulieu and Robel, 1990), their circulating half-lives are longer than those of peptide or protein hormones and have no difficulties in crossing through or interacting with the cell membranes (Rao, 1981; Oren et al., 2004); they may even have membrane-bound receptors (Nemere and Farach-Carson, 1998; Jain et al., 2005) or binding proteins (Fortunati et al., 1996).

A plausible way to explain the delay in the appearance in full regalia of the metabolic syndrome in adults is to consider the brain responsible for the timing and progressive alterations that characterize its appearance. This theory is based mainly in the possibility to change (or misadjust) the ponderostat setting by a number of (largely unknown) conditions, such as a psychiatric disorder (Tuthill et al., 2006), iatrogenic effects of some drugs [Schwartz et al., 2004; Virk et al., 2004; or environmental poisons (Irigaray et al., 2006)], hypercortisolism (Peeke and Chrousos, 1995; Björntorp and Rosmond, 2000), long time exposure to fattening food (nil for some people, very fast for others; Seidell, 1998; Blundell et al., 2005), coincidence of a combination of alleles from a long list of genes (Borecki et al., 1998; Swarbrick and Vaisse, 2003), in utero conditioning (Beall et al., 2004; DeSai et al., 2005), epigenetic inheritance (Whitaker et al., 2010), triggering of thrifty genes (Romao and Roth, 2008), etc. The ponderostat setting also changes along our lives, so that mature men tend to present wider girths than younger adults (Yoshinaga et al., 2002; Alley and Chang, 2010). These long-term cycles are essentially governed by the brain, which ultimately favors the secretion of androgens and estrogens (but also the stress-immunity hormones, glucocorticoids; Mauras et al., 1996; Demerath et al., 1999; Matchock et al., 2007).

The list of factors potentially modifying body fat set-point is longer: estrone (Ferrer-Lorente et al., 2005; and the ponderostat signal derived from estrone; Vilà et al., 2011) dehydroepiandrosterone (Tchernof and Labrie, 2004), progesterone, aldosterone. In addition, the possibilities of regulation include retinoids (Kriegsfeld and Silver, 2004), hydroxycalciferols (Wortsman et al., 2000), hormone-transporting globulins (Barat et al., 2005; Li et al., 2010), and especially, hormone receptors (Mauvais-Jarvis, 2011).

Androgens are closely related to insulin (or IGF-1; Sheffield-Moore, 2000) and growth hormone (Mauras, 2006) as anabolic protein-deposing agents (Griggs et al., 1989). Estrogens are antiinflammatory (Schaefer et al., 2005; Straub, 2007), antioxidant protective agents (Prokai et al., 2005; Reyes et al., 2006). And glucocorticoids are defense agents (and thus faster-acting; Orchinik et al., 1994) which prevent and correct damages (Hafezi-Moghadam et al., 2002), and control the immune system (Franchimont, 2004; Tait et al., 2008).

The roles for androgens and estrogens go much beyond their function as sexual and reproductive hormones. In the metabolic syndrome, androgens’ levels (Gooren, 2006; Gould et al., 2007; and to a lesser extent estrogens) decrease considerably (and corticosteroids increase; Duclos et al., 2005) in parallel to advancing age (Blouin et al., 2005). However, androgens decrease earlier and more markedly. This seems to be the main deviation from the pre-established normal (i.e., non-metabolic syndrome) pattern. The dependence of the pathologic manifestations of the metabolic syndrome on the secretion, availability, and function of steroid hormones can be speculatively established by:

Globally, in the metabolic syndrome there is a decrease in all functions related to the androgen–estrogen system, with a parallel increase (by stress, counteraction, or previously established genetic design) of glucocorticoids. This is a rather sketchy explanation, which requires more data, since there is a considerable lack of information on the long-term changes of these hormones’ metabolism, the polycystic ovary syndrome being a significant exception (Kauffman et al., 2008; Guastella et al., 2010). The role of glucocorticoids in the genesis and maintenance of obesity has been widely studied (Livingstone et al., 2000; Achard et al., 2006), but seldom in relation to other types of steroid hormones.

A very important environmental factor, that may play a significant role in the unbalancing of the steroid hormone equilibrium, is the massive use of steroids as drugs for the treatment of a large, diverse, and growing number of diseases, corticosteroids being a case in point (van der Laan and Meijer, 2008). Synthetic glucocorticoids are widely (albeit not always sagely) used in Medicine (Borchers et al., 2003). They elicit marked effects through classical glucocorticoid receptors (Rousseau et al., 1972), but they are not subjected to the normal (physiological) systems of control; i.e., dexamethasone may bind the glucocorticoid receptors and elicit a blockage response of corticotropin secretion (Pasquali et al., 2002), but it does not bind the corticosteroid-binding globulin (Westphal, 1969; Perogamvros et al., 2011), a key element in the control of glucocorticoids (Grasa et al., 2001; Perogamvros et al., 2011).

There is also a growing challenge in environmental antiandrogens (Hotchkiss et al., 2008), and, especially, estrogenic compounds (Shappell, 2006; Foster, 2008), found almost anywhere as contaminants, that reinforce part of the actions of estrogens (but not along the whole spectrum of their functions; Knight and Eden, 1996; Ørgaard and Jensen, 2008), and are neither subject to their physiological mechanisms of control (Mueller et al., 2004; Wang et al., 2010). These effects are more marked in some tissues (gonads, mammary glands; Cassidy, 1999; Dang, 2009), and in the induction of estrogen-dependent cancer (Ososki and Kennelly, 2003), but we do not know much about their effects on brain and on endothelial inflammation processes. Environmental estrogens may diminish the secretion of gonadotropins (McGarvey et al., 2001), depriving the body of necessary estrogens acting on a wide spectrum of places, and substituting their finely tuned function by unspecific sexual hormone-like-related tissue stimulation. Food is an important source of unnecessary or unwanted estrogen (Remesar et al., 1999; Malekinejad et al., 2006; often with a wide spectrum of functions), promoting out of tune growth and fat deposition, as is the case of animal fats (Holmes et al., 2000), isoflavones (Suetsugi et al., 2003; Choi et al., 2008), and especially, dairy products (Malekinejad et al., 2006). Estrogen is present in the milk as a growth factor that helps the suckling to better use the milk nutrients (Remesar et al., 1999), but milk was not designed to feed adults… which thus receive repeated and potentially damaging doses of dietary estrogen (Qin et al., 2004) and other growth –including diabetogenic– factors (Martin et al., 1991; Wasmuth and Kolb, 2000).

A peculiarity of steroid hormones is their considerable ability to interconvert to different molecular species, forming families of compounds that show different global activity, but also marked differences in metabolic roles, such is the case of estrone and estradiol (Miller, 1969; Myking et al., 1986; Kirilovas et al., 2007). The simplified panorama described above must be completed with the influence of agents different from the typical estradiol for estrogen, testosterone for androgen and cortisol (corticosterone in rats) for glucocorticoids. Receptor dimerization and complexity [Sonoda et al., 2008; including their presence in the cell surface (Kim et al., 2008; Levin, 2009) and/or nucleus/cytoplasm (Welshons et al., 1984; Sebastian et al., 2004)], is compounded by the existence of converting enzymes, typically aromatase (Simpson, 2000; Miller, 2006), 17βOH- (Labrie et al., 1997; Adamski and Jakob, 2001) and 11βOH-steroid dehydrogenases (Agarwal, 2003; Isomura et al., 2006). Other hormones, such as progesterone, play a particular role under specific conditions (i.e., pregnancy; Spencer and Bazer, 2002; Gellersen et al., 2009) or act as supplemental signals for the three classical lines described, largely glucocorticoid (and antiglucocorticoid) effects (Pedersen et al., 2003; Zhang et al., 2007).

The existence, and growing incidence (Yoshinaga et al., 2004; Reilly, 2005), of infantile and juvenile obesity, compounded by other manifestations of the metabolic syndrome (Goran and Gower, 1998; Rosenbloom, 2003; Tauman and Gozal, 2006) apparently seems to be contradictory with the delayed appearance of the metabolic syndrome in full maturity. In some cases, obesity appears fairly early, even during infancy (Yoshinaga et al., 2004). This same phenomenon can be observed in rats, weaned on high-lipid cafeteria diet (Maxwell et al., 1988), which grow faster for a time and become obese at an early age (Bayol et al., 2005). The causes of childhood obesity are considered a combination of genetic (Wardle et al., 2008) and environmental factors: sedentary behavior (Tremblay and Willms, 2003), but mainly overnutrition, with abundance of lipid (Ailhaud and Guesnet, 1997; Macé et al., 2006). The role of diet, however, is far from being fully proven (Newby, 2007). The presence of growth factors in the diet, i.e., from milk (Remesar et al., 1999) or meats (Meyer, 2001) is a significant factor contributing to the early manifestation of obesity. Childhood obesity is parallel to serious disturbances of the endocrine system, including advanced menarche in girls (Freedman et al., 2003), hypogonadism or delayed puberty (Kaplowitz, 1998) and gynecomastia (Ersöz et al., 2002) in boys, and a generalized tendency to altered cortisol function (i.e., depression; Goodman and Whitaker, 2002; Dockray et al., 2009).

The rapid development of the metabolic syndrome in children exposed to obesogenic diets and other metabolic syndrome-inducing factors in fact is not too much different from the situation in mature adults: in both cases, androgens and estrogens have not yet achieved their adult levels of functionality (or are in frank decline in mature subjects). Both situations have in common the low levels/availability of these steroid hormones. In fact, in children there is a higher response to hormones inducing the accumulation of body fat, as is the case of estrone (Tang et al., 2001). As expected, the setting on of childhood obesity also alters the normal sexual development into adulthood (Esposito et al., 2008; Goldbeck-Wood, 2010). This condition affects boys more deeply than girls, especially when environmental or iatrogenic factors delay their gonadal development, affect their fertility and maintain low testosterone levels throughout (Rozati et al., 2002; Sikka and Wang, 2008).

The differences in the timing of metabolic syndrome manifestation in children and adults agree with low androgen and estrogen and high glucocorticoid levels in both sections of the life cycle. However, coincidence is not proof enough, and more studies on the interactive influence of sexual hormones in the development of the metabolic syndrome (or its arrest) are needed to fully sustain the hypothesis presented here. In the case of glucocorticoids, their direct implication in the development of the metabolic syndrome both in childhood and in maturity has been already proven (Björntorp and Rosmond, 2000; Wolf, 2002; Spencer and Tilbrook, 2011).

The hypothesis presented here does not cover all cases of manifestation or control of the metabolic syndrome, since there are a number of factors which may deeply change or modulate the presentation of the metabolic syndrome. Genetic factors may not only modulate the proclivity to favor the appearance of the metabolic syndrome (Goulart et al., 2009; Sookoian and Pirola, 2011), but may trigger responses inducing disease, such as obesity, through massive alteration of the mechanisms of control, as is the case of some genetic-based obesities such as the Prader–Willi syndrome (Cassidy, 1997). In animal models, such as the Zucker obese rats, containing the Lepr^fa/fa mutation (Phillips et al., 1996), we know the altered mechanism, the lack of responsiveness to leptin. Evidently, these cases could not be correlated with the hypothesis postulated here, in spite of altered glucocorticoid (Pesonen et al., 1992) and infertility observed in Zucker obese rats. In humans with the Prader–Willi syndrome there are alterations (with wide variations) in sexual maturation (Eiholzer et al., 2006), and hypothalamic steroid hormone regulation (Brandau et al., 2008). In both cases, despite their large differences in genetic cause and triggering agents, steroid hormones’ changes are not at the root of the problem, but nevertheless their function is deeply altered.

The ponderostat mechanism of control of body weight (Bradley, 1978) has been postulated as a homoeostatic system in which the brain regulated energy expenditure and energy intake in parallel to maintain the desired mass of body fat reserves (Bradley, 1978; Cabanac, 2001). This mechanism is maintained through signals from adipose tissue informing the brain of the actual fat mass. Leptin has been postulated as a possible ponderostat signal (Zhang et al., 1994); it is generally accepted that leptin participates in the control of energy balance (Gautron and Elmquist, 2011), but not in this role. Oleoyl-estrone has been also postulated as a ponderostat signal (Adán et al., 1999), and its structure and function is closely related to estrogen (Sanchis et al., 1996). Glucocorticoids inhibit its lipostatic effects (Grasa et al., 2007), and oleoyl-estrone modulates increases glucocorticoid synthesis (Romero et al., 2010) and decreases the synthesis of testosterone (Romero et al., 2009). However, recent studies have shown that oleoyl-estrone is not the active agent producing changes in ponderostat setting and metabolic changes, but a derivative of this compound, which structure has not yet been discovered but which is nonetheless related to estrogens too (Vilà et al., 2011).

The question of different intensities of manifestation of metabolic syndrome diseases (or their absence) in different individuals subjected to the same stimuli remains open. Genetic adaptive factors may play an important role, but so far they are not known, and neither the possible consequences this resistance plays on (or is played by) steroid hormones.

Steroid hormones are the only known medium- to long-term signals capable of eliciting procrastinated, often imperceptible, changes along time that shape our vital cycle. They are also closely controlled by the brain along pre-established patterns of change, and probably are also implied in the magnification of the problems caused by the metabolic syndrome. These effects in fact largely reflect the lifetime consequences of their own altered equilibrium.

The normal decrease in androgen and estrogen levels along with advancing age prevent these hormones to overcome the growing insult of environmental factors which elicit a immune system defense reaction countered by an increase in glucocorticoids which prevail over androgens (but also estrogens) to fully allow the metabolic syndrome and related pathologies to fully manifest. In consequence, I postulate that the timing of appearance of the metabolic syndrome-related pathologies is closely linked to parallel decreases in androgens and estrogens, and thus the syndrome fully flourished mainly under conditions of low sex hormone levels (infancy, advancing age in men, menopause in women; Figure 1).

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.