Metabolic syndrome (MetS) is not a single disease but a collection of medical conditions that occur together and increase the risk of cardiovascular disease (CVD). Although MetS had been defined slightly differently by various organizations [1], the main components of MetS include obesity, hypertension, dyslipidemia and insulin resistance. The prevalence estimates vary, based on the criteria used for the diagnosis of MetS. Thus far, global MetS prevalence is estimated to affect approximately one quarter of the world population [2]. More importantly, MetS-related disorders account for two thirds of the non-communicable disease (NCDs) deaths [3]. Also important is that it displays multiple and diverse phenotypes with indications for differing treatment strategies. In the absence of specific therapeutic regimens, the prevalence of MetS remains on the increase globally [2]. Therefore, a superior strategy to stop the spread of the MetS epidemic is required to for prevention, in addition to treatment.

Most NCDs may start in early life [4]. The establishment of various adverse environmental conditions, which takes place during pregnancy and lactation, could be involved in the early-life programming of health. This concept is now known as the developmental origin of health and disease (DOHaD) [5], which is supported by evidence coming from a large number of epidemiological and experimental observations.

Various early-life risk factors often linked to nutritional imbalance may lead to vulnerability to later MetS [6,7,8,9,10]. Remarkably, there is evidence for the programming of some similar features of MetS from different early-life insults, possibly suggesting a commonality of mechanism and highlighting that identifying underlying mechanistic pathways is vital to develop ideal prevention interventions [6]. By intervening before disease ever occurs, we have the potential to stop undesirable programming processes resulting in MetS, which is referred to as reprogramming [11].

Extensive epidemiological studies have linked adverse early-life conditions with the risk of MetS in the offspring in later life. First, there is evidence from severe famines [12,13,14,15,16]. The Dutch Famine Birth Cohort Study demonstrated that the children of pregnant women exposed to famine displayed various characteristics of MetS, like obesity, dyslipidemia, hypertension, insulin resistance and CVDs [12,13]. Findings similar to those of the Dutch famine were also established in other famine studies [14,15,16]. Of particular interest, maternal undernutrition during early gestation had greater effects in increasing cardiometabolic risk in adult offspring, compared to maternal undernutrition during middle- or late-gestation [12]. Another line of evidence comes from research in twin pregnancy. These studies reported there were associations between low birth weight (LBW) and different characteristics of MetS, including hypertension, type 2 diabetes and insulin resistance [17,18]. Third, a prior systematic review of 39 studies revealed that rapid postnatal catch-up growth of LBW neonate had an approximately 80% increased risk for CVDs, a major complication of MetS [19]. The risk factors for MetS of developmental origins have been assessed in a number of observational studies. Risk factors reported in these cohorts relating to adverse cardiometabolic outcomes in adult offspring include maternal obesity [20,21], gestational diabetes [21,22], excessive postnatal weight gain, [23] and environmental chemicals exposure [16]. To date, literature on paternal risk factors is scare. There is emerging evidence that paternal risk factors, such as obesity, diabetes mellitus, advanced age, and cigarette smoke are associated with adverse metabolic and cardiovascular outcomes in their offspring [24,25]. All of these observations provide links between the suboptimal early-life environment and the risks for developing MetS in adulthood.

However, these epidemiological studies do not propose molecular mechanisms underlying programming processes for the development of potential reprogramming interventions. Therefore, animal models have been established to demonstrate the biological plausibility of the associations observed in epidemiological studies, providing proof of causality.

In view of the difficulties in establishing animal models that manifest all the characteristics of MetS, most investigations into MetS of developmental origin are done using models that display certain hallmarks of MetS [6,7,8]. To date, a broad range of adverse early-life environmental factors are associated with certain features of MetS in adult offspring, including nutrition imbalance, maternal conditions or disease, chemical exposure, medication use, etc. [6,7,8,9,10,26,27,28,29]. However, excessive information is available based on only one characteristic of MetS, and in the interest of brevity, we have limited this review to at least two of the listed components that are present [30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72] (See Table 1). Diverse small- and large-animal models have been developed for DOHaD research [29,73], each with its own natural advantages and disadvantages. This review was restricted to rodent models for appropriate comparisons of major characteristics of MetS appear through a lifetime. Table 1 reveals the outcomes relating to MetS determined in rats ranging from eight weeks to one year of age. Considering one human year is almost equivalent to two rat weeks in adulthood [74], most outcomes are determined from childhood to middle adulthood in terms of human age. Each category is discussed in turn.