Litter Size Reduction Model: Short- and Long-Term Effects: History
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Patricia Lisboa
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Litter size reduction model is an interesting model to learn the late impact of early overnutrition. The variable “litter size” must be taken into account in the development of any experimental ome with animals, regardless of the outcome to be investigated. Care must be taken to extrapolate the outcomes of this model to human beings, since mothers usually have one baby per pregnancy.

  • overnutrition
  • small litters
  • obesity
  • DOHaD concept

1. Metabolic Syndrome

Early postnatal overfeeding, promoting higher susceptibility to obesity and its metabolic disorders throughout life, is experimentally simulated in rodents by the litter size reduction model [1][2][3]. In this model, in early life (3 or 4 days after birth), the litter is reduced to 3 or 4 pups per dam, while the control litter is maintained with 8 to 12 pups per dam [4]. Normally, rodent dams have fewer nipples than pups, which causes them to compete for suckling. Usually, males have more access than females to nipples, and some nipples produce less milk than others [5]. Thus, in the litter size reduction model, as the number of dam nipples is higher than the pup number, there is no competition for suckling. Therefore, a small litter (SL) exhibits a higher milk intake per pup (approximately 1.5-fold) than a normal-sized litter [6]. Additionally, the milk composition of SL dams changes, providing a higher lipid content and reduced amounts of protein [6].
Because of this early overfeeding, the SL offspring have an accelerated body weight gain and increased adiposity before weaning, exhibiting a body weight 30% higher than the control offspring at weaning [7]. Some experimental studies have reported persistent hyperphagia, visceral obesity, elevated serum triacylglycerides, increased systolic blood pressure, and hyperinsulinemia in later SL offspring life, findings last reviewed before by Habbout and colleagues [8], featuring a metabolic syndrome phenotype. This is a result of adaptive modifications in response to early overnutrition, including epigenetic and hormonal changes in central and peripheral mechanisms involved in the control of food intake and energy balance in adulthood, which favors the obesity phenotype. This phenotype is reproducible in mice (C57BL/6, Swiss and FVB) and rats (Wistar and Sprague–Dawley); it has been extensively explored in male offspring [4]. Recently, the female response has been investigated, revealing a differentiated phenotype in several aspects.

2. Central Dysfunction: Impact on Energy Metabolism and Hormonal Axis

During the lactation period, the hypothalamic circuits that regulate energy homeostasis are still in development and are sensitive to the early hyperinsulinemia and hyperleptinemia exhibited by the SL model [9]. These hormonal changes could be involved in the altered responses to orexigenic and anorexigenic neuropeptides in paraventricular (PVN) hypothalamic neurons [10], favoring hyperphagia.
Then, the metabolic phenotype of SL offspring involves peripheral changes, especially central changes in pathways involved in energy homeostasis control. Many authors have described central resistance to hormones such as leptin [11][12], insulin [13], adiponectin [14], ghrelin [15], and cholecystokinin (CCK) [16]. In addition, there are other central modifications that affect the hormonal axis and contribute to metabolic disorders in adulthood. Adaptive changes in the hypothalamus–pituitary–adrenal (HPA) axis have been reported [17], affecting stress responses; in the hypothalamus–pituitary–thyroid (HPT) axis [18], impacting energy expenditure; and in the reproductive axis [19], causing reproductive disorders.
Interestingly, several hypothalamic changes occur before weaning, such as leptin resistance at postnatal day (PND) 12 [11], with a downregulation of hypothalamic Ob-Rb at PND 24 [20]. At weaning, the male rat SL offspring show, in the hypothalamic arcuate nucleus (ARC), increased expression of pro-opiomelanocortin (POMC), cocaine and amphetamine regulated transcript (CART), neuropeptide Y (NPY), and ghrelin receptors (GHS-R) [20]. Additionally, this animal model exhibits early alteration of astrocyte morphology at weaning, and it persists until adult life, with increased susceptibility to hypothalamic inflammation [9][21]. This phenotype can affect satiety control and could be due to early hyperinsulinemia and hyperleptinemia [9]. However, this hypothalamic microgliosis does not seem to be the major factor involved in the SL obesity phenotype [22].
In mice, these early changes promoted by neonatal overfeeding could affect neural projections [23] and synaptic transmission [24] in the ARC nucleus of females during adulthood, impacting mechanisms such as satiety control. Supporting the hyperphagic phenotype, SL offspring exhibit higher NPY and lower POMC contents in the ARC [25], suggestive of leptin resistance. Indeed, in adulthood, although their serum leptin and insulin levels are normal, male SL offspring have lower insulin and leptin signaling in the hypothalamus [12] and impairment of leptin-induced satiety [26]. However, leptin resistance is area-specific, since the hypothalamus–pituitary–thyroid axis is still responsive to leptin because the paraventricular (PVN) thyrotropin-releasing hormone (TRH) mRNA levels and T4 serum concentration are increased by exogenous leptin [26].
In addition to hyperphagia, male SL offspring have a food preference for a high-fat diet, an alteration that could be associated with changes in the dopaminergic reward system [25]. This food preference could contribute to a higher susceptibility to metabolic dysfunction in response to high-fat diet exposure [27].

3. Peripheral Dysfunction

In addition to central dysfunction, SL offspring exhibit several peripheral changes involved in their metabolic profile. The early energy and fat overload promoted by the SL model [6] has been involved in many metabolic disorders by affecting the postnatal development and function of glands such as the pancreas, adrenal, adipose tissue, thyroid, and gonads and metabolic tissues such as liver [6][18][19][28][29][30]. These hormonal changes can act as an imprinting factor or a mechanism of developmental adaptations in metabolic programming models. These hormonal changes can be involved in the adjustments of energy expenditure, stress response, and food intake behavior of the early overfeeding model.

4. Epigenetic Changes

Epigenetic changes are the key mechanisms in developmental programming, causing differentiated pattern of gene expression and transgenerational features, without altering the DNA nucleotide sequence [31]. DNA methylation, by the addition of a methyl group on the cytosine of cytosine–guanine dinucleotides (CpG), histone modifications, and microRNA (miRNA) expression, which modify the translation of RNA targets into proteins, are involved in the SL phenotype [32][33][34]. These modifications affect the gene transcription, silencing some genes or promoting overexpression of others, which has an impact on cellular or tissue function. Therefore, these gene changes become adaptive mechanisms in the programming models, modifying cellular signaling, hormonal action, and metabolism. In addition, such epigenetic changes are stably transmitted to the fetus or newborn, favoring the development of metabolic dysfunction in adult offspring. It is possible that some epigenetic changes will be passed on to future generations. At weaning, SL offspring exhibit hypermethylation of the hypothalamic POMC promoter [33], which seems to be involved in the impairment of POMC expression even in the presence of hyperinsulinemia. The insulin receptor (IR) gene promoter is hypermethylated, which is positively correlated with glucose levels [35]. In addition to changes in global hypothalamic methylation in mice [36], changes in pancreatic islet DNA methylation have also been reported, accelerating epigenetic aging in islets and changing the expression of genes involved in insulin secretion, which impairs this function in SL animals [34]. Peripheral changes also contribute to the dysfunction of glucose homeostasis in the SL model. In adult SL offspring, muscular hypermethylation of insulin receptor substrate 1 (IRS1) promotes lower IRS1 expression [37], which could contribute to insulin resistance. In the SL liver, histone modifications may be involved in higher monoacylglycerol acyltransferase 1 (Mogat1) expression, favoring NAFLD development and hepatic insulin resistance [32]. Additionally, there is hepatic miR-221 overexpression, suggesting its involvement in the impairment of the PI3K/AKT pathway in SL offspring [38].
Therefore, some epigenetic changes are involved in the SL offspring phenotype, promoting other adaptive mechanisms, such as hormonal changes. Together, these adjustments favor the increased susceptibility to metabolic disorders in the offspring subjected to early overfeeding. More studies about the epigenome in the SL model are necessary.

5. Sex-Related Differences

The impact of postnatal overnutrition has been extensively explored in male offspring. Only in recent years has the female phenotype and the comparative response of both offspring to early postnatal overnutrition been explored. These findings have enriched the knowledge about sex-related differences in many developmental programming models [39][40], which could explain the sex differences in the global obesity prevalence and the associated risk of comorbidities.
Sex-related differences were reported regarding the reproductive axis, highlighting the differentiated susceptibility to reproductive dysfunction and time of puberty in the male and female offspring. Postnatal overfeeding increases body weight during the pubertal transition in both sexes [41]. However, differences in the timing of external signs of puberty have been described in male and female offspring [19][41][42]. Interestingly, female SL offspring exhibit higher levels of hormonal markers of puberty, such as LH, FSH, leptin, and insulin, at the time of vaginal opening than normal litter offspring [41]. In males, hormonal changes showed less of a disturbance.
Regarding energy metabolism, early postnatal overnutrition promotes an obesity phenotype in both sexes (PND 10), which can be maintained [7] or abolished in young adulthood (PND 60) [43]. Additionally, in early life (PND 10), the SL male offspring had higher serum insulin, TNF alpha, and HOMA index than the SL female offspring. At the time of puberty onset, leptin levels are higher only in SL females, appearing only in SL males subjected to a combination of postnatal overnutrition and a postweaning high-fat diet [41]. In young adulthood, only SL female offspring exhibit lower BAT thermogenesis during part of the dark phase (at 22 °C), which does not change their whole body energy expenditure [7]. Interestingly, at PND 150, higher adiposity and hyperphagia are observed only in SL male offspring [44], together with higher serum triglycerides and NEFA and signs of hypothalamic gliosis and inflammation [43]. Additionally, despite the early hyperleptinemia in both sexes, postnatal overnutrition promoted hypothalamic changes in NPY and AgRP expression only in the male SL offspring. In female offspring, these central changes did not occur, even in the presence of early hyperleptinemia and adiposity, suggesting sex-dependent differences in the hypothalamic circuits that are sensitive to early overnutrition [45]. These sex-related phenotypes in adulthood suggest an estrogen protective role in female offspring, attenuating metabolic disorders in response to early overnutrition [43] or a contribution of the neonatal testosterone surge [44].
Early overnutrition reduces pituitary growth hormone (GH) mRNA expression in both sexes in response to a high-fat diet. While in the male SL offspring, GH suppression seems to be due to lower GHRH expression, in the female SL offspring, another mechanism is involved, such as reduced pituitary ghrelin action [46]. Indeed, pituitary ghrelin signaling is dysregulated only in female offspring [47].
Recently, it was pointed to the impairment of the gut-brain axis as another contributor to the obesity phenotype in the SL model, whose regulation is also sex-related. In adult SL males, the lower expression of the glucagon-like peptide 1 (GLP-1) receptor in the ARC may impair the satiety role of GLP-1. Despite the paradoxical CCK1-R overexpression in the ARC, the female SL offspring have lower acetate and propionate contents in their feces, which may impair PYY secretion [48]. These different changes may favor hyperphagic behavior in both sexes. Additionally, male and female offspring exhibit dysbiosis (higher abundance of the phylum Firmicutes, lower abundance of Bacteroidetes), which per se may impair energy metabolism [48], appearing before puberty [49] and being maintained until adult life [48].
The obesity phenotype of the SL female is also of special concern due to its transgenerational role. The offspring from SL female dams, even weaned with 6 pups by the dam, exhibit early obesity and cardiac remodeling in the F2 offspring of both sexes, with cardiac dysfunction only in the F2 male offspring. On the other hand, F2 female offspring show hormonal changes suggestive of polycystic ovarian syndrome, with lower blood estradiol levels and higher testosterone levels [50].

This entry is adapted from the peer-reviewed paper 10.3390/nu14102045

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