Decoding the Mechanisms Behind Early Weaning–Driven Obesity and the Leucine “Solution”

The global incidence of obesity and associated metabolic diseases is high and continues to rise, causing huge personal and socioeconomic costs. In addition to genetics and contemporary environmental exposures, early-life exposures during critical developmental periods—and even the parental preconception status—may condition metabolic health and the susceptibility to obesity in adulthood through a biological phenomenon called “programming” or “metabolic programming” (1). In this issue of Diabetes, Sun et al. (2) provide new insights into the mechanism of early weaning–induced “malprogramming” and the benefits of leucine supplementation in adulthood to ameliorate its consequences.

Most attention has been paid traditionally to the gestational/fetal period as a programming window, yet the lactation period is also critical (3–5). Breastfeeding represents optimal nutrition at this stage and protects against later obesity and metabolic disorders (6). However, breast milk composition is highly dynamic and varies according to many factors, including the mothers’ diet and metabolic status. An optimal diet during lactation can offset the deleterious consequences of an unbalanced diet during gestation on rat offspring health (7,8). Intertwined with the maternal diet, breastfeeding duration is another player in programming. The shortening of lactation may compromise the supply of breast milk bioactive compounds such as leptin, which is required for the normal development of neuroendocrine pathways controlling energy metabolism and is considered a key programming factor of a healthy phenotype (9). The World Health Organization recommends exclusive breastfeeding during the first 6 months of life (10). However, interruption before 6 months is common, particularly among women with obesity (11,12). Epidemiological evidence points to a dose-dependent association between a longer duration of breastfeeding and a decreased risk of overweight and obesity (13,14). Early weaning is thus a factor of concern in the context of public health and the current obesity epidemic.

Animal (generally rodent) models are essential in the field of metabolic programming since they allow the identification of direct effects and mechanistic insight. Studies in rodent models of early weaning (maternal deprivation, inhibition of prolactin production, and breast bandage) have revealed metabolic and, depending on the model, also behavioral defects in the adult offspring (15). Shortening the standard (21 days) lactation period (usually by the last 3 days, comparable to 1 month in humans [16]) results in obesity (on a regular diet), dyslipidemia, resistance to leptin and insulin, anxiety, aggressive behavior, and preference for fat and palatable foods in the adult offspring (15). On the contrary, delayed weaning protects rat offspring from obesity (17). Hence, animal models may recapitulate to some extent the human situations.

The mechanisms underlying early weaning–driven adult-onset obesity have been poorly defined so far. Sun et al. (2), using the maternal deprivation model, longitudinal study designs, and sequential liver transcriptomics, provide new clues. One is the hyperinsulinemia found in the early-weaned rats already at postnatal day (PND) 23–25 (weanlings). High insulin promotes fat storage and body growth, and its presence in the immediate postnatal period was associated with adult-onset obesity in rats (3). Hyperinsulinemia may be mechanistically upstream of the development of obesity (18,19). Interestingly, higher glucose-stimulated insulin secretion by isolated pancreatic islets was reported in rat models of early weaning at a time when obesity was not yet present (PND 45) (20). A second clue is the contribution of hyperphagia: increased orexigenic neuropeptide Y levels in the hypothalamus and (with some delay) increased food intake preceded obesity in the early-weaned rats of Sun et al. (2). Overall, early weaning seems to program increased energy intake from palatable foods (21) and with aging (2), through effects on central circuitries regulating energy balance. A third clue comes from the sequential liver transcriptomes, which showed that the expression of a set of lipid metabolism–related genes is altered in the liver of early-weaned rats long before excess body weight/adiposity and metabolic dysfunctions become apparent in these animals.

Additionally, Sun et al. (2) extend the characterization of the metabolic phenotype of adult early-weaned rats to cover aspects little studied up to now, such as the development of diabetes symptoms by PND 80 (polydipsia, polyuria, and glycosuria) and alterations in renal health (increased serum urea nitrogen), bile acid metabolism (increased total bile acids and bilirubin in serum indicative of cholestasis, with compatible alterations in the liver metabolome such as decreased taurine levels), and the gut microbiome (with changes in line with the propensity to obesity and cholestasis) at PND 211. Last, but not least, they show that—even if their results do not sustain alterations in branched-chain amino acid (BCAA) metabolism in their model—supplementation of leucine to early-weaned rats starting in adulthood (at PND 150) mitigates most metabolic disorders and hampers the programmed obesity development. Leucine is a BCAA with controversial effects on obesity (22,23), yet it was chosen because, in the authors’ hands, it effectively counteracted the development of diet-induced obesity in mice (24) (Fig. 1).

Strengths of the article by Sun et al. (2) include the longitudinal study design, which allows the detection of potential causal mechanisms of the early weaning–programmed later alterations; the application of unbiased, omics approaches, uncommon so far in studies in models of early weaning, and which are a generating source of novel working hypothesis; and the fact that, besides phenotyping the programmed disorder, a potential “solution” to it is tested. A limitation is that only male offspring were studied, although sex-specific effects are common in metabolic programming and have recently been described in early weaning models as well (15). Sequential molecular characterization at different ages is restricted to the liver, yet there are results within the article, e.g., the increased age-related “whitening” of brown adipose tissue and altered gut microbiota in adulthood, that suggest the possible causal contribution of early alterations in additional tissues to the adult “malprogrammed” phenotype an aspect that deserves further investigation. Finally, without underestimating its benefits, the timing of the leucine supplementation, beginning in adulthood, leaves open the question of the specificity of its effects. In fact, in other models of early weaning, the derived metabolic disorders are attenuated (at least some of them) by exercise and selected dietary interventions with purported antiobesity agents (resveratrol, yerba mate, and calcium) during the adult life of the early-weaned offspring (15).

Therefore, the work by Sun et al. (2) is of great interest, as it reveals potential underlying mechanisms of programmed obesity by early weaning and supports novel uses of leucine supplementation in adulthood. Whether the causal mechanisms suggested contribute to programmed obesity by other early-life factors such as maternal obesity or early exposure to endocrine disruptors or are specific to early weaning is an issue for future studies. The combined effects of early weaning superimposed on adverse maternal conditions remain to be explored. It will also be interesting to identify interventions during the lactation period itself or at weaning that are able to counteract the malprogramming by targeting the triggering mechanisms, especially indicated in cases in which early weaning is unavoidable. Research in rodent models of early weaning can help generate public consciousness and novel policies to further promote breastfeeding for at least 6 months as a preventive strategy to reduce overweight and obesity in childhood and adulthood, and perhaps provide novel strategies to combat programmed obesity.