High Fat Diet and Childhood Diseases Maternal High Fat Diets and Offspring Diseases

    

    

    Figure 1: Basic schematic outlining consequences of maternal high fat diets on the health and well-being of offspring.
    

Several mechanistic pathways, including alterations in the offspring muscle, may effectively impair glucose metabolism and result in the development of insulin resistance and diabetes in the offspring once they reach adulthood. Skeletal muscle, the principal site responsible for insulin-stimulated utilization of glucose and Fatty Acids (FAs), is affected by maternal obesity. Fetal development of skeletal muscle implicates myogenesis, adipogenesis, and fibrogenesis, all of which are derived from Mesenchymal Stem Cells (MSCs) [16]. An increasing body of evidence demonstrated that in response to maternal obesity, fetal skeletal muscle exhibited increased intramuscular fat and reduced myogenesis, along with altered AMP-activated Protein Kinase (AMPK) signaling and increased expression of inflammatory markers [17-19]. In addition, fetal skeletal muscle exhibited increased collagen content in response to maternal obesity, indicating increased fibrogenesis in fetal muscle [20]. All of these alterations in fetal skeletal muscle suggest that MSCs commitment shifts from myogenesis to adipogenesis and fibrogenesis, thus impairing skeletal muscle physiological functions, such as reduction in oxidative capacity [21] and muscle force [22]. Notably, this shift of MSCs commitment may be mediated by maternal obesity-induced chronic inflammation through three major mechanisms: down regulation of wingless and int (WNT)/β-catenin, inhibition of AMPK signaling, and induction of epigenetic modifications [16,18]. As a result, elevated intramuscular fat and inflammatory signaling in offspring muscle may correlate with increases in adipogenesis and insulin resistance, predisposing offspring to later-life obesity and diabetes [19].

Intestinal diseases

Numerous evidence has linked maternal HFD consumption to intestinal development and health in offspring [23]. Maternal HFDs (60% energy from fat) for 8 weeks can elicit many structural and functional adaptations in the intestine of offspring, including increased intestinal permeability and gut inflammation as well as decreased villus to crypt ratio and goblet cells density in the ileum [24]. These alterations increase gene expression of proinflammatory cytokines in offspring intestine and may translate into increased susceptibility to Inflammatory Bowel Diseases (IBD) and other associated diseases in offspring. One recent study showed that maternal and postnatal HFDs accelerated the onset of ileitis in the distal ileum of offspring TNF?ARE/WT mice, a genetically susceptible model for CD-like ileitis [25]. Similarly, using a dextran sulfate sodium-induced colitis mouse model, previous studies found that maternal consumption of HFDs (60% energy from fat) during gestation and lactation predisposes female offspring to a higher susceptibility to develop IBD and related inflammatory gut diseases [23]. The increased gut inflammation and colitis may be associated with elevated production of proinflammatory cytokines such as interleukin (IL)-1β, IL-6, and IL-17, reduced AMPK signaling, and amplified NF-κB signaling cascade in the offspring [23].

Although conflicting, the underlying mechanism for the impacts of maternal intake of a HFD on the intestinal development and function in offspring may involve the TGF-β signaling pathway and Jak-STAT signaling pathway [26]. Another possible mechanism may be perturbation of gut microbiome induced by a maternal HFD in gestation [27]. In response to a maternal HFD, shifts in gut microbial composition of the mother can be transferred to the offspring and influence its gut microbiome [27-29]. Moreover, alterations in the bacterial composition of offspring are associated with the maternal consumption of nutrients, especially a HFD, independent of maternal body mass [27,30-33]. Along this line, maternal HFD per se but not maternal obesity can restructure the offspring’s intestinal microbiome, which in turn influences intestinal maintenance of metabolic health [34]. Further investigations are warranted to confirm this hypothesis.

Cardiovascular disease

There is compelling evidence showing that a maternal HFD during pregnancy and/or suckling is related to increased risk of CVD in the offspring. For instance, in a study of 37,709 subjects, maternal obesity was related to elevated mortality from cardiovascular events in adult offspring [35]. Similar observations were made in animal studies where using an integrated approach of determining both cardiac structure and molecular markers of cardiac hypertrophy, cardiac hypertrophy and dysfunction was observed in the offspring, even in the absence of any change in its body weight and adiposity at 12 weeks of age [36]. In addition, other studies reported that increased systolic blood pressure and endothelial dysfunction were observed in offsprings, who were exposed to maternal pre-pregnancy obesity/overweight [12,37-39]. Although poorly defined, mechanisms implicated in the programming of offspring CVD may include increased inflammation, oxidative stress, lipotoxicity, and epigenetics [40]. In support, elevated oxidative stress was observed in the offspring heart due to maternal obesity, accompanied by activation of p38 and JNK and downregulation of cardioprotective AMPK expression [41]. The combination of oxidative stress and inflammation may have an additive effect. Studies have shown that inflammation is a risk factor for cardiac fibrosis in fetal sheep offspring [20]. The roles of lipotoxicity and epigenetics in developing offspring CVD have also been described in numerous animal models. Interested readers can refer to [42-44] for further reading.

Liver disease

Non-Alcoholic Fatty Liver Disease (NAFLD) is regarded as the commonest cause of chronic liver disease. Developmental programming has been shown to be implicated in the pathogenesis of NAFLD and chronic liver disease. In support, after 3 months of exposure to maternal obesity and a postnatal obesogenic diet, offspring exhibited increased adiposity, hepatic Triglyceride (TG) content and upregulation of tumor necrosis factor (TNF)-α, IL-6, and alpha smooth muscle actin, indicative of liver injury and fibrosis [45]. Upon further investigation, the same study found a more-profound evidence of hepatosteatosis and a more-robust NAFLD phenotype with hepatic fibrosis at 12 months [45]. Intriguingly, offspring, which were born to lean dams but were suckled by obese dams, exhibited an exaggerated NAFLD phenotype, accompanied by elevated body weight, elevated concentrations of insulin, leptin, aspartate transaminase, IL-6, TNF-α, liver TGs, steatosis, hepatic fibrogenesis, renal norepinephrine, and liver α1-D plus β1-adrenoceptors, indicative of activation of Sympathetic Nervous System (SNS) [46]. SNS activation promotes fibrosis progression via the actions of norepinephrine [47]. These data suggest that exposure to maternal obesity during pregnancy and lactation programs development of a NAFLD phenotype. The mechanisms may involve alterations of hypothalamic appetite nuclei signaling by neonatal adipose tissue derived leptin and maternal breast milk [46], and disturbance of the hepatic innate immune system with increased Kupffer cell numbers and reduced NKT cell populations [45].

Brain health and function

Maternal nutritional status during gestation exerts crucial roles in modulating fetal brain formation and development, with long-lasting consequences on its function, such as memory, learning, and brain senescence. When pregnant rats were exposed to a HFD beginning with gestational day 5, their fetuses displayed enhanced proliferation of neural progenitors (indicative of decreased neurogenesis) within the hypothalamus at embryonic day 14 [48]. In agreement, other lines of evidence demonstrated that long-lasting (until postnatal day P70) decreased neurogenesis in the dentate gyrus was observed in pups from mothers fed a HFD (57.5% fat with mainly lard) for 6 weeks prior to and during gestation as well as during lactation [49]. Neonatal brain development may also be affected in suckling pups exposed to a maternal HFD [50]. In addition, maternal exposure to a HFD (60% calories from fat) for 10 weeks prior to and during gestation altered fetal hippocampal development at embryonic day 17, as shown by region-specific alterations in proliferation of neural precursors, reduced apoptosis, and by reduced neuronal differentiation within the dentate gyrus [51]. Altogether, maternal exposure to a HFD can affect prenatal and postnatal brain development.

Several mechanisms may be responsible for adverse effects of a maternal HFD on brain. Peroxidized lipid accumulation in the dentate gyrus may be associated with alterations in hippocampal neurogenesis [49]. Decreased levels of brain-derived neurotrophic factor in the cortex and hippocampus may be related to reduced hippocampal spatial learning performance and to alterations in discrimination reversal [52-54]. Another hypothesized mechanism implicated in the dietary modulation of hippocampal development is associated with the leptin receptor [55], which plays a key role in facilitating memory and learning [56]. The expression of leptin receptor in the hypothalamus and liver is reduced in response to obesity [57].

Pancreatic cancer

The prevalence of pancreatic cancer in developed countries is rising at an alarming rate and may parallel rising rates of obesity and dysmetabolism [58]. Intriguingly, the phenomenal rises in the rates of pancreatic cancer may be attributed to transgenerational amplification of obesity through epigenetic mechanisms [59], a possible link being Non-Alcoholic Fatty Pancreas Disease (NAFPD) [60]. In parallel with increases in body weight, TG content in pancreas tissue was dramatically elevated in offspring of maternal obesity. Meanwhile, pancreatic expression of fibrogenic markers TGF-β and collagen type 1-α2 genes was greatly upregulated in offspring of maternal obesity, accompanied by increases in the response of night-time systolic blood pressure and systolic blood pressure to restraint. Therefore, a fatty pancreas with induced fibrogenesis developed in offspring when exposed to an obesogenic environment, indicating a dysmetabolic and NAFPD phenotype [60]. Therefore, maternal obesity-induced pancreatic cancer in offspring may result from pancreatic fat accumulation and fibrosis in offspring.

Breast cancer

Exposure (in utero and lactation) to maternal HFD predisposed female progeny to elevated risk for breast cancer [61]. Previous studies found that maternal consumption of HFD (45% kcal from fat), beginning at weaning (postnatal day 21) and maintained on the same diet 12 weeks prior to mating and throughout pregnancy and lactation, alters mother’s metabolism and systemic oxidative status, leading to systemic alterations in female offspring in the absence of dramatic weight gains. On one hand, maternal HFD elevated IL-6 levels and oxidative stress status, both of which could directly contribute to the development of breast cancer. In addition, maternal HFD promoted hyperinsulinemia and suppression of PTEN (a tumor suppressor) expression/function, both of which increased breast cancer risk via upregulation of Insulin Receptor Substrate-1 (IRS-1) expression [61]. Other studies also demonstrated increased risk for breast cancer in the offspring of dams-fed HFD [62]. These data have important implications for developing novel strategies for the prevention of maternal HFD-induced breast cancer.

Potential treatment options

Given the close relationship between maternal HFDs and the offspring health, it is of great importance for obese mothers to eat balanced meals and to reduce their body weight. In this regard, diet reversal from HFDs to control diets during pregnancy resulted in improvements in fetal hepatic triglycerides, normalization of the melanocortin levels, and partial normalization of the expression of gluconeogenic enzymes [43]. Similar results were obtained in male offspring of obese rats, in which dietary intervention prior to pregnancy reversed metabolic programming of offspring [63]. In addition, interventions with exendin-4, folic acid, and leptin in the early phases of developmental plasticity have been reported to alleviate or reverse some of the effects related to developmental programming [64-66]. In addition, exercise exerts beneficial effects in obesity-prone offspring of undernourished mothers [67,68]. In support, children had reduced birth weight and exhibited improved metabolic profiles with greater insulin sensitivity and improved lipid profile when their mothers reduced their body weight (36 ± 1.8%) [69].

Conclusions and Perspectives for Future Studies

Overall, many animal and human studies have indicated that maternal HFDs and/or obesity negatively affect offspring health, which has profound implications for public health policy. Based upon evidence to date, we suggest that intake of SFA should be avoided, and clear guidelines for fat intake (just like trace elements iron and folic acid) should be established for mothers in pregnancy, thus improving body health status. However, lots of questions remained to be addressed. For instance, when is the appropriate time for obese woman to lose weight when planning pregnancy, and how should they manage their weight when pregnant? In addition, further studies are urgently warranted to identify appropriate interventions to reduce the risks of these complications in the offspring.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (31802077) and the science and technology project of Guangxi Province (2018JJB130239).

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