Leucine supplementation in maternal high-fat diet alleviated adiposity and glucose intolerance of adult mice offspring fed a postweaning high-fat diet

Abstract

Background Combined maternal and postnatal high-fat (HF) diet intake predisposes offspring to metabolic dysregulation during adulthood. As the inhibitory effects of leucine consumption on obesity and metabolic disorders have been reported, the effects of maternal leucine supplementation on metabolic dysregulation in adult offspring were investigated. Methods Female mice were exposed to a control (C) or HF diet, with or without leucine (L) supplementation (1.5%, w/v), 3 weeks before mating, during pregnancy, and during lactation (C, CL, HF, and HFL). Male offspring were exposed to an HF diet for 12 weeks after weaning (C/HF, CL/HF, HF/HF, and HFL/HF). Serum biochemical parameters were determined for both the dams and offspring. Oral glucose tolerance test and qRT-PCR analysis were used to investigate metabolic dysregulation in the offspring. Results HFL dams exhibited higher relative adipose tissue weights than HF dams. Body weight, relative adipose tissue weight, and serum glucose levels were lower in the HFL/HF offspring than in the HF/HF offspring. Maternal leucine supplementation tended to alleviate glucose intolerance in the offspring of HF diet-fed dams. Additionally, mRNA levels of fibroblast growth factor 21 (FGF21), a hepatokine associated with glucose homeostasis, were higher in HFL/HF offspring than in HF/HF offspring and were negatively correlated with adiposity and serum glucose levels. The mRNA levels of genes encoding a FGF21 receptor complex, Fgf receptor 1 and klotho β, and its downstream targets, proliferator‐activated receptor‐γ co‐activator 1α and sirtuin 1, were higher in adipose tissues of the HFL/HF offspring than in those of the HF/HF offspring. Serum lipid peroxide levels were lower in HFL dams than in HF dams and positively correlated with body and adipose tissue weights of offspring. Conclusions Leucine supplementation in HF diet-fed dams, but not in control diet-fed dams, resulted in an anti-obesity phenotype accompanied by glucose homeostasis in male offspring challenged with postnatal HF feeding. Activation of FGF21 signaling in the adipose tissue of offspring may be responsible for these beneficial effects of leucine.

The Effect of Maternal Exposure to a Diet High in Fats and Cholesterol on the Placental Function and Phenotype of the Offspring in a Rabbit Model: A Summary Review of About 15 Years of Research

“…As for the supplementation of fish oil, which is rich in ω-3 PUFA, in overweight or obese mothers during pregnancy, it does not show a positive effect on the body composition of the infant and remains to be determined whether this is confirmed or not in the longer term [98]. Nevertheless, in mice, leucine supplementation in high-fat diet-fed dams resulted in an anti-obesity phenotype accompanied by improved glucose tolerance in male offspring challenged with postnatal high-fat feeding, probably through the activation of signaling involving fibroblast growth factor 21 (FGF21), a hepatokine associated with glucose homeostasis, in the adipose tissue of offspring [99]. The isocaloric exchange of casein protein for yellow pea protein (YPPN) in a high-calorie obesity-inducing diet did not protect against obesity but did improve several aspects of lipid metabolism in adult male offspring, including the serum total cholesterol, LDL and VLDL cholesterol, triglyceride (TG) and hepatic TG concentrations, suggesting that the exchange of proteins in a deleterious maternal diet selectively protects male offspring from the malprogramming of lipid metabolism in adulthood [74].…”

Amino Acids during Pregnancy and Offspring Cardiovascular–Kidney–Metabolic Health

“…In a distinct approach, BCAA supplementation during pregnancy demonstrated efficacy in preventing hypertension primed by maternal caloric restriction in adult offspring [136]. Additionally, another study showcased the benefits of perinatal leucine supplementation in mitigating obesity and glucose intolerance in adult mouse offspring exposed to a high-fat diet during the perinatal period [137]. The inconclusive nature of previous studies addressing the association of BCAAs with hypertension [159][160][161] highlights the need for further investigations to comprehensively understand the reprogramming effects of perinatal BCAA use, especially in the context of hypertension.…”

“…Numerous developmental programming models have been investigated, encompassing diverse approaches such as the following: the maternal protein restriction model [116,135], the maternal caloric restriction model [117,136], antenatal dexamethasone exposure [118], streptozotocin (STZ)-induced diabetes [119,126], the maternal N G -nitro-L-arginine-methylester (L-NAME) exposure model [120,133], maternal CKD [121,125,130,138], a maternal high-fat/high-fructose diet [122], the genetic hypertension model [62,129,130], a combination of antenatal dexamethasone and a postnatal high-fat diet [131], the suramin-induced preeclampsia model [132], maternal nicotine exposure [134], and a maternal and postweaning high-fat diet [137]. The primary focus in evaluating the components of CKM syndrome involves hypertension, followed by kidney disease, obesity, diabetes, and dyslipidemia.…”

“…Reprogramming effects have been observed through amino-acid-targeted therapies in rats ranging from 4 weeks to 50 weeks old, coarsely equivalent to human ages spanning from young children to middle adulthood [139]. Amino acid supplementation utilized as reprogramming interventions includes arginine [116], citrulline [62,[117][118][119][120][121], taurine [122][123][124][125][126][127][128][129], cysteine [130][131][132][133][134], glycine [135], BCAAs [136,137], and tryptophan [138]. The subsequent sections will delve into each of these aspects in detail.…”

“…There are other amino-acid-targeted interventions by which CKM phenotypes could be prohibited in adult progeny, such as supplementation with glycine [135], BCAAs [136,137], and tryptophan [138]. One study uncovered that perinatal glycine supplementation shields the offspring from hypertension induced by maternal low-protein intake [135].…”