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. 2018 Jan 12;10(1):76.
doi: 10.3390/nu10010076.

Gender-Associated Impact of Early Leucine Supplementation on Adult Predisposition to Obesity in Rats

Nora López  1 , Juana Sánchez  2 , Andreu Palou  3 , Francisca Serra  4
Affiliations

Gender-Associated Impact of Early Leucine Supplementation on Adult Predisposition to Obesity in Rats

Nora López et al. Nutrients. .

Abstract

Early nutrition plays an important role in development and may constitute a relevant contributor to the onset of obesity in adulthood. The aim of this study was to evaluate the long-term impact of maternal leucine (Leu) supplementation during lactation on progeny in rats. A chow diet, supplemented with 2% Leu, was supplied during lactation (21 days) and, from weaning onwards, was replaced by a standard chow diet. Then, at adulthood (6 months of age), this was replaced with hypercaloric diets (either with high-fat (HF) or high-carbohydrate (HC) content), for two months, to induce obesity. Female offspring from Leu-supplemented dams showed higher increases in body weight and in body fat (62%) than their respective controls; whereas males were somehow protected (15% less fat than the corresponding controls). This profile in Leu-females was associated with altered neuronal architecture at the paraventricular nucleus (PVN), involving neuropeptide Y (NPY) fibers and impaired expression of neuropeptides and factors of the mTOR signaling pathway in the hypothalamus. Interestingly, leptin and adiponectin expression in adipose tissue at weaning and at the time before the onset of obesity could be defined as early biomarkers of metabolic disturbance, predisposing towards adult obesity under the appropriate environment.

Keywords: biomarkers; leucine supplementation; metabolic imprinting; obesity; perinatal nutrition.

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Conflict of interest statement

The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Figures

Figure 1
Figure 1
Body weight, food intake and food preferences in offspring of rats supplemented with leucine during lactation. Left side panel (A,C,E,G) refers to female and right side panel (B,D,F,H) to male siblings. (A,B) Body weight over time in offspring from dams who received a dietary supplementation of Leu (2%) during lactation, in comparison with non-supplemented controls; (C,D) Lee’s index measured in adulthood (five months old); (E,F) Food intake from weaning to adulthood (fed with standard diet); (G,H) A food preference test was performed (165 days of age) allowing animals free-selection between a fat (FR) or sugary/carbohydrate (CR) enriched liquid diet. Anova: T (time), L (Leu), B (bottle composition). All data represent mean ± SEM. * p < 0.05, ** p < 0.01.
Figure 2
Figure 2
Glucose and insulin response to an oral glucose tolerance test (OGTT). Left side panel (A,C,E,G) refers to female and right side panel (B,D,F,H) to male siblings. (A,B) Glucose response to an OGTT in adult offspring from dams who received a dietary supplementation of Leu during lactation, in comparison with non-supplemented controls; (C,D) Glucose area under the curve (AUC); (E,F) Insulin levels during OGTT; (G,H) AUC for insulin. All data represent mean ± SEM. * p < 0.05, ** p < 0.01.
Figure 3
Figure 3
Body weight, body fat content and food intake in response to HF and HC diets. Left side panel (A,C,E,G) refers to female and right side panel (B,D,F,H) to male siblings. (A,B) Body weight over time associated with the period (3 months) of feeding with a hypercaloric diet, either high fat (HF) (squares) or high carbohydrate (HC) (circles); (C,D) Body weight gain after 3 months of feeding a hypercaloric diet; (E,F) Body fat content accumulated during the period of HF/HC diet; (G,H) Food intake along the period of HF/HC feeding. Anova: T (time), L (Leu vs. C), D (diet, HF vs. HC). All data represent mean ± SEM, n = 6, * p < 0.05 C vs. L.
Figure 4
Figure 4
Hypothalamic gene expression in response to HF and HC diets. (A) Gene expression of mTOR related factors; (B) Expression of neuropeptides associated with the control of energy balance; and (C) Gene expression of leptin-associated proteins. Analyses were performed in C and Leu animals at the end of the HF/HC feeding (at nine months of age). mRNA levels have been analyzed by RT-PCR. All data represent mean ± SEM. The insert with the correspondence between the bar color and the experimental groups applies to (A,B,C) panels. Relative expression of control males (C-HC) has been set at 100% and used as a reference for the data of the rest of groups. Anova: S (sex), L (Leu), D (diet, HF vs. HC). * p < 0.05, student’s t-test.
Figure 5
Figure 5
Pattern of correlations within hypothalamic neuropeptide expression in Leu-females in comparison with Leu-males. Linear relationships between the expressions of hypothalamic peptides were tested using Pearson’s correlation coefficients. Statistically significant correlations (p < 0.05) found are depicted. A continuous line between two peptides denotes the existence of a positive correlation in their expression in L-females, which was not present in L-males. A dotted line indicates that a negative correlation was found in L-males, which was not observed in L-females and a dashed-dotted line indicates that a positive correlation was found in L-males, which was not observed in L-females. Bold line shows the lack of response to Leu seen in females. The full set of data is shown in Table S2.
Figure 6
Figure 6
Expression of genes in the adipose tissue and hypothalamus at weaning. Expression of genes in (A) mesenteric adipose tissue and (B) hypothalamus at weaning in offspring from C and Leu-supplemented dams. mRNA have been analysed by RT-PCR. All data represent mean ± SEM. Relative expression of control males has been set at 100% and used to refer the data of the rest of groups. Anova: S (sex), L (Leu). * p < 0.05, ** p < 0.01, student’s t-test. Lep = leptin; Adipoq = Adiponectin; Ucp2 = uncoupling protein 2; Npy = Neuropeptide Y; Pomc = Pro-opiomelanocortin.
Figure 7
Figure 7
Morphometry of the paraventricular nucleus (PVN) and immunohistochemistry of NPY+ fibers at weaning. (A) PVN area, (B) number of neurons, (C) neuronal density, (D) innervation of neuropeptide Y (NPY+) fibers towards PVN and (E) representative brain sections immunostained for NPY in PVN. All data are from offspring (21 days of age) obtained from dams supplemented with Leu (L) during lactation and the corresponding sex-controls (C). All data represent mean ± SEM. * p < 0.05, student’s t-test.
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