Maternal Chromium Restriction Leads to Glucose

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International Journal of

Molecular Sciences Article

Maternal Chromium Restriction Leads to Glucose Metabolism Imbalance in Mice Offspring through Insulin Signaling and Wnt Signaling Pathways Qian Zhang 1 , Xiaofang Sun 2 , Xinhua Xiao 1, *, Jia Zheng 1 , Ming Li 1 , Miao Yu 1 , Fan Ping 1 , Zhixin Wang 1 , Cuijuan Qi 1 , Tong Wang 1 and Xiaojing Wang 1 1

2

*

Key Laboratory of Endocrinology, Translational Medicine Centre, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China; [email protected] (Q.Z.); [email protected] (J.Z.); [email protected] (M.L.); [email protected] (M.Y.); [email protected] (F.P.); [email protected] (Z.W.); [email protected] (C.Q.); [email protected] (T.W.); [email protected] (X.W.) Department of Endocrinology, The Affiliated Hospital of Qingdao University, Qingdao 266003, China; [email protected] Correspondence: [email protected]; Tel./Fax: +86-10-6915-5073

Academic Editor: Charles J. Malemud Received: 24 August 2016; Accepted: 17 October 2016; Published: 22 October 2016

Abstract: An adverse intrauterine environment, induced by a chromium-restricted diet, is a potential cause of metabolic disease in adult life. Up to now, the relative mechanism has not been clear. C57BL female mice were time-mated and fed either a control diet (CD), or a chromium-restricted diet (CR) throughout pregnancy and the lactation period. After weaning, some offspring continued the diet diagram (CD-CD or CR-CR), while other offspring were transferred to another diet diagram (CD-CR or CR-CD). At 32 weeks of age, glucose metabolism parameters were measured, and the liver from CR-CD group and CD-CD group was analyzed using a gene array. Quantitative real-time polymerase chain reaction (qPCR) and Western blot were used to verify the result of the gene array. A maternal chromium-restricted diet resulted in obesity, hyperglycemia, hyperinsulinemia, increased area under the curve (AUC) of glucose in oral glucose tolerance testing and homeostasis model assessment of insulin resistance (HOMA-IR). There were 463 genes that differed significantly (>1.5-fold change, p < 0.05) between CR-CD offspring (264 up-regulated genes, 199 down-regulated genes) and control offspring. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) analysis revealed that the insulin signaling pathway and Wnt signaling pathway were in the center of the gene network. Our study provides the first evidence that maternal chromium deficiency influences glucose metabolism in pups through the regulation of insulin signaling and Wnt signaling pathways. Keywords: development programming; gene expression; glucose metabolism; insulin signaling pathway; Wnt pathway

1. Introduction Diet has important health effects at any stage of life, but nutrition during fetal and early postnatal life is particularly important for later life, even throughout the whole life. Increasing evidence suggests that the occurrence of diabetes is related to nutrition status in fetus period [1–4]. Growing evidence proves that under-nutrition in early life is an important risk of metabolic disease in later life [5,6]. The nutrition status of mothers will affect children’s health for a long period. Malnutrition in this sensitive window may lead the occurrence of metabolic disorder in later life [7,8]. Offspring gene Int. J. Mol. Sci. 2016, 17, 1767; doi:10.3390/ijms17101767

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changes in this sensitive window are a long-term effect, as they remain in adult life even when dietetic recovery occurs [9]. Damage this time will disturb gene expression for aOffspring long time. in this sensitive windowduring may lead thesensitive occurrence of metabolic disorder in later life [7,8]. Besides proteins, and carbohydrates, alsoasare necessary the human body. gene changes in fats, this sensitive window aremicronutrients a long-term effect, they remain for in adult life even Although we just need them in trace or tiny during amounts some chromium, when dietetic recovery occurs [9]. Damage thisdaily, sensitive timemicronutrients will disturb gene(zinc, expression for a long copper, time. iron, and potassium) are proven to have an important role in mediation of glucose magnesium, Besides proteins, fats,can andreduce carbohydrates, micronutrients arein necessary the human metabolism. [10]. Chromium fasting blood glucose also levels diabeticfor patients andbody. diabetic Although we just need them in trace or tiny amounts daily, some micronutrients (zinc, chromium, rodent models [11], and enhance insulin action, including activation of insulin receptor sites [12]. magnesium, copper, iron, and potassium) are proven to have an important role in mediation of Diabetic animals [13] and patients [14,15] have lower chromium levels than that of controls. Chromium glucose metabolism. [10]. Chromium can reduce fasting blood glucose levels in diabetic patients and deficiency is common among our population. Chromium levels decrease with advancing age, both diabetic rodent models [11], and enhance insulin action, including activation of insulin receptor sites in type 2 diabetic patients and normal subjects [16]. A recent study reported that Wistar of National [12]. Diabetic animals [13] and patients [14,15] have lower chromium levels than that of controls. Institute of Nutrition (WNIN) rats born from chromium resistance Chromium deficiency is common among our population.restriction Chromiumdams levelsshowed decrease insulin with advancing and glucose intolerance. Increased oxidative stress was one underlying mechanism [16]. age, both in type 2 diabetic patients and normal subjects [16]. A recent study reported that Wistar of However, genome-wide study has been conducted to look for key genes andshowed pathways which National no Institute of Nutrition (WNIN) rats born from chromium restriction dams insulin resistance and glucose intolerance.restriction Increased oxidative stressgenome. was one underlying [16]. the are affected by maternal chromium in the whole Therefore,mechanism we employed However, no genome-wide studyall hasgene been expression conducted toin look for key genes and that pathways which whole genomic microarray to quantify adult mice livers had maternal are to affected by maternal chromium restriction inthat the whole genome. employed the in exposure chromium restriction. We hypothesized there might be Therefore, some key we genes/pathways whole genomic microarray to quantify all gene expression in adult mice livers that had maternal the liver which are affected by maternal chromium restriction. The aim of this research is to identify exposure to chromium restriction. We hypothesized that there might be some key genes/pathways the key genes/pathways in the liver, which are responsible for generating programmed glucose in the liver which are affected by maternal chromium restriction. The aim of this research is to identify metabolism disorder. the key genes/pathways in the liver, which are responsible for generating programmed glucose metabolism disorder.

2. Results

2. Results

2.1. Dams

Dams At2.1. weaning, body weight (22.1 ± 2.5 g vs. 22.8 ± 3.1 g, n = 8 per group) and fasting blood glucose (5.9At±weaning, 0.8 mmol/L 6.1 ±(22.1 1.2 mmol/L, = 8 per mother mice notblood affected bodyvs. weight ± 2.5 g vs.n 22.8 ± 3.1group) g, n = in 8 per group) andwere fasting glucose (5.9 ± 0.8 mmol/L vs. 6.1 serum ± 1.2 mmol/L, n = 8 concentrations per group) in mother were affected by CR by chromium restriction. However, chromium weremice lower (p not < 0.01) in the chromium restriction. However, serum chromium werethan lower (p in < 0.01) in the CR (chromium-restricted diet) group (0.33 ± 0.04 ng/mL,concentrations n = 8 per group) that CD (control diet) (chromium-restricted diet) group (0.33 ± 0.04 ng/mL, n = 8 per group) than that in CD (control diet) group (0.75 ± 0.12 ng/mL, n = 8 per group). group (0.75 ± 0.12 ng/mL, n = 8 per group).

2.2. Pups

2.2. Pups

2.2.1. Serum Chromium Concentration

2.2.1. Serum Chromium Concentration

As expected, CD-CR (pups born from control diet dams were fed with chromium restriction diet As expected, CD-CR (pups born from control diet dams were fed with chromium restriction diet from weaning) and CR-CR (pups born from chromium restriction dams were fed with chromium from weaning) and CR-CR (pups born from chromium restriction dams were fed with chromium restriction diet from pups had lower concentrations than controls (p < 0.01, restriction dietweaning) from weaning) pups had serum lower chromium serum chromium concentrations than controls Figure (p 1a), whereas CR-CD (pups born from chromium restriction dams were fed with control < 0.01, Figure 1a), whereas CR-CD (pups born from chromium restriction dams were fed withdiet from weaning) pups caught up pups with caught controls 32 weeks (Figure control diet from weaning) upatwith controlsofatage 32 weeks of 1a). age (Figure 1a).

Figure 1. Cont.

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Figure 1. Serum chromium level week 32; 32; body body weight day (b);(b); week 3 (c);3 and weekweek Figure 1. Serum chromium level (a)(a)atatweek weightononbirth birth day week (c); and 32 (d); food intake (e); fasting blood glucose (FBG) at week 3 (f) and week 32 (g); and blood glucose 32 (d); food intake (e); fasting blood glucose (FBG) at week 3 (f) and week 32 (g); and blood glucose in oral glucose tolerance test (OGTT) (h) and blood glucose area under the curve (AUC) (i) in OGTT, in oral glucose tolerance test (OGTT) (h) and blood glucose area under the curve (AUC) (i) in OGTT, fasting insulin (j) and homeostasis model assessment of insulin resistance (HOMA-IR) (k) at week 32 fasting insulin (j) and homeostasis model assessment of insulin resistance (HOMA-IR) (k) at week 32 in male offspring. CD, control diet; CR: chromium restriction. Each bar represents the mean ± SD. For in male offspring. controlfordiet; CR: restriction. Each bar represents the mean ± SD. (a,d,e,g–j), n = 8CD, per group; (b,c,f), n =chromium 16 per group. * p < 0.05, ** p < 0.01 For (a,d,e,g–j), n = 8 per group; for (b,c,f), n = 16 per group. * p < 0.05, ** p < 0.01. 2.2.2. Body Weight and Food Intake

2.2.2. Body Weight Intake Despite theand birthFood weight and weaning weight being comparable in different groups, at 32 weeks of age, male offspring body weight in CD-CR, and CR-CR in groups was groups, higher than Despite the birth weight and weaning weightCR-CD, being comparable different at 32the weeks CD-CD (pups born from control diet dams were fed with control diet from weaning) group (p < 0.05, of age, male offspring body weight in CD-CR, CR-CD, and CR-CR groups was higher than the Figure 1b–d). However, food intake was comparable among the four groups at 32 weeks of age CD-CD (pups born from control diet dams were fed with control diet from weaning) group (p < 0.05, (Figure 1e). Figure 1b–d). However, food intake was comparable among the four groups at 32 weeks of age (Figure 1e).

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2.2.3.Int. Fasting Blood Glucose and Glucose Tolerance J. Mol. Sci. 2016, 17, 1767

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In postnatal week 3, fasting blood glucose level was comparable between CR and CD groups 2.2.3. Fasting Blood Glucose and Glucose Tolerance (Figure 1f). In postnatal week 32, male CR-CR offspring had significantly higher fasting blood glucose postnatal 3, fastingregimen blood glucose comparable between CR andtoCD groupslevels (p < 0.05, In Figure 1g).week The CR-CD couldlevel not was correct fasting blood glucose normal (Figure 1f). In postnatal week 32, male CR-CR offspring had significantly higher fasting blood glucose (p < 0.05, Figure 1g). Glucose tolerance was assessed by an oral glucose tolerance test in the offspring < 0.05, Figure 1g). The CR-CD regimen could not correct fasting blood glucose to normal levels at 32 (p weeks of age. Blood glucose was higher in the CR-CR group and in the CD-CR group before (p < 0.05, Figure 1g). Glucose tolerance was assessed by an oral glucose tolerance test in the offspring and 30, 60, and 120 min after oral glucose gavage than that in the CD-CD group (p < 0.05 or p < 0.01, at 32 weeks of age. Blood glucose was higher in the CR-CR group and in the CD-CR group before Figure 1h). In the CR-CD group, blood glucose was higher than the CD-CD group before and 60 and and 30, 60, and 120 min after oral glucose gavage than that in the CD-CD group (p < 0.05 or p < 0.01, 120 min after oral glucose gavage < 0.05 or p

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