The insulin-signaling pathway of the pancreatic islet is impaired in adult mice offspring of mothers fed a high-fat diet

doi:10.1016/j.nut.2016.03.001

Nutrition

Volume 32, Issue 10, October 2016, Pages 1138-1143

https://doi.org/10.1016/j.nut.2016.03.001 Get rights and content

Highlights

•
Maternal high-fat diet (MHF) leads to remodeling altering the natural disposition of alpha / beta cells in pancreatic islet of male offspring in adulthood.
•
MHF causes alpha / beta cell hyperplasia as an adaptive response to hyperglycemia in pancreatic islet of male offspring in adulthood.
•
MHF impairs insulin-signaling pathway in pancreatic islet of male offspring in adulthood.

Abstract

Objective

Mothers fed a high-fat (HF) diet can cause different adverse alterations in their offspring. The study aimed to verify the pancreatic islet structure and insulin-signaling pathway in adulthood of offspring of mothers fed a HF diet during the pregnancy.

Methods

Female mice (mothers) were randomly assigned to receive either standard chow (Mo-SC) or a HF diet (Mo-HF) ad libitum. After 2 mo on the experimental diets, 3-mo-old female mice were mated with male C57 BL/6 mice that were fed a SC diet. The male offspring was evaluated at 6 mo old.

Results

At 6 mo of age, Mo-HF offspring had an increment in body mass and adiposity, hypercholesterolemia, and hypertriacylglycerolemia, higher levels of insulin, and leptin with a concomitant decrease in adiponectin levels. In the islet, we observed an alteration in the structure characterized by the migration of some alpha cells from the edge to the core of the islet in association with an increase in the masses of the islet, beta cell, and alpha cell, featuring a pancreatic islet remodeling. Additionally, the Mo-HF offspring demonstrated a decrease in IRS1, PI3 k p-Akt, Pd-1, and Glut2 protein expressions compared to Mo-SC offspring. However, an increase was observed in FOXO1 and insulin protein expressions in Mo-HF offspring compared to Mo-SC offspring.

Conclusion

The present study demonstrated that a maternal HF diet is responsible for remodeling the islet structure coupled with an adverse carbohydrate metabolism and impairment of the insulin-signaling pathway in adult male mice offspring.

Graphical abstract

Maternal high-fat diet alters insulin-signaling in the pancreas (Akt-PI3 k pathway) of offspring in adulthood, resulting in a framework of beta cell dysfunction. The insulin-signaling activation needs an insulin receptor substrate (IRS1) in beta cells, which was decreased in the Mo-HF offspring, featuring a downregulation of the Akt-PI3 k signaling. With the impairment of the pathway, FOXO1 is overexpressed, resulting in Pdx-1 inhibition impairing the regulation of genes, such as Glut2. Adult offspring from mother fed HF diet during pregnancy showed beta cell dysfunction with compensatory hypersecretion of insulin and hyperglycemia. Up-arrows (↑) indicate an increase in protein expression and down-arrows (↓) indicate a decrease in protein expression. Forkhead box protein O1 (FOXO1); glucose transporter 2 (GLUT2); insulin receptor substrate 1 (IRS1); phosphatidylinositide 3-kinase (PI3 K); pyruvate dehydrogenase kinase (PDK1); protein kinase B (PKB), also known as Akt, is a serine/threonine-specific protein kinase; pancreatic and duodenal homeobox 1(Pdx1).

Introduction

The animal model supports the concept that a high-fat (HF) diet is associated with an adverse metabolic outcome featuring by dyslipidemia, overweight/obesity, and insulin resistance (IR) [1]. Moreover, the effects of a HF diet during critical periods of development have a direct action on the failure of the pancreatic beta cells, resulting in the appearance of IR and type 2 diabetes mellitus (DM2) [2], [3].

The IR development is followed by hyperglycemia, inflammatory cytokines, and free fatty acids circulating, which impair glucose-stimulated-insulin secretion [4], [5], [6].

Several studies have found the impact of maternal programming of insulin signaling in target organs in the offspring. It has been demonstrated impairment of hepatic insulin signaling pathway [7], as well skeletal muscle IR in mice offspring, associated with oxidative stress in this tissue [8]. Studies relating maternal low-protein diet and pancreatic alterations in offspring indicate defects of insulin secretion and glucose homeostasis [9], [10], but the insulin signaling pathway in the pancreas of offspring is still a scarce theme in literature.

It is well described that the phosphoinositide 3-kinase (PI3 K) has a critical role in the metabolic action of insulin [11]. Previous data have shown that a disruption in insulin-PI3 K signaling may induce a development of beta cell dysfunction, leading to the onset of IR and consequently DM2 [6], [12].

The initiation of IR is characterized by a decrease in receptor concentration and kinase activity. In addition, the concentration and phosphorylation of IRS-1 and -2, PI3 K activity, glucose transporter translocation, and the activity of intracellular enzymes also decrease in the IR and DM2 framework [13].

In this context, the aim of the present study was to verify if the maternal HF diet programming induces beta cell failure couple with insulin signaling is impaired as mice mature in later life.

Section snippets

Animals and diets

Female C57 BL/6 mice were taken immediately after weaning and kept under controlled temperature (21 ± 2°C) and humidity (60 ± 10%) with free access to food and water on a 12/12-h light/dark cycle. The experimental protocol was approved by the Ethics Committee of the State University of Rio de Janeiro (protocol CEUA 070/2012) and followed the rules established in the current guideline for experimentation with animals (NIH Publication No. 85-23, revised 1996).

The animals were randomly assigned to

Results

Six months old Mo-HF offspring were heavier than Mo-SC offspring at the same age (+20%; Table 2). Consequently, Mo-HF group showed a greater adiposity index than Mo-SC group (+61%; Table 2). It is important to reinforce that both groups (Mo-HF and Mo-SC) were fed the control diet after weaning. The difference between the two groups is associated with the hyperphagia observed in the Mo-HF group with consequent greater energy intake in comparison to the Mo-SC offspring (+37%, Table 2).

The AUC in

Discussion

The present study demonstrated that a maternal HF diet programming yielded an increase in BM, adiposity index, feed consumption, hyperinsulinemia, hyperleptinemia, and a decrease in adiponectin levels in mice offspring. In addition, the programmed offspring demonstrated hypercholesterolemia and elevated triacylglycerol level framework as well as an increase in islet and beta cell mass, coupled with an alteration of insulin signaling pathway.

Diet-induced obese mother programs the offspring to

Conclusion

The current result with a diet-induced maternal obesity model demonstrated an insult in the offspring; even the offspring being fed a standard chow after weaning. The Mo-HF offspring at 6 mo of age had an increase in the masses of the islet, beta, and alpha cells, characterizing a pancreatic islet remodeling. Additionally, the present study described an impaired insulin signaling pathway, featuring a beta cell dysfunction in adulthood in the male mice offspring.

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Emergence of ageing-related changes in insulin secretion by pancreatic islets of male rat offspring of mothers fed a low-protein diet

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The literature is wide about the matter, and much is discussed about the effect of high-fat diet intake during gestation and lactation on the offspring, a phenomenon known as fetal programming (Desai et al., 2014; Umekawa et al., 2015). Maternal high-fat diet intake during critical periods of body development compromise key metabolic organs such as the liver, adipose tissue (Almeida et al., 2017; Gregorio et al., 2010), and pancreas (Bringhenti et al., 2016; Gregorio et al., 2013), as well as important organs such as the heart and the kidneys (Kruse et al., 2017). Likewise, parental administration of these diets has increased the incidence of aging-related prostatic diseases (Tikoo et al., 2017).
We investigated the effect of a high-fat diet on body metabolism and ventral prostate morphology in 4-months-old offspring. The mother was fed with a control (C) or a high-fat (HF) diet during gestation and lactation. At weaning, the offspring diet remained the same (C/C, n = 8; HF/HF, n = 8) or it was switched (C/HF, n = 8; HF/C, n = 9). Biometry, blood pressure (BP), glucose, lipid metabolism and ventral prostate were evaluated. Triacylglycerol of HF/C increased, and the C/HF group had decreased HDL-c levels (P = 0.0005 and P = 0.0100, respectively). All groups on the HF diet presented hyperglycemia (P = 0.0064). Serum testosterone diminished in the C/HF group (P = 0.0218). The HF diet, regardless of the period, reduced prostatic acinar area (P < 0.0001). The epithelium height was smaller in HF/C and HF/HF groups compared with C/C and C/HF (P < 0.0001), and the volume density of epithelium was lower in HF/C group compared with the C/C and C/HF (P = 0.0024). The volume density of smooth muscle cells diminished in C/HF and HF/C (P = 0.0013), and the volume density of connective tissue was reduced in HF/C and HF/HF (P < 0.0001). High-fat diet intake during prenatal and postnatal life leads to prostatic atrophy, which may impair prostate secretory activity and contractility, and thus disturb reproductive function in adulthood.
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Rodents have been a great model to investigate the effects of maternal overnutrition on the pancreatic β cell. Upon exposure to maternal HF diet, offspring were found to have sex-dependent phenotypes in islet remodeling [3,6]. Only the male offspring displayed enlarged islet area indicating increased oxidative stress in islets [3,6].
Novel progress has been made to understand the adverse pathophysiology in the pancreas of offspring exposed to overnutrition in utero. Our study is the first to evaluate whether the adverse effects of maternal overnutrition on offspring β-cell function are reversible or preventable through preconception maternal diet interventions. Herein, offspring mice were exposed in utero to one of the following: maternal normal-fat diet (NF group), maternal high-fat diet (HF group) or maternal diet transition from an HF to NF diet 9 weeks before pregnancy (H9N group). Offspring mice were subjected to postweaning HF diet for 12 weeks. HF offspring, but not H9N, displayed glucose intolerance and insulin resistance. HF male offspring had enlarged islet β-cells with reduced β-cell density, whereas, H9N male offspring did not show these changes. Co-immunofluorescent (Co-IF) staining of glucose transporter 2 (Glut2) and insulin (Ins) revealed significantly more Glut2⁺Ins⁻ cells, indicative of insulin degranulation, in HF male offspring but not H9N. In addition, Co-IF of insulin and p-H3S10 indicated that β cells of HF male offspring, but not H9N, had proliferation defects likely due to inhibited protein kinase B (AKT) phosphorylation. In summary, our study demonstrates that maternal H9N diet effectively prevents functional deterioration of β cells seen in HF male offspring by avoiding β-cell proliferation defects and degranulation.
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: The authors would like to thank Ms. Aline Penna, Ms. Thatiany Marinho, Ms. Michele Soares, and Ms. Gezileia Lau for their technical assistance. This research was supported by the Brazilian agencies CNPq (Brazilian Council of Science and Technology, www.cnpq.br, grant #302.154/2011-6 to CAML, and #306.077/2013-2 to MBA), FAPERJ (Rio de Janeiro Foundation for Research, www.faperj.br, grant #102.944/2011 to CAML, and #103.062/2011 to MBA), and CAPES (Coordination for Perfectionnement of Superior Personal, www.capes.br), scholarship to IB. The authors disclose no other conflicts of interest in this research.

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Basic nutritional investigationThe insulin-signaling pathway of the pancreatic islet is impaired in adult mice offspring of mothers fed a high-fat diet

Highlights

Abstract

Objective

Methods

Results

Conclusion

Graphical abstract

Introduction

Section snippets

Animals and diets

Results

Discussion

Conclusion

J Nutr

J Nutr

Life Sci

A mouse model of metabolic syndrome: Insulin resistance, fatty liver and non-alcoholic fatty pancreas disease (NAFPD) in C57 BL/6 mice fed a high fat diet

J Clin Biochem Nutr

Compromised beta-cell development and beta-cell dysfunction in weanling offspring from dams maintained on a high-fat diet during gestation

Pancreas

Maternal obesity during the preconception and early life periods alters pancreatic development in early and adult life in male mouse offspring

PLoS One

Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin

J Clin Endocrinol Metab

Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes

Diabetes

Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: Evidence that beta-cell death is caspase-mediated, partially dependent on ceramide pathway, and Bcl-2 regulated

Diabetes

Differential effects of maternal obesity and weight loss in the periconceptional period on the epigenetic regulation of hepatic insulin-signaling pathways in the offspring

FASEB J

Emergence of ageing-related changes in insulin secretion by pancreatic islets of male rat offspring of mothers fed a low-protein diet

Br J Nutr

Maternal diet-induced microRNAs and mTOR underlie beta cell dysfunction in offspring

J Clin Invest

IRS-1 activates phosphatidylinositol 3'-kinase by associating with src homology 2 domains of p85

Proc Natl Acad Sci U S A

Beta-cell-specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter beta-cell mass

Nat Genet

Signaling pathways in insulin action: Molecular targets of insulin resistance

J Clin Invest

The anogenital distance index of mice (Mus musculus domesticus): An analysis

Contemp Top Lab Anim Sci

Weight cycling enhances adipose tissue inflammatory responses in male mice

PLoS One

A counting method for measuring volumes of tissue components in microscopical aections

Q J Microsc Sci

Stereological tools in biomedical research

An Acad Bras Cienc

Basic nutritional investigation
The insulin-signaling pathway of the pancreatic islet is impaired in adult mice offspring of mothers fed a high-fat diet