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Cited by 141Birth, Development, and HealthCardiac Fibrosis and RemodelingCardiovascular Function and Risk Factors

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The Programming of Cardiac Hypertrophy in the Offspring by Maternal Obesity Is Associated with Hyperinsulinemia, AKT, ERK, and mTOR Activation

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Fernandez-Twinn, Denise S., Blackmore, Heather L., Siggens, Lee, Giussani, Dino A., Cross, Christine M., Foo, Roger, Ozanne, Susan E.·2012·Endocrinology
DOI 10.1210/en.2012-1508PMC PMC3568261
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Abstract

Human and animal studies suggest that suboptimal early nutrition during critical developmental periods impacts long-term health. For example, maternal overnutrition during pregnancy and lactation in mice programs insulin resistance, obesity, and endothelial dysfunction in the offspring. Here we investigated the effects of diet-induced maternal obesity on the offspring cardiac phenotype and explored potential underlying molecular mechanisms. Dams fed the obesogenic diet were heavier (P < 0.01) and fatter (P < 0.0001) than controls throughout pregnancy and lactation. There was no effect of maternal obesity on offspring body weight or body composition up to 8 wk of age. However, maternal obesity resulted in increased offspring cardiac mass (P < 0.05), increased heart-body weight (P < 0.01), heart weight-tibia length (P < 0.05), increased left ventricular free wall thickness and area (P < 0.01 and P < 0.05, respectively), and increased myocyte width (P < 0.001). Consistent with these structural changes, the expression of molecular markers of cardiac hypertrophy were also increased [Nppb(BNP), Myh7-Myh6(βMHC-αMHC) (both P < 0.05) and mir-133a (P < 0.01)]. Offspring were hyperinsulinemic and displayed increased insulin action through AKT (P < 0.01), ERK (P < 0.05), and mammalian target of rapamycin (P < 0.05). p38MAPK phosphorylation was also increased (P < 0.05), suggesting pathological remodeling. Increased Ncf2(p67(phox)) expression (P < 0.05) and impaired manganese superoxide dismutase levels (P < 0.01) suggested oxidative stress, which was consistent with an increase in levels of 4-hydroxy-2-trans-nonenal (a measure of lipid peroxidation). We propose that maternal diet-induced obesity leads to offspring cardiac hypertrophy, which is independent of offspring obesity but is associated with hyperinsulinemia-induced activation of AKT, mammalian target of rapamycin, ERK, and oxidative stress.

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Fig. 1. A, Maternal phenotype prepregnancy, postpregnancy, and weaning body weight. B, Offspring weekly body weights. Data are presented as means ± sem (n = 7 control, n = 9 Mat-Ob) and analyzed by unpaired two-tailed Student t test. ***, P < 0.001; **, P < 0.01; *, P < 0.05.
Fig. 1. A, Maternal phenotype prepregnancy, postpregnancy, and weaning body weight. B, Offspring weekly body weights. Data are presented as means ± sem (n = 7 control, n = 9 Mat-Ob) and analyzed by unpaired two-tailed Student t test. ***, P < 0.001; **, P < 0.01; *, P < 0.05.CC BY-NC · PubMed Central
Fig. 2. A, Combined left ventricular wall width (includes both the intraventricular septum and left ventricular free wall), left ventricular free wall only, and intraventricular septum only. Left ventricular free wall data were log transformed and an unpaired Student t test was performed. B, Frozen sections (5 μm) of cardiac tissue were stained with wheat germ agglutinin and imaged for measurements of myocyte width. Consecutive sections of the same representative images were then stained for hematoxylin-and-eosin-stained sections. Scale bar, 50 μm for all images. Only myocytes in longitudinal axis cross-section were measured and widths measured from a total of 80–100 cells from two separate images per sample. Open bars [control (Ctrl)] and filled bars (Mat-Ob). Data are expressed as means ± sem. RNA from ventricular tissue of control and Mat-Ob males at 8 wk of age (n = 7 and 9, respectively, in which one offspring represents one litter) was isolated, purified, and cDNA obtained by reverse transcription. C, Gene expression of Nppb, Nppa, Myh7, and Myh6 was quantified by real-time PCR using primers shown in Supplemental Table 1. All data were normalized to Gapdh as described in Materials and Methods. The ratio of Mhy7 to Myh6 was analyzed by a Mann-Whitney U test and presented as means ± interquartile ranges (n = 7 control and n = 9 Mat-Ob for all analyses). ***, P < 0.001; **, P < 0.01; *, P < 0.05.
Fig. 2. A, Combined left ventricular wall width (includes both the intraventricular septum and left ventricular free wall), left ventricular free wall only, and intraventricular septum only. Left ventricular free wall data were log transformed and an unpaired Student t test was performed. B, Frozen sections (5 μm) of cardiac tissue were stained with wheat germ agglutinin and imaged for measurements of myocyte width. Consecutive sections of the same representative images were then stained for hematoxylin-and-eosin-stained sections. Scale bar, 50 μm for all images. Only myocytes in longitudinal axis cross-section were measured and widths measured from a total of 80–100 cells from two separate images per sample. Open bars [control (Ctrl)] and filled bars (Mat-Ob). Data are expressed as means ± sem. RNA from ventricular tissue of control and Mat-Ob males at 8 wk of age (n = 7 and 9, respectively, in which one offspring represents one litter) was isolated, purified, and cDNA obtained by reverse transcription. C, Gene expression of Nppb, Nppa, Myh7, and Myh6 was quantified by real-time PCR using primers shown in Supplemental Table 1. All data were normalized to Gapdh as described in Materials and Methods. The ratio of Mhy7 to Myh6 was analyzed by a Mann-Whitney U test and presented as means ± interquartile ranges (n = 7 control and n = 9 Mat-Ob for all analyses). ***, P < 0.001; **, P < 0.01; *, P < 0.05.CC BY-NC · PubMed Central
Fig. 3. Gene expression was quantified by real-time PCR using primers shown in Supplemental Table 1, and all data were normalized to Gapdh. A–D, mir-133a, mir-1, p300, and Gata-4 expression. E, Gene expression of Srf and myocardin. F, Western blotting of SRF. G, Crossed-linked chromatin from ventricular tissue of control and Mat-Ob males was immunoprecipitated with anti-SRF, and enrichment of mir-133a SRF cis elements was quantified by quantitative PCR amplification of an approximately 100 bp amplicon around the two cis-elements. Open bars [control (Ctrl)] and filled bars (Mat-Ob). Data expressed as means ± sem (n = 7 control and n = 9 Mat-Ob for all analyses). **, P < 0.01; *, P < 0.05.
Fig. 3. Gene expression was quantified by real-time PCR using primers shown in Supplemental Table 1, and all data were normalized to Gapdh. A–D, mir-133a, mir-1, p300, and Gata-4 expression. E, Gene expression of Srf and myocardin. F, Western blotting of SRF. G, Crossed-linked chromatin from ventricular tissue of control and Mat-Ob males was immunoprecipitated with anti-SRF, and enrichment of mir-133a SRF cis elements was quantified by quantitative PCR amplification of an approximately 100 bp amplicon around the two cis-elements. Open bars [control (Ctrl)] and filled bars (Mat-Ob). Data expressed as means ± sem (n = 7 control and n = 9 Mat-Ob for all analyses). **, P < 0.01; *, P < 0.05.CC BY-NC · PubMed Central
Fig. 4. A, Fasting insulin concentration of serum. B, Fasting insulin concentration of fasting glucose to insulin ratio of control (Ctrl) and Mat-Ob males (n = 7 and n = 9, respectively). C–G, Protein lysates from ventricular tissue of control and Mat-Ob males (n = 7 and n = 9, respectively) were subject to SDS-PAGE and Western blotted and analyzed by band densitometry. The levels of insulin receptor-β subunit (IRβ), IRS-1, phospho-IRS-1 Ser307, PI3K catalytic subunit p110β, and PI3K regulatory subunit p85α are expressed as a percentage relative to chow-fed control means ± sem (n = 7 control and n = 9 Mat-Ob for all analyses). **, P < 0.01; *, P < 0.05.
Fig. 4. A, Fasting insulin concentration of serum. B, Fasting insulin concentration of fasting glucose to insulin ratio of control (Ctrl) and Mat-Ob males (n = 7 and n = 9, respectively). C–G, Protein lysates from ventricular tissue of control and Mat-Ob males (n = 7 and n = 9, respectively) were subject to SDS-PAGE and Western blotted and analyzed by band densitometry. The levels of insulin receptor-β subunit (IRβ), IRS-1, phospho-IRS-1 Ser307, PI3K catalytic subunit p110β, and PI3K regulatory subunit p85α are expressed as a percentage relative to chow-fed control means ± sem (n = 7 control and n = 9 Mat-Ob for all analyses). **, P < 0.01; *, P < 0.05.CC BY-NC · PubMed Central
Fig. 5. Protein lysates from ventricular tissue of control and Mat-Ob males (n = 7 and n = 9, respectively) were subject to SDS-PAGE and Western blotted and analyzed by band densitometry. A, D, G, and J, Total AKT, ERK1/2, mTOR, and p38MAPK. B, E, H, and K, Phospho-AKT1 Ser 473, phospho-ERK1/2, phospho-mTOR, and phospho-p38MAPK are expressed as a percentage relative to chow-fed control means ± sem. C, F, I, and L, Ratios of phosphoprotein to total protein (n = 7 control and n = 9 Mat-Ob for all analyses). **, P < 0.01; *, P < 0.05.
Fig. 5. Protein lysates from ventricular tissue of control and Mat-Ob males (n = 7 and n = 9, respectively) were subject to SDS-PAGE and Western blotted and analyzed by band densitometry. A, D, G, and J, Total AKT, ERK1/2, mTOR, and p38MAPK. B, E, H, and K, Phospho-AKT1 Ser 473, phospho-ERK1/2, phospho-mTOR, and phospho-p38MAPK are expressed as a percentage relative to chow-fed control means ± sem. C, F, I, and L, Ratios of phosphoprotein to total protein (n = 7 control and n = 9 Mat-Ob for all analyses). **, P < 0.01; *, P < 0.05.CC BY-NC · PubMed Central
Fig. 6. A–D, Protein lysates from ventricular tissue of control and Mat-Ob males (n = 7 and n = 9, respectively) were subject to SDS-PAGE and Western blotted and analyzed by band densitometry. The levels of MnSOD, catalase, and SIRT3 are expressed as a percentage relative to chow-fed control means ± sem. Phosphorylation level of FOXO3a is presented as a ratio to total FOXO3a protein levels; means ± sem (n = 7 control and n = 9 Mat-Ob for all analyses. **, P < 0.01; *, P < 0.05.
Fig. 6. A–D, Protein lysates from ventricular tissue of control and Mat-Ob males (n = 7 and n = 9, respectively) were subject to SDS-PAGE and Western blotted and analyzed by band densitometry. The levels of MnSOD, catalase, and SIRT3 are expressed as a percentage relative to chow-fed control means ± sem. Phosphorylation level of FOXO3a is presented as a ratio to total FOXO3a protein levels; means ± sem (n = 7 control and n = 9 Mat-Ob for all analyses. **, P < 0.01; *, P < 0.05.CC BY-NC · PubMed Central

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Metadata

Authors
Fernandez-Twinn, D. S., Blackmore, H. L., Siggens, L., Giussani, D. A., Cross, C. M., Foo, R., & Ozanne, S. E.
Affiliations
  • Metabolic Research Laboratories (D.S.F.-T., H.L.B., S.E.O.), University of Cambridge, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom
  • University of Cambridge (GB)
ORCID
Venue
Endocrinology
Publisher
The Endocrine Society
Published
2012-12-01
Volume
153
Issue
12
Pages
5961-5971
ISSN
  • 0013-7227 (ISSN-L)
  • 1945-7170
DOI
10.1210/en.2012-1508
PMC
PMC3568261
OpenAlex
W2075074527
Cited by
141
References
43
Citations by year
2026: 4 · 2025: 8 · 2024: 5 · 2023: 8 · 2022: 17 · 2021: 7 · 2020: 10 · 2019: 7 · 2018: 18 · 2017: 9 · 2016: 14 · 2015: 11 · 2014: 13 · 2013: 10
FWCI
9.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Endocrinology (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • Wellcome Trust (EU-FP7-, 086797, 086797/Z/08/Z)
  • British Heart Foundation (FS/09/050, FS/09/029/27902)
  • European Commission (289346)
  • Directorate for Biological Sciences
  • Medical Research Council (EU FP7)
  • Biotechnology and Biological Sciences Research Council (BB/F015364/1)
Topics
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
Keywords
maternal obesity, diet-induced obesity, cardiac hypertrophy, hyperinsulinemia, Akt signaling, ERK signaling, mTOR signaling, p38 MAPK, oxidative stress, manganese superoxide dismutase, lipid peroxidation, cardiomyocyte hypertrophy, developmental programming, cardiac remodeling
MeSH terms
Animals, Body Composition, Body Weight, Female, Cardiomegaly, Hyperinsulinism, Male, Mice, Inbred C57BL, Mothers, Obesity, Phenotype, Pregnancy, Pregnancy, Animal, Prenatal Exposure Delayed Effects, Lipid Peroxidation, Oxidative Stress, Maternal Nutritional Physiological Phenomena, Extracellular Signal-Regulated MAP Kinases, Proto-Oncogene Proteins c-akt, Mice, TOR Serine-Threonine Kinases

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