Fetal hyperglycemia changes human preadipocyte function in adult life

Ninna Schiøler Hansen; Klaudia Stanislawa Strasko; Line Hjort; Louise Kelstrup; Azadeh Houshmand-ØRegaard; Maren Schrölkamp; Heidi Schiøler Schultz; Camilla Scheele; Bente Klarlund Pedersen; Charlotte Ling; Tine Dalsgaard Clausen; Peter Damm; Allan Vaag; Christa Broholm

doi:10.1210/jc.2016-3907

Fetal hyperglycemia changes human preadipocyte function in adult life

Ninna Schiøler Hansen^*, Klaudia Stanislawa Strasko, Line Hjort, Louise Kelstrup, Azadeh Houshmand-ØRegaard, Maren Schrölkamp, Heidi Schiøler Schultz, Camilla Scheele, Bente Klarlund Pedersen, Charlotte Ling, Tine Dalsgaard Clausen, Peter Damm, Allan Vaag, Christa Broholm

^*Corresponding author for this work

Department of Clinical Medicine

15 Citations (Scopus)

Abstract

Context: Offspring of women with gestational diabetes (O-GDM) or type 1 diabetes mellitus (O-T1DM) have been exposed to hyperglycemia in utero and have an increased risk of developing metabolic disease in adulthood. Design: In total, we recruited 206 adult offspring comprising the two fetal hyperglycemic groups, O-GDM and O-T1DM, and, as a control group, offspring from the background population (O-BP). Subcutaneous fat biopsies were obtained and preadipocyte cell cultures were established from adult male O-GDM (n = 18, age 30.1 ± 2.5 years), O-T1DM (n = 18, age 31.6 ± 2.2 years), and O-BP (n = 16; age, 31.5 ± 2.7 years) and cultured in vitro. Main Outcome Measures: First, we studied in vivo adipocyte histology. Second, we studied in vitro preadipocyte leptin secretion, gene expression, and LEP DNA methylation. This was studied in combination with in vitro preadipocyte lipogenesis, lipolysis, and mitochondrial respiration. Results: We show that subcutaneous adipocytes from O-GDM are enlarged compared with O-BP adipocytes. Preadipocytes isolated from male O-GDM and O-T1DM and cultured in vitro displayed decreased LEP promoter methylation, increased leptin gene expression, and elevated leptin secretion throughout differentiation, compared with adipocytes established from male O-BP. In addition, the preadipocytes demonstrated functional defects including decreased maximal mitochondrial capacity with increased lipolysis and decreased ability to store fatty acids when challenged with 3 days of extra fatty acid supply. Conclusions: Taken together, these findings show that intrinsic epigenetic and functional changes exist in preadipocyte cultures from individuals exposed to fetal hyperglycemia who are at increased risk of developing metabolic disease.

Original language	English
Journal	Journal of Clinical Endocrinology and Metabolism
Volume	102
Issue number	4
Pages (from-to)	1141-1150
Number of pages	10
ISSN	0021-972X
DOIs	https://doi.org/10.1210/jc.2016-3907
Publication status	Published - 1 Apr 2017

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Hansen, N. S., Strasko, K. S., Hjort, L., Kelstrup, L., Houshmand-ØRegaard, A., Schrölkamp, M., Schultz, H. S., Scheele, C., Pedersen, B. K., Ling, C., Clausen, T. D., Damm, P., Vaag, A., & Broholm, C. (2017). Fetal hyperglycemia changes human preadipocyte function in adult life. Journal of Clinical Endocrinology and Metabolism, 102(4), 1141-1150. https://doi.org/10.1210/jc.2016-3907

Hansen, NS, Strasko, KS, Hjort, L, Kelstrup, L, Houshmand-ØRegaard, A, Schrölkamp, M, Schultz, HS, Scheele, C, Pedersen, BK, Ling, C, Clausen, TD, Damm, P , Vaag, A & Broholm, C 2017, 'Fetal hyperglycemia changes human preadipocyte function in adult life', Journal of Clinical Endocrinology and Metabolism, vol. 102, no. 4, pp. 1141-1150. https://doi.org/10.1210/jc.2016-3907

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title = "Fetal hyperglycemia changes human preadipocyte function in adult life",

abstract = "Context: Offspring of women with gestational diabetes (O-GDM) or type 1 diabetes mellitus (O-T1DM) have been exposed to hyperglycemia in utero and have an increased risk of developing metabolic disease in adulthood. Design: In total, we recruited 206 adult offspring comprising the two fetal hyperglycemic groups, O-GDM and O-T1DM, and, as a control group, offspring from the background population (O-BP). Subcutaneous fat biopsies were obtained and preadipocyte cell cultures were established from adult male O-GDM (n = 18, age 30.1 ± 2.5 years), O-T1DM (n = 18, age 31.6 ± 2.2 years), and O-BP (n = 16; age, 31.5 ± 2.7 years) and cultured in vitro. Main Outcome Measures: First, we studied in vivo adipocyte histology. Second, we studied in vitro preadipocyte leptin secretion, gene expression, and LEP DNA methylation. This was studied in combination with in vitro preadipocyte lipogenesis, lipolysis, and mitochondrial respiration. Results: We show that subcutaneous adipocytes from O-GDM are enlarged compared with O-BP adipocytes. Preadipocytes isolated from male O-GDM and O-T1DM and cultured in vitro displayed decreased LEP promoter methylation, increased leptin gene expression, and elevated leptin secretion throughout differentiation, compared with adipocytes established from male O-BP. In addition, the preadipocytes demonstrated functional defects including decreased maximal mitochondrial capacity with increased lipolysis and decreased ability to store fatty acids when challenged with 3 days of extra fatty acid supply. Conclusions: Taken together, these findings show that intrinsic epigenetic and functional changes exist in preadipocyte cultures from individuals exposed to fetal hyperglycemia who are at increased risk of developing metabolic disease.",

author = "Hansen, {Ninna Schi{\o}ler} and Strasko, {Klaudia Stanislawa} and Line Hjort and Louise Kelstrup and Azadeh Houshmand-{\O}Regaard and Maren Schr{\"o}lkamp and Schultz, {Heidi Schi{\o}ler} and Camilla Scheele and Pedersen, {Bente Klarlund} and Charlotte Ling and Clausen, {Tine Dalsgaard} and Peter Damm and Allan Vaag and Christa Broholm",

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T1 - Fetal hyperglycemia changes human preadipocyte function in adult life

AU - Hansen, Ninna Schiøler

AU - Strasko, Klaudia Stanislawa

AU - Hjort, Line

AU - Kelstrup, Louise

AU - Houshmand-ØRegaard, Azadeh

AU - Schrölkamp, Maren

AU - Schultz, Heidi Schiøler

AU - Scheele, Camilla

AU - Pedersen, Bente Klarlund

AU - Ling, Charlotte

AU - Clausen, Tine Dalsgaard

AU - Damm, Peter

AU - Vaag, Allan

AU - Broholm, Christa

PY - 2017/4/1

Y1 - 2017/4/1

N2 - Context: Offspring of women with gestational diabetes (O-GDM) or type 1 diabetes mellitus (O-T1DM) have been exposed to hyperglycemia in utero and have an increased risk of developing metabolic disease in adulthood. Design: In total, we recruited 206 adult offspring comprising the two fetal hyperglycemic groups, O-GDM and O-T1DM, and, as a control group, offspring from the background population (O-BP). Subcutaneous fat biopsies were obtained and preadipocyte cell cultures were established from adult male O-GDM (n = 18, age 30.1 ± 2.5 years), O-T1DM (n = 18, age 31.6 ± 2.2 years), and O-BP (n = 16; age, 31.5 ± 2.7 years) and cultured in vitro. Main Outcome Measures: First, we studied in vivo adipocyte histology. Second, we studied in vitro preadipocyte leptin secretion, gene expression, and LEP DNA methylation. This was studied in combination with in vitro preadipocyte lipogenesis, lipolysis, and mitochondrial respiration. Results: We show that subcutaneous adipocytes from O-GDM are enlarged compared with O-BP adipocytes. Preadipocytes isolated from male O-GDM and O-T1DM and cultured in vitro displayed decreased LEP promoter methylation, increased leptin gene expression, and elevated leptin secretion throughout differentiation, compared with adipocytes established from male O-BP. In addition, the preadipocytes demonstrated functional defects including decreased maximal mitochondrial capacity with increased lipolysis and decreased ability to store fatty acids when challenged with 3 days of extra fatty acid supply. Conclusions: Taken together, these findings show that intrinsic epigenetic and functional changes exist in preadipocyte cultures from individuals exposed to fetal hyperglycemia who are at increased risk of developing metabolic disease.

AB - Context: Offspring of women with gestational diabetes (O-GDM) or type 1 diabetes mellitus (O-T1DM) have been exposed to hyperglycemia in utero and have an increased risk of developing metabolic disease in adulthood. Design: In total, we recruited 206 adult offspring comprising the two fetal hyperglycemic groups, O-GDM and O-T1DM, and, as a control group, offspring from the background population (O-BP). Subcutaneous fat biopsies were obtained and preadipocyte cell cultures were established from adult male O-GDM (n = 18, age 30.1 ± 2.5 years), O-T1DM (n = 18, age 31.6 ± 2.2 years), and O-BP (n = 16; age, 31.5 ± 2.7 years) and cultured in vitro. Main Outcome Measures: First, we studied in vivo adipocyte histology. Second, we studied in vitro preadipocyte leptin secretion, gene expression, and LEP DNA methylation. This was studied in combination with in vitro preadipocyte lipogenesis, lipolysis, and mitochondrial respiration. Results: We show that subcutaneous adipocytes from O-GDM are enlarged compared with O-BP adipocytes. Preadipocytes isolated from male O-GDM and O-T1DM and cultured in vitro displayed decreased LEP promoter methylation, increased leptin gene expression, and elevated leptin secretion throughout differentiation, compared with adipocytes established from male O-BP. In addition, the preadipocytes demonstrated functional defects including decreased maximal mitochondrial capacity with increased lipolysis and decreased ability to store fatty acids when challenged with 3 days of extra fatty acid supply. Conclusions: Taken together, these findings show that intrinsic epigenetic and functional changes exist in preadipocyte cultures from individuals exposed to fetal hyperglycemia who are at increased risk of developing metabolic disease.

U2 - 10.1210/jc.2016-3907

DO - 10.1210/jc.2016-3907

M3 - Journal article

C2 - 28204515

AN - SCOPUS:85017329683

SN - 0021-972X

VL - 102

SP - 1141

EP - 1150

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 4

ER -

Fetal hyperglycemia changes human preadipocyte function in adult life

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