Excessive Glucocorticoids During Pregnancy Impair Fetal Brown Fat Development and Predispose Offspring to Metabolic Dysfunctions

Chen, Yanting; Hu, Yun; Yang, Qiyuan; Son, Jun Seok; Liu, Xiangdong; Avila, Jeanene M. de; Zhu, Mei‐Jun; Du, Min

doi:10.2337/db20-0009

Cited by 25 publications

(33 citation statements)

References 49 publications

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“…Some studies have also shown that changes in offspring adiposity with gestational hypoxia are coupled with changes in DNA methylation patterns in the adipose tissue [101,142]. There was also increased DNA methylation of the Ppargc1a promoter in neonatal BAT and brown adipocyte progenitor cells, which was linked with attenuated BAT development in response to glucocorticoid over-exposure during gestation [125]. Finally, the methylation of multiple genes was aberrant in the visceral WAT of infant and adult offspring exposed to excess androgens, which likely contributed to the development of obesity and PCOS in the experimental model [133].…”

Section: Epigenetic Mechanismsmentioning

confidence: 97%

“…This was coupled with alterations in adipocyte morphology, expression of lipogenic genes, insulin signaling proteins and inflammatory cytokine expression in the offspring WAT [124]. There were also cellular and molecular changes in the BAT of offspring overexposed to glucocorticoids prenatally, namely decreased UCP1 expression, increased lipid droplet size, upregulated prolactin receptor and decreased mitochondria content, which would be expected to compromise tissue function [64,125]. However, sex effects have not been explored and further work is required to identify the importance of length, timing and level of glucocorticoid over-exposure during gestation to the developmental programming of offspring adipose biology and obesity.…”

Section: Glucocorticoids and Offspring Adipositymentioning

confidence: 99%

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Developmental programming of offspring adipose tissue biology and obesity risk

Rodgers

Sferruzzi‐Perri

2021

Int J Obes

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Obesity is reaching epidemic proportions and imposes major negative health crises and an economic burden in both high and low income countries. The multifaceted nature of obesity represents a major health challenge, with obesity affecting a variety of different organs and increases the risk of many other noncommunicable diseases, such as type 2 diabetes, fatty liver disease, dementia, cardiovascular diseases, and even cancer. The defining organ of obesity is the adipose tissue, highlighting the need to more comprehensively understand the development and biology of this tissue to understand the pathogenesis of obesity. Adipose tissue is a miscellaneous and highly plastic endocrine organ. It comes in many different sizes and shades and is distributed throughout many different locations in the body. Though its development begins prenatally, quite uniquely, it has the capacity for unlimited growth throughout adulthood. Adipose tissue is also a highly sexually dimorphic tissue, patterning men and women in different ways, which means the risks associated with obesity are also sexually dimorphic. Recent studies show that environmental factors during prenatal and early stages of postnatal development have the capacity to programme the structure and function of adipose tissue, with implications for the development of obesity. This review summarizes the evidence for a role for early environmental factors, such as maternal malnutrition, hypoxia, and exposure to excess hormones and endocrine disruptors during gestation in the programming of adipose tissue and obesity in the offspring. We will also discuss the complexity of studying adipose tissue biology and the importance of appreciating nuances in adipose tissue, such as sexual dimorphism and divergent responses to metabolic and endocrine stimuli. Given the rising levels of obesity worldwide, understanding how environmental conditions in early life affects adipose tissue phenotype and the subsequent development of obesity is of absolute importance.

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Section: Epigenetic Mechanismsmentioning

confidence: 97%

Section: Glucocorticoids and Offspring Adipositymentioning

confidence: 99%

Developmental programming of offspring adipose tissue biology and obesity risk

Rodgers

Sferruzzi‐Perri

2021

Int J Obes

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“…Epigenetic regulation during fetal development can alter the gene expression profile in the offspring, which may predispose them to either health or disease susceptibilities in adult life 45,46 . Among the targets analyzed ( Gck , Abcc8.1 , Camk2d , and Hnf4a ) we did not identify any epigenetic effect by DEX exposure during gestation.…”

Section: Discussionmentioning

confidence: 71%

Excess of glucocorticoids during late gestation impairs the recovery of offspring’s β‐cell function after a postnatal injury

et al. 2021

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Since prenatal glucocorticoids (GC) excess increases the risk of metabolic dysfunctions in the offspring and its effect on β-cell recovery capacity remains unknown we investigated these aspects in offspring from mice treated with dexamethasone (DEX) in the late pregnancy. Half of the pups were treated with streptozotocin (STZ) on the sixth postnatal day (PN). Functional and molecular analyses were performed in male offspring on PN25 and PN225. Prenatal DEX treatment resulted in low birth weight. At PN25, both the STZ-treated offspring developed hyperglycemia and had lower β-cell mass, in parallel with higher α-cell mass and glucose intolerance, with no impact of prenatal DEX on such parameters. At PN225, the β-cell mass was partially recovered in the STZ-treated mice, but they remained glucose-intolerant, irrespective of being insulin sensitive. Prenatal exposition to DEX predisposed adult offspring to sustained hyperglycemia and perturbed islet function (lower insulin and higher glucagon response to glucose) in parallel with exacerbated glucose intolerance. β-cell-specific knockdown of the Hnf4α in mice from the DS group resulted in exacerbated glucose intolerance. We conclude that high GC exposure during the prenatal period exacerbates the metabolic dysfunctions in adult life of mice exposed to STZ early in life, resulting in a lesser ability to recover the islets' function over time.This study alerts to the importance of proper management of exogenous GCs during 2 of 17 | DOS SANTOS eT Al.

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“…Alterations in PGC1α expression were more pronounced in the SDF than BF and were accompanied by parallel changes in SDF expression of MFN2 , a gene essential for normal membrane dynamics and OXPHOS function that is regulated by PGC1α ( Liang & Ward 2006 ). Previous studies on rodents have shown that PGC1α expression is glucocorticoid sensitive and increases towards term in fetal heart and adipose tissue ( Rog-Zielinska et al 2015 , Chen et al 2020 ). Deletion of PGC1α expression in fetal mice also impairs mitochondrial OXPHOS function and the metabolic response to glucocorticoids in developing cardiomyocytes ( Rog-Zielinska et al 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid maturation of mitochondrial respiratory capacity in skeletal muscle before birth

Davies

Camm

Smith

et al. 2021

Journal of Endocrinology

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In adults, glucocorticoids act to match the supply and demand for energy during physiological challenges, partly through actions on tissue mitochondrial oxidative phosphorylation (OXPHOS) capacity. However, little is known about the role of the natural prepartum rise in fetal glucocorticoid concentrations in preparing tissues for the increased postnatal energy demands. This study examined the effect of manipulating cortisol concentrations in fetal sheep during late gestation on mitochondrial OXPHOS capacity of two skeletal muscles with different postnatal locomotive functions. Mitochondrial content, biogenesis markers, respiratory rates and expression of proteins and genes involved in the electron transfer system (ETS) and OXPHOS efficiency were measured in the biceps femoris (BF) and superficial digital flexor (SDF) of fetuses either infused with cortisol before the prepartum rise or adrenalectomised to prevent this increment. Cortisol infusion increased mitochondrial content, biogenesis markers, substrate-specific respiration rates and abundance of ETS Complex I and adenine nucleotide translocator (ANT1) in a muscle-specific manner that was more pronounced in the SDF than BF. Adrenalectomy reduced mitochondrial content and expression of PGC1α and ANT1 in both muscles, and ETS Complex IV abundance in the SDF near term. Uncoupling protein gene expression was unaffected by cortisol manipulations in both muscles. Gene expression of the myosin heavy chain isoform, MHCIIx, was increased by cortisol infusion and reduced by adrenalectomy in the BF alone. These findings show that cortisol has a muscle-specific role in prepartum maturation of mitochondrial OXPHOS capacity with important implications for the health of neonates born pre-term or after intrauterine glucocorticoid overexposure.

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Excessive Glucocorticoids During Pregnancy Impair Fetal Brown Fat Development and Predispose Offspring to Metabolic Dysfunctions

Cited by 25 publications

References 49 publications

Developmental programming of offspring adipose tissue biology and obesity risk

Developmental programming of offspring adipose tissue biology and obesity risk

Excess of glucocorticoids during late gestation impairs the recovery of offspring’s β‐cell function after a postnatal injury

Glucocorticoid maturation of mitochondrial respiratory capacity in skeletal muscle before birth

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