Theranostics 2022; 12(13):5803-5819. doi:10.7150/thno.70752 This issue

Research Paper

Postnatal Dexamethasone Therapy Impairs Brown Adipose Tissue Thermogenesis and Autophagy Flux in Neonatal Rat Pups

Yu-Shan Chang1,2, Shun-Yun Hou1,2, Shang-Shiuan Yu1, Shin-Yu Tsai1,2, Ying-Yi Chen1,2, Li-Jin Hsu3, Pei-Jane Tsai3, Hui-Kuan Lin4, Chyi-Her Lin2,5✉, Yau-Sheng Tsai1,4,6✉

1. Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
2. Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
3. Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
4. Department of Cancer Biology, Wake Forest Baptist Medical Center, Wake Forest University, Winston Salem, NC, 27101, USA
5. Department of Pediatrics, E-Da Hospital, Post-baccalaureate Program, College of Medicine, I-Shou University, Kaohsiung, Taiwan, ROC
6. Center for Clinical Medicine Research, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Chang YS, Hou SY, Yu SS, Tsai SY, Chen YY, Hsu LJ, Tsai PJ, Lin HK, Lin CH, Tsai YS. Postnatal Dexamethasone Therapy Impairs Brown Adipose Tissue Thermogenesis and Autophagy Flux in Neonatal Rat Pups. Theranostics 2022; 12(13):5803-5819. doi:10.7150/thno.70752. Available from https://www.thno.org/v12p5803.htm

File import instruction

Abstract

Graphic abstract

Rationale: Very preterm infants may require dexamethasone (Dex) for facilitating extubation or treating bronchopulmonary dysplasia. However, Dex may result in disturbance of metabolisms. This study was to investigate the effects of postnatal short course Dex exposure on brown adipose tissue (BAT) in neonatal rats.

Method: Neonatal rats received either three consecutive doses of daily Dex (0.2 mg/kg/day) or saline from postnatal P1 to P3. We investigated the effects of Dex on BAT including thermogenesis, mitochondrial dynamics and autophagy flux. We also compared diurnal temperature variation between preterm infants who received systemic corticosteroid and their treatment-naïve controls.

Results: Postnatal Dex treatment induced growth retardation, BAT whitening, UCP1 downregulation and cold intolerance in neonatal rats. BAT mitochondria were damaged, evident by loss of normal number, structure, and alignment of cristae. Mitochondrial fission-fusion balance was disrupted and skewed toward increased fusion, reflected by increased OPA1 and MFN2 and decreased DRP1, FIS1 and phosphorylated MFF protein levels. Autophagosome synthesis was increased but clearance was inhibited, indicated by accumulation of p62 protein after Dex treatment and no further increase of LC3-II after chloroquine co-treatment. While autophagy modulators, including chloroquine and rapamycin, did not improve UCP1 downregulation and BAT whitening, AMPK activators could partially rescue these damages. We also demonstrated that preterm infants had higher diurnal temperature variation during corticosteroid treatment.

Conclusions: Postnatal short course Dex impaired BAT mitochondrial function and autophagy flux in rat pups. AMPK activators had the potential to rescue the damage.

Keywords: glucocorticoid, preterm infants, brown adipose tissue, mitochondria, autophagy