Imprinted lncRNA Dio3os preprograms intergenerational brown fat development and obesity resistance

Area of Science:

• Endocrinology
• Developmental Biology
• Metabolic Health

Background:

• Maternal obesity (MO) is linked to offspring metabolic disorders.
• The role of offspring brown adipose tissue (BAT) in this process is unclear.
• MO may affect fetal BAT development and function.

Purpose of the Study:

• Investigate the impact of MO on fetal BAT development.
• Elucidate the mechanisms linking MO to offspring metabolic dysfunction.
• Identify potential targets for preventing intergenerational obesity.

Main Methods:

• Analysis of fetal BAT development in a mouse model of MO.
• Gene expression analysis of Dio3 and Dio3os in BAT.
• Gain- and loss-of-function studies of Dio3os.
• DNA methylation analysis of the Dio3os promoter.

Main Results:

• MO impairs fetal BAT development and suppresses BAT thermogenesis in female offspring.
• MO increases Dio3 expression and decreases Dio3os expression in fetal BAT, causing T3 deficiency.
• Dio3os activation reduces D3 activity, enhances BAT thermogenesis, and protects against diet-induced obesity.
• Dio3os promoter hypermethylation in oocytes, fetal, and adult BAT suggests an epigenetic origin.

Conclusions:

• MO-induced suppression of Dio3os in BAT contributes to intergenerational obesity.
• Dio3os activation in BAT is a key mechanism to prevent metabolic dysfunction.
• Epigenetic modifications in oocytes may mediate the intergenerational effects of MO.