YTHDC1 promotes postnatal brown adipose tissue development and thermogenesis by stabilizing PPARγ.

Area of Science:

• Biochemistry
• Metabolism
• Molecular Biology

Background:

• Brown adipose tissue (BAT) is crucial for non-shivering thermogenesis and energy balance.
• Factors such as temperature, aging, and obesity influence BAT activity.
• The precise molecular regulators of BAT development and thermogenesis remain incompletely understood.

Purpose of the Study:

• To identify novel molecular mechanisms governing brown adipose tissue (BAT) development and thermogenesis.
• To investigate the role of the m6A reader protein YTHDC1 in regulating BAT.
• To elucidate the interaction between YTHDC1 and PPARγ in the context of energy metabolism.

Main Methods:

• Utilized mouse models with targeted deletion of Ythdc1 in BAT.
• Investigated protein-protein interactions between YTHDC1, PPARγ, and ARIH2 using biochemical assays.
• Assessed the impact of Ythdc1 deletion on PPARγ stability, BAT development, thermogenesis, and energy expenditure.

Main Results:

• YTHDC1 acts as a key regulator of postnatal interscapular BAT development and energy metabolism in mice.
• YTHDC1 directly binds to PPARγ via its intrinsically disordered region (IDR), preventing its degradation by the E3 ubiquitin ligase ARIH2.
• Deletion of Ythdc1 leads to increased PPARγ degradation, resulting in impaired BAT development, reduced thermogenesis, and compromised energy expenditure.

Conclusions:

• YTHDC1 plays a critical role in maintaining BAT development and function by stabilizing PPARγ.
• This regulatory mechanism operates independently of YTHDC1's known m6A recognition function.
• These findings offer new insights into the molecular control of energy homeostasis and BAT biology.