KMT5c modulates adipocyte thermogenesis by regulating Trp53 expression

Area of Science:

• Metabolic regulation
• Epigenetics
• Adipocyte biology

Background:

• Brown and beige adipocytes possess thermogenic capabilities crucial for adapting to environmental and nutritional shifts.
• Histone methylation is a key epigenetic mechanism regulating nonshivering thermogenesis in adipocytes.

Purpose of the Study:

• To elucidate the role of KMT5c, a H4K20 methyltransferase, in regulating adipocyte thermogenesis and systemic energy expenditure.
• To investigate the molecular network governed by KMT5c in brown and beige adipocytes.

Main Methods:

• Investigated KMT5c expression induced by β3-adrenergic signaling in adipocytes.
• Utilized in vivo adipocyte-specific KMT5c depletion (knockout mice).
• Analyzed thermogenic gene expression, metabolic phenotypes, and epigenetic modifications (H4K20me3) on the Trp53 promoter.

Main Results:

• KMT5c expression is induced by β3-adrenergic signaling in brown and beige fat cells.
• KMT5c depletion in adipocytes reduced thermogenic gene expression and led to high-fat-diet-induced obesity and glucose intolerance.
• KMT5c knockout mice exhibited increased Trp53 expression due to reduced H4K20me3 on its promoter, contributing to metabolic dysfunction.

Conclusions:

• KMT5c plays a critical role in maintaining and activating the thermogenic program in adipocytes through H4K20 methylation.
• KMT5c is a key regulator of systemic energy expenditure and metabolic homeostasis.