Short-term cold exposure induces persistent epigenomic memory in brown fat

Area of Science:

• Metabolism and Endocrinology
• Epigenetics
• Thermoregulation

Background:

• Histone deacetylase 3 (HDAC3) is crucial for brown adipose tissue (BAT) function.
• HDAC3 deficiency in BAT impairs thermogenic responses and cold survival.
• The mechanisms underlying cold adaptation and memory in BAT are not fully understood.

Purpose of the Study:

• To investigate whether short-term mild cold exposure (STEMCT) can protect HDAC3-deficient BAT mice from hypothermia.
• To elucidate the molecular mechanisms, including key transcription factors and epigenetic changes, involved in this cold adaptation.
• To determine the duration and underlying basis of this protective effect.

Main Methods:

• Utilized HDAC3 BAT knockout (KO) mice and wild-type littermates.
• Exposed mice to short-term mild cold temperature (15°C for 24 h) followed by acute cold challenge (4°C).
• Assessed thermogenic gene expression (PGC-1α, UCP1) and the role of transcription factor C/EBPβ using genetic deletion and viral-mediated knockdown.

Main Results:

• STEMCT conferred significant protection against lethal hypothermia in HDAC3 BAT KO mice.
• Protection was associated with restored induction of PGC-1α and UCP1, dependent on these factors.
• A persistent increase in the transcriptional activator C/EBPβ was observed for up to 7 days, mediating this cold-adaptive memory independently of HDAC3.

Conclusions:

• Short-term mild cold exposure can establish a lasting protective memory in brown adipose tissue.
• This memory is mediated by a C/EBPβ-dependent epigenetic mechanism, enhancing thermogenesis.
• This finding reveals a novel HDAC3-independent pathway for cold adaptation in brown adipose tissue.