Adipose ABHD6 regulates tolerance to cold and thermogenic programs.

Area of Science:

• Metabolic Disease Research
• Adipose Tissue Biology
• Thermogenesis

Background:

• Enhanced energy expenditure in brown and white adipose tissues offers therapeutic potential for metabolic diseases.
• Adipose α/β-hydrolase domain 6 (ABHD6) hydrolyzes monoacylglycerol (MAG) and its role in thermogenesis requires investigation.

Purpose of the Study:

• To investigate the thermogenic role of adipose ABHD6 using adipose-specific ABHD6-knockout (KO) mice.
• To elucidate the molecular mechanisms by which ABHD6 influences adaptive thermogenesis and cold tolerance.

Main Methods:

• Generation and analysis of adipose-specific ABHD6-KO mice.
• Assessment of metabolic phenotypes under various temperature conditions (room temperature, thermoneutrality, cold stress).
• Measurement of lipolysis, lipogenesis, uncoupling protein 1 expression, and nuclear 2-MAG levels.

Main Results:

• ABHD6-KO mice exhibited resistance to hypothermia, linked to increased lipolysis and lipogenesis in the visceral fat glycerolipid/free fatty acid (GL/FFA) cycle.
• Cold stress elevated nuclear 2-MAG levels in visceral WAT of KO mice, activating PPARα and enhancing GL/FFA cycle enzymes.
• ABHD6-ablated brown adipose tissue showed elevated glucose and oxidative metabolism upon cold induction, without altering the GL/FFA cycle.

Conclusions:

• Adipose ABHD6 acts as a negative modulator of adaptive thermogenesis.
• A MAG/PPARα/GL/FFA cycling metabolic signaling network in visceral adipose tissue contributes to cold tolerance.
• Targeting ABHD6 may offer a novel strategy for treating metabolic diseases by enhancing energy expenditure.