Copper Import via CTR1 Supports the β3-Adrenergic Thermogenic Program.

Area of Science:

• Metabolic physiology
• Mitochondrial function
• Adipose tissue biology

Background:

• Adaptive thermogenesis relies on coordinated mitochondrial oxidation and metabolic remodeling.
• Signals coordinating these processes during cold exposure are not fully understood.

Purpose of the Study:

• To investigate the role of copper importer CTR1 in adaptive thermogenesis.
• To elucidate the mechanisms by which CTR1 influences energy expenditure and cold tolerance.

Main Methods:

• Utilized adipocyte-specific Ctr1 knockout (ACKO) and brown adipose tissue-specific Ctr1 knockout (BCKO) mouse models.
• Performed proteomic analysis of brown adipose tissue (BAT).
• Assessed energy expenditure, cold tolerance, and lipolytic activation (e.g., HSL phosphorylation).

Main Results:

• Cold exposure and β3-adrenergic receptor (β3-AR) stimulation upregulate CTR1 and promote copper (Cu) accumulation in thermogenic adipose tissues.
• ACKO mice showed reduced energy expenditure and severe hypothermia during cold challenge.
• Cu deficiency suppressed oxidative phosphorylation and thermogenic programs, impairing lipolysis and lipid clearance in BAT and iWAT.
• BAT-specific deletion of CTR1 caused cold intolerance despite intact acute β3-adrenergic responses.

Conclusions:

• CTR1-dependent copper import is essential for sustained thermogenic capacity during adaptive thermogenesis.
• Intracellular copper availability is a key determinant of the β3-adrenergic thermogenic program.
• Copper homeostasis is indispensable for maintaining energy expenditure and cold tolerance.