p62 links β-adrenergic input to mitochondrial function and thermogenesis

Area of Science:

• Cellular Biology
• Metabolism
• Obesity Research

Background:

• The scaffold protein p62 (sequestosome 1; SQSTM1) links cellular metabolic, immune, and proliferative processes.
• Understanding p62's role in energy balance is critical for metabolic disease research.

Purpose of the Study:

• To investigate the role of p62 in regulating energy metabolism and thermogenesis.
• To determine the specific tissues where p62 deficiency impacts metabolic rate.

Main Methods:

• Generation of tissue-specific p62-deficient mouse models (adipocyte, CNS, liver, muscle, myeloid).
• Assessment of metabolic rate, nonshivering thermogenesis, and mitochondrial function in brown adipose tissue (BAT).
• Analysis of signaling pathways, including p38 targets, in primary brown adipocytes and HIB1B cells.

Main Results:

• Adipocyte-specific p62 deficiency resulted in obesity and decreased metabolic rate due to impaired nonshivering thermogenesis.
• p62 deficiency in brown adipose tissue (BAT) led to impaired mitochondrial function and unresponsiveness to β-adrenergic stimuli.
• Ablation of p62 affected key signaling molecules controlling mitochondrial function and thermogenesis (e.g., PGC1α, UCP1).
• p62 controls thermogenesis in a cell-autonomous manner within brown adipocytes.

Conclusions:

• p62 is a novel and critical regulator of mitochondrial function and thermogenesis in brown adipose tissue.
• Targeting p62 may offer a therapeutic strategy for metabolic disorders like obesity.