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Significance Thermogenesis by brown adipose tissue (BAT) dissipates energy as heat and combats obesity. The detection of BAT in human adults sparked an interest in treating metabolic disorders through BAT activation. However, the current browning regimen suffers from patient incompliance and systemic toxicity. We show that phosphocholine phosphatase-1 (PHOSPHO1) is highly enriched in BAT and negatively regulates thermogenesis. PHOSPHO1 knockout mice are cold-tolerant and are protected from high-fat diet-induced obesity and insulin resistance. Phosphocholine, the PHOSPHO1 substrate, induced cold tolerance and allied metabolic benefits in mice. Our results identified a BAT-enriched negative regulator of thermogenesis. Inhibition of PHOSPHO1 or enhancement of phosphocholine may represent innovative approaches to manage obesity and its related metabolic syndrome.

Phosphocholine accumulation and PHOSPHO1 depletion promote adipose tissue thermogenesis