Phosphomannomutase 1 Restrains Adipose Thermogenic Programming via Inosine Signaling.

Summary

PMM1 expression inversely tracks with obesity metrics and is induced by thermogenic cues. Adipocyte-specific Pmm1 loss enhances thermogenic remodeling and energy expenditure, protecting mice from diet-induced obesity and insulin resistance via rerouting glucose into the pentose phosphate pathway to raise inosine, which activates adenosine A-receptor signaling.

Key Findings

• PMM1 expression in human adipose tissue inversely correlates with obesity-related anthropometric and biochemical measures and is induced by thermogenic stimulation.
• Adipocyte-specific Pmm1 knockdown increases thermogenic remodeling and energy expenditure, protecting mice from diet-induced obesity and insulin resistance.
• PMM1 deficiency redirects glucose into the pentose phosphate pathway, elevating inosine monophosphate and extracellular inosine, which engages adenosine A-receptor signaling to drive thermogenesis.

Clinical Implications

Although preclinical, modulating the PMM1–inosine pathway could offer a therapeutic strategy to treat obesity and insulin resistance by safely augmenting adipose thermogenesis.

Limitations

• Preclinical evidence without human interventional validation.
• Exact adenosine receptor subtype and dose–response are not specified in the abstract.
• Sample sizes for experimental groups are not reported in the abstract.

Future Directions

Define receptor subtypes and pharmacology of inosine–adenosine signaling in adipose tissue, test PMM1/inosine-targeting interventions in humans, and assess long-term safety of thermogenesis augmentation.