Phosphomannomutase 1 restrains adipose thermogenic programming via inosine signaling

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Objectives Phosphomannomutase 1 (PMM1) is an evolutionarily conserved metabolic enzyme classically linked to mannose metabolism, but its physiological role in adipose tissue remains unknown. This study aimed to define the function of PMM1 in thermogenic regulation and systemic metabolism. Methods An unbiased, integrative transcriptomic analysis of human subcutaneous adipose tissue was performed to relate PMM1 expression to clinical measures. Functional studies in mice and in primary murine and human adipocytes with PMM1 loss- and gain-of-function were conducted to investigate PMM1's role in the thermogenic program, assessed by metabolic phenotyping, RNA sequencing, targeted metabolomics, and signaling assays. Results PMM1 expression was inversely associated with obesity-related anthropometric and biochemical measures and was markedly induced by thermogenic stimulation. Adipocyte-specific Pmm1 knockdown promoted adipose thermogenic remodeling, increased energy expenditure, and protected mice from diet-induced obesity and insulin resistance. Mechanistically, PMM1 deficiency rerouted glucose metabolism into the pentose phosphate pathway, increasing inosine monophosphate and extracellular inosine. The elevated inosine engaged adenosine A 2A /A 2B receptors, activated the PKA-CREB signaling cascade, and enhanced a thermogenic program in both murine and human adipocytes. Pharmacologi

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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