Phosphomannomutase 1 restrains adipose thermogenic programming via inosine signaling

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.

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.

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. Pharmacologic blockade of A_2A/A_2B receptors or PKA abrogated these effects, confirming the requirement of inosine signaling. In contrast, PMM1 overexpression in primary adipocytes blunted thermogenic activation.

PMM1 functions as a key metabolic brake on the adipose thermogenic program by limiting inosine production and downstream A_2A/A_2B-PKA signaling. These findings reveal a previously unrecognized PMM1-inosine regulatory pathway linking purine metabolism to energy homeostasis and identify PMM1 as a potential therapeutic target for obesity and related metabolic disorders.