Could inhibiting aldose reductase encourage human fat cells to develop?

Details

Aldose reductases (AKR1B) are widely expressed oxidoreductase enzymes, but their physiological function remains unclear. Some isoforms synthesize prostaglandin F2α (PGF2α), which inhibits fat-cell formation, suggesting a possible role in adipose homeostasis. Previous work showed that deleting the Akr1b7 gene in mice increased adiposity in association with lower PGF2α content in fat. Humans, however, have no ortholog of Akr1b7, leaving the role of aldose reductases in human adipose homeostasis unresolved.

This comparative laboratory study analyzed expression of genes encoding human and mouse aldose reductase isoforms in adipose tissues and differentiating adipocytes. The aim was to assess conserved mechanisms regulating PGF2α synthesis and fat-cell differentiation.

In mouse adipose tissue, Akr1b3 encoded the most abundant isoform, while Akr1b7 encoded the only isoform enriched in the stromal vascular fraction. Expression of most mouse aldose reductase genes peaked early in fat-cell formation in 3T3-L1 cells and declined as differentiation progressed.

In contrast to its mouse ortholog Akr1b3, human AKR1B1 expression increased throughout differentiation of human multipotent adipose-derived stem cells, paralleling PGF2α release. Meanwhile, levels of the PGF2α receptor, FP, fell sharply early in differentiation.

In pharmacological experiments, inhibiting aldose reductase with Statil altered PGF2α production and enhanced differentiation of human multipotent adipose-derived stem cells into adipocytes. As expected, the FP receptor agonist cloprostenol counteracted Statil's promotion of fat-cell differentiation.

The findings suggest that, in both species, aldose reductase-dependent PGF2α production could help restrict fat-cell formation during early differentiation. This antiadipogenic signaling could subsequently be reduced through downregulation of the FP receptor in human cells or of aldose reductases in mouse cells. The authors conclude that aldose reductase inhibitors could have obesity-promoting potential.