(P10-029-23) ALDH1L2 Controls High-Fat Diet Induced Obesity-Linked Pathways in Female Mice

Objectives: Aldehyde dehydrogenase 1 family member L2 (ALDH1L2) is a mitochondrial enzyme that converts 10-formyltertrahydrofolate to tetrahydrofolate and CO₂ in an NADP⁺-dependent reaction. Our previous study demonstrated that ALDH1L2 loss caused neuro-ichthyotic syndrome, which is linked to ALDH1L2-dependent lipid homeostasis and energy balance degradation. Based on the role of ALDH1L2 in lipid metabolism, we hypothesized that the enzyme is involved in the regulation of obesity caused by a high-fat diet.

Methods: To investigate the role of ALDH1L2 in energy metabolism, ALDH1L2^-/- and ALDH1L2^+/+ mice were fed a high-fat diet (HFD, 60% calories from fat) for 12 weeks and body composition and metabolic measurements were measured by MRI and TSE-chamber, respectively. Insulin sensitivity was determined by glucose tolerance test (GTT) and HOMA-IR scores. Folate metabolism was assessed by evaluating levels of relevant enzymes (Western blot assays) and measuring reduced folate pools (the ternary complex assay). H&E staining was used for histological analysis of the liver and spleen. The overall liver metabotypes of Aldh1l2^-/- and Aldh1l2^+/+ mice were evaluated by untargeted metabolomics (Metabolon).

Results: On a control diet (15% calories from fat), body weight did not change between Aldh1l2^-/- and Aldh1l2^+/+ mice in both males and females. However, Aldh1l2^-/- female mice fed HFD did not gain as much body weight and fat mass as Aldh1l2^+/+ mice whereas male mice showed no differences. Aldh1l2^-/- mice also attenuated HFD-induced glucose intolerance compared to Aldh1l2^+/+ mice. HFD-induced hepatic lipid accumulation and injury were increased in Aldh1l2^-/- mice. Strikingly, spleen weight was elevated as much as 3-fold in the HFD-fed Aldh1l2^-/-, but the RBC production was not affected. Untargeted metabolomics in the liver showed greater differences in the lipid profiles and levels of lipid-derived inflammatory mediators between Aldh1l2^-/- and Aldh1l2^+/+ mice.

Conclusions: Our study suggests that the loss of ALDH1L2 suppresses diet-induced obesity by restricting metabolic pathways associated with lipid conversions. These findings underscore the enzyme as a critical metabolic mediator, dysregulation of which can lead to lipid disorders and rare metabolic diseases.

Funding Sources: This research was supported by NIH R01 grant DK117854.