Mechanisms for sex- and depot-specific fat formation are unclear. We investigated the role of retinoic acid (RA) production by aldehyde dehydrogenase 1 (Aldh1a1, -a2, and -a3), the major RA-producing enzymes, on sex-specific fat depot formation. Female Aldh1a1−/− mice, but not males, were resistant to high-fat (HF) diet–induced visceral adipose formation, whereas subcutaneous fat was reduced similarly in both groups. Sexual dimorphism in visceral fat (VF) was attributable to elevated adipose triglyceride lipase (Atgl) protein expression localized in clusters of multilocular uncoupling protein 1 (Ucp1)-positive cells in female Aldh1a1−/− mice compared with males. Estrogen decreased Aldh1a3 expression, limiting conversion of retinaldehyde (Rald) to RA. Rald effectively induced Atgl levels via nongenomic mechanisms, demonstrating indirect regulation by estrogen. Experiments in transgenic mice expressing an RA receptor response element (RARE-lacZ) revealed HF diet–induced RARE activation in VF of females but not males. In humans, stromal cells isolated from VF of obese subjects also expressed higher levels of Aldh1 enzymes compared with lean subjects. Our data suggest that an HF diet mediates VF formation through a sex-specific autocrine Aldh1 switch, in which Rald-mediated lipolysis in Ucp1-positive visceral adipocytes is replaced by RA-mediated lipid accumulation. Our data suggest that Aldh1 is a potential target for sex-specific antiobesity therapy.

The deregulation of B cell differentiation has been shown to contribute to autoimmune disorders, hematological cancers, and aging. We provide evidence that the retinoic acid-producing enzyme aldehyde dehydrogenase 1a1 (Aldh1a1) is an oncogene suppressor in specific splenic IgG1+/CD19− and IgG1+/CD19+ B cells populations. Aldh1a1 regulated transcription factors during B cell differentiation in a sequential manner: 1) retinoic acid receptor alpha (Rara) in IgG1+/CD19− and 2) zinc finger protein Zfp423 and peroxisome proliferator-activated receptor gamma (Pparg) in IgG1+/CD19+ splenocytes. In Aldh1a1−/− mice, splenic IgG1+/CD19− and IgG1+/CD19+ B cells acquired expression of proto-oncogenic genes c-Fos, c-Jun, and Hoxa10 that resulted in splenomegaly. Human multiple myeloma B cell lines also lack Aldh1a1 expression; however, ectopic Aldh1a1 expression rescued Rara and Znf423 expression in these cells. Our data highlight a mechanism by which an enzyme involved in vitamin A metabolism can improve B cell resistance to oncogenesis.

Unraveling mechanisms regulating gammopathies, abnormal immunoglobulin production is necessary to improve treatments of a number of blood cancers, such as multiple myeloma. Retinoic acid and retinaldehyde, a transcriptionally active metabolites of vitamin A, play a key role in differentiation processes. RA is produced by the aldehyde dehydrogenase‐1 family of enzymes (Aldh1a1, a2, a3). Our objective was to identify key genes regulating the cellular levels of these metabolites.Our studies in healthy subjects’ showed that Aldh1a1 is the predominantly expressed Aldh1 enzyme in circulating B cells comprising majority of PBMC fraction. In contrast, two myeloma B cell lines, U266 and RPMI8226 lack Aldh1a1 expression. PBMC from multiple myeloma patients showed an expression profile similar to that of U266. We showed that similar to human B cells, naïve (CD19−) and committed (CD19+) splenic B cells from WT mice predominantly expressed Aldh1a1, whereas in Aldh1a1−/− mice these B cells were complete depleted of Aldh1 expression. In both genotypes B cell differentiation from CD19− to CD19+ phenotype was associated with the loss of Aldh1a1 and a2. The change in the RA production in CD19− and CD19+ cells was accompanied by changed levels of key proteins such as RARa, HoxA10, and PPARg. Our studies suggest that Aldh1 enzymes are important for regulation of Ig production and their deficiency is associated with malignant B cells.Grant Funding Source: Nutrition (ASN)

Abnormal immunoglobulin (Ig) production underlines hematological cancers. Studies show association of these cancers with obesity. However, it is unclear how high‐fat (HF) diets influence Ig levels in the circulation. We used six 59 weeks‐old C57BL/6 mice (wild type WT), fed a diet of 5.67% by calorie of saturated fat, compared to six age and sex‐matched WT mice fed a HF diet of 45% by calorie saturated fat for 42 weeks. Using ELISA we quantified Ig classes (IgG1, IgG2a, IgG2b, IgG3, IgA, IgM, Igκ and Igλ) in the plasma of both groups. The intra and inter‐assay variations of the ELISA assay were 2–12% and 5–30% respectively. Mice fed regular and HF diets have similar proportions of Ig's with exception of a 9% increase in IgLκ in HF diets. There was a quantitative increase of 200% to over 500% in Ig's of every class present in plasma from mice on HF diets. However, the increase in Ig production on a HF diet was suppressed by retinoic acid‐generating enzyme aldehyde dehydrogenase 1a1 (Aldh1a1). We studied this relationship in Aldh1a1−/− mice (n=6) vs. WT (n=6) mice on HF diets. Aldh1a1 −/− mice exhibited an increase in plasma Ig's: IgG1 224%, IgG2a 978%, IgG2b 106%, IgG3 217%, IgA 156%, IgLλ 105%. We confirmed polyclonal gammopathy in Aldh1a1−/− compared to WT mice on HF diet using serum protein electrophoresis. We conclude that dietary fat content increases Ig concentration in plasma dependent on the expression of Aldh1a1 enzyme.