Raldh1 promotes adiposity during adolescence independently of retinal signaling

Abstract

All-trans-retinoic acid (RA) inhibits adipogenesis in established preadipocyte cell lines. Dosing pharmacological amounts of RA reduces weight gain in mice fed a high-fat diet, i.e. counteracts diet-induced obesity (DIO). The aldehyde dehydrogenase Raldh1 (Aldh1a1) functions as one of three enzymes that converts the retinol metabolite retinal into RA, and one of many proteins that contribute to RA homeostasis. Female Raldh1-ablated mice resist DIO. This phenotype contrasts with ablations of other enzymes and binding-proteins that maintain RA homeostasis, which gain adiposity. The phenotype observed prompted the conclusion that loss of Raldh1 causes an increase in adipose tissue retinal, and therefore, retinal functions independently of RA to prevent DIO. A second deduction proposed that low nM concentrations of RA stimulate adipogenesis, in contrast to higher concentrations. Using peer-reviewed LC/MS/MS assays developed and validated for quantifying tissue RA and retinal, we show that endogenous retinal and RA concentrations in adipose tissues from Raldh1-null mice do not correlate with the phenotype. Moreover, male Raldh1-null mice resist weight gain regardless of dietary fat content. Resistance to weight gain occurs during adolescence in both sexes. We show that RA concentrations as low as 1 nM, i.e. in the sub-physiological range, impair adipogenesis of embryonic fibroblasts from wild-type mice. Embryonic fibroblasts from Raldh1-null mice resist differentiating into adipocytes, but retain ability to generate RA. These fibroblasts remain sensitive to an RA receptor pan-agonist, and are not affected by an RA receptor pan-antagonist. Thus, the data do not support the hypothesis that retinal itself represses weight gain and adipogenesis independently of RA. Instead, the data indicate that Raldh1 functions as a retinal and atRA-independent promoter of adiposity during adolescence, and enhances adiposity through pre-adipocyte cell autonomous actions.

Modest Decreases in Endogenous All-trans-Retinoic Acid Produced by a MouseRdh10Heterozygote Provoke Major Abnormalities in Adipogenesis and Lipid Metabolism

“…Raldh1 ablation decreases atRA in liver and in some female fat pads of 6-to 7-week-old mice fed an HFD, which should enhance adiposity but does not affect retinal in these mice. These and other data indicate that the multifunctional Raldh1, which also has a diverse array of substrates, acts independently of retinal and RA in adipose to permit adiposity (50).…”

Vitamin A signaling and homeostasis in obesity, diabetes, and metabolic disorders

“…There is now a general consensus that RDH10 is the major enzyme involved in the synthesis of retinoic acid within the body (Kedishvili, 2013). RDH1 and Dhrs9 too are proposed by some investigators to have a physiologic role in this metabolic process (Kedishvili, 2013;Yang et al, 2017;Yang et al, 2018). The RDHs, ones that are now understood to be important for catalyzing retinol oxidation as the first enzymatic step needed for retinoic acid formation, are members of the short chain dehydrogenase/reductase protein family.…”

The nutrigenomic metabolite L‑carnitine directly modulates the activity and expression of nuclear receptors in adipocytes, liver and muscle cells

“…LXR activation in both murine and human adipocytes has already been shown to shift substrate oxidation towards utilization of lipids and upregulate mitochondrial β-oxidation [28]. Concordant with these findings, RAR activation in adipocytes seems to suppress adipogenesis and to down-regulate mRNA expression of PPAR-γ, a key regulator of adipocyte differentiation [29,30]. These results further substantiate our hypothesis, that L-carnitine acts as potent promoter of catabolic pathways via increase of lipolysis and decrease of lipid storage in multiple tissues.…”

“…6). ALDH1A1 is a major gene of the oxidative pathway of alcohol metabolism and has been shown to act as a promoter of adipogenesis [29,30]. Lcarnitine supplementation led to a significant decrease of ALDH1A1 expression, substantiating the hypothesis that Lcarnitine substitution effectively decreases adipogenesis.…”