Retinaldehyde represses adipogenesis and diet-induced obesity

Abstract

The metabolism of vitamin A and the diverse effects of its metabolites are tightly controlled by distinct retinoid-generating enzymes, retinoid-binding proteins and retinoid-activated nuclear receptors. Retinoic acid regulates differentiation and metabolism by activating the retinoic acid receptor and retinoid X receptor (RXR), indirectly influencing RXR heterodimeric partners. Retinoic acid is formed solely from retinaldehyde (Rald), which in turn is derived from vitamin A. Rald currently has no defined biologic role outside the eye. Here we show that Rald is present in rodent fat, binds retinol-binding proteins (CRBP1, RBP4), inhibits adipogenesis and suppresses peroxisome proliferator-activated receptor-c and RXR responses. In vivo, mice lacking the Rald-catabolizing enzyme retinaldehyde dehydrogenase 1 (Raldh1) resisted diet-induced obesity and insulin resistance and showed increased energy dissipation. In ob/ob mice, administrating Rald or a Raldh inhibitor reduced fat and increased insulin sensitivity. These results identify Rald as a distinct transcriptional regulator of the metabolic responses to a high-fat diet.Although vitamin A and its metabolite retinoic acid have therapeutic applications, frequent side effects limit their use 1-3 . In clinical trials involving β-carotene supplementation, worrisome increases in cardiovascular events and mortality have been noted, despite evidence suggesting possible beneficial vascular effects of this treatment 3 . These variable responses to retinoids probably derive from the fact that β-carotene and vitamin A (retinol) and their major metabolites-retinaldehyde (Rald) and retinoic acid-regulate diverse cellular responses, including development, immune function and vision 4,5 . The tight control of retinoid biology is evident in the elaborate system that governs the absorption, formation, transportation and action of these structurally and functionally distinct retinoid metabolites. Despite this, retinoids

Thyroid hormone activation of retinoic acid synthesis in hypothalamic tanycytes

“…Many components of the RA signalling pathway are upregulated in the hypothalamus of long day‐acclimatized rodents including the retinoic X receptor (RXR) which can heterodimerize with either the TH receptor or the RA related receptor (Helfer et al, 2012; Ross et al, 2005; Ross et al, 2004; Shearer et al, 2010; Shearer et al, 2012b). Finally, the importance of Raldh1 in energy balance is highlighted in the finding that Raldh1 −/− mice are highly resistant to diet‐induced obesity (Ziouzenkova et al, 2007). This phenotype was ascribed to an excess of retinaldehyde in adipose tissue due to a lack of Raldh1.…”

β-Carotene conversion products and their effects on adipose tissue

“…Indeed, it is well known that vitamin A derivatives are strong repressors of adipocyte differentiation. This was established long ago for RA [42], and a recent article elegantly demonstrated that physiological concentration of retinal represses adipogenesis in vitro and in vivo [85] through inhibition of RXRa (retinoid X receptor a) and PPARc-activation by their respective ligands (Fig. 2).…”

“…Bovine marbling (which is the presence of a high amount of fat in muscle) is enhanced in the cattle by diets low in carotenoids, so that marbling development is inversely correlated with serum vitamin A levels [39]. In rodents, the administration of RA (reviewed in [6]) or retinal [85] reduces body weight and body fat, and increases insulin sensitivity. Long-term vitamin A supplementation (as retinyl palmitate) has been shown to associate with a mild reduction of adiposity in rats [41] and has certain counterbalancing effect on the development of diet-induced obesity in mice [15].…”

“…Since BCMO1 and BCDO2 are expressed in adipocytes [29], the possibility exists that the cleavage products could be found in adipocytes. In fact, retinal, which can be produced via BCMO1 cleavage, has been detected in adipose tissue [85]. RAs resulting from oxidation of retinal by RALDHs are also quantifiable in adipose tissue in vivo [52], especially all-trans RA; whereas evidence of the existence of 9-cis RA in vivo is still lacking [35,52,68].…”

HPLC/UV quantitation of retinal, retinol, and retinyl esters in serum and tissues

“…Quantifying how manipulation of retinoid metabolism effects the flux of retinoids through metabolic paths and/or effects availability of substrate for RA production will provide insight into retinoid homeostasis and metabolism, and thereby function. Dysfunctions in retinoid homeostasis have been linked to dyslipidemia, diabetes, obesity, cancer, and Alzheimer's Disease (33)(34)(35)(36)(37)(38)(39)(40).…”