Retinoic Acid Upregulates Preadipocyte Genes to Block Adipogenesis and Suppress Diet-Induced Obesity

Abstract

Retinoic acid (RA) protects mice from diet-induced obesity. The activity is mediated in part through activation of the nuclear receptors RA receptors (RARs) and peroxisome proliferator–activated receptor β/δ and their associated binding proteins cellular RA binding protein type II (CRABP-II) and fatty acid binding protein type 5 in adipocytes and skeletal muscle, leading to enhanced lipid oxidation and energy dissipation. It was also reported that RA inhibits differentiation of cultured preadipocytes. However, whether the hormone suppresses adipogenesis in vivo and how the activity is propagated remained unknown. In this study, we show that RA inhibits adipocyte differentiation by activating the CRABP-II/RARγ path in preadipose cells, thereby upregulating the expression of the adipogenesis inhibitors Pref-1, Sox9, and Kruppel-like factor 2 (KLF2). In turn, KLF2 induces the expression of CRABP-II and RARγ, further potentiating inhibition of adipocyte differentiation by RA. The data also indicate that RA suppresses adipogenesis in vivo and that the activity significantly contributes to the ability of the hormone to counteract diet-induced obesity.

Vitamin A supplementation in early life affects later response to an obesogenic diet in rats

“…[15][16][17][18][19][20][21][22][23][24] On the opposite, in the present study a three-fold excess of vitamin A intake in early life (day 1 to day 20 of life) exacerbated WAT expansion in response to a HF diet later in life. The reason(s) of this apparent discrepancy is unknown but could relate to concentration-dependent effects, because studies in adult animals typically used relatively high retinoid concentrations (reviewed in 10 ).…”

“…9,10 Retinoic acid (RA), its acid form, potently blocks adipogenesis of cultured preadipose cells when introduced at early stages of the differentiation process, 11 although other reports indicate that RA at low doses may in fact promote adipogenesis. [12][13][14] Studies in adult rodents treated with RA [15][16][17][18][19][20][21][22][23] or retinaldehyde 24 sustain an antiadiposity action of vitamin A derivatives in vivo. Furthermore, results from animal studies 16,[25][26][27][28] and human observational studies 29,30 point to an inverse relationship between vitamin A status and body fat content.…”

“…Furthermore, results from animal studies 16,[25][26][27][28] and human observational studies 29,30 point to an inverse relationship between vitamin A status and body fat content. The antiadiposity action of RA has been traced to increased fatty acid oxidation and energy expenditure in adipose tissues, 15,19,21,31 skeletal muscle 20,32 and the liver, 33 and to reduced peroxisome proliferator-activated receptor g (PPARg) levels and activity in white fat. 16,34,35 PPARg is a nuclear receptor transcription factor key for adipogenesis and also required for lipogenesis and survival in mature adipocytes.…”

Retinoic Acid Receptor β Stimulates Hepatic Induction of Fibroblast Growth Factor 21 to Promote Fatty Acid Oxidation and Control Whole-body Energy Homeostasis in Mice

“…This mechanism would allow hepatocytes to increase mitochondrial fatty acid oxidation and ketogenesis and meet the energetic requirement in the circumstance of energy stress. Multiple studies have established that the treatment of RA, the active vitamin A metabolite, induces weight loss and attenuates insulin resistance in obesity and diabetes (6,7). One critical mechanism of the actions of RA is that activation of RAR may reduce hepatic lipid accumulation and normalize serum triglyceride levels (6,46).…”

Role of PPARγ in the nutritional and pharmacological actions of carotenoids

“…Therefore, they pointed out that RA suppresses adipogenesis in vivo. 53 Interestingly, Dave et al reported that stem bromelain (SBM) inhibited adipogenesis irreversibly. SBM and all-trans-retinoic acid (atRA) treatment together inhibited adipocyte differentiation more effectively than either alone.…”