All-trans retinoic acid induces oxidative phosphorylation and mitochondria biogenesis in adipocytes

Abstract

Typical white adipocytes are poor in mitochondria and have a low oxidative capacity. Because of this, the contribution of white adipose tissue (WAT) to whole body energy expenditure is considered relatively small. However, there are studies in both humans and rodents documenting a negative association between mitochondrial content in WAT and obesity, as well as examples of nutritional and pharmacological interventions in animals resulting in obesity resistance that associate with increased oxidative capacity in WAT [reviewed in ( 1 )]. Stimulation of mitochondrial biogenesis and oxidative capacity in white adipocytes, when linked to increased energy expenditure in these cells through increased energy uncoupling and/or waste (e.g., futile cycles), emerges therefore as a potential novel target in the control of obesity and its related medical complications ( 1 ).Vitamin A metabolites (i.e., retinoids) modulate the growth and differentiation of a wide range of cells and tissues. Dietary vitamin A and pro-vitamin A are stored as retinyl esters or intracellularly metabolized to retinoic acid (RA), the main active form of vitamin A ( 2 ). There are two isoforms of RA, all-trans -RA (ATRA) and 9-cis -RA, which exert their effects on cell processes through both genomic and nongenomic mechanisms ( 3 ). After the liver, adipose tissue is a major site of vitamin A storage and metabolism, as well as a main target of ATRA action ( 4, 5 ).

Hoxa5 Promotes Adipose Differentiation via Increasing DNA Methylation Level and Inhibiting PKA/HSL Signal Pathway in Mice

“…Retinoic acid may reduce body fat and improve insulin sensitivity in lean and obese rodents. Importantly, it induces oxidative phosphorylation and mitochondria biogenesis in adipocytes [27-29]. The down-regulation of Hoxa5 expression in iWAT by HFD may contribute to the adipose tissue functional changes and remodeling.…”

Retinoic Acid Increases Fatty Acid Oxidation and Irisin Expression in Skeletal Muscle Cells and Impacts Irisin In Vivo

“…Treatment with all-trans retinoic acid (ATRA) reduces body weight and adiposity independently of changes in food intake and improves insulin sensitivity and glucose tolerance in lean and obese mice [7]. ATRA-induced body fat loss associates with WAT browning [10, 11] and increased capabilities for fatty acid oxidation (FAO), oxidative metabolism and thermogenesis in skeletal muscle [12-14], besides activation of BAT [15] and of FAO in the liver [16]. Along with effects on lipid and energy metabolism, ATRA modulates adipose tissue/adipocyte-born signalling proteins (adipokines) involved in the control of energy balance and insulin sensitivity such as leptin, resistin and retinol binding protein [17-20].…”

“…Along with effects on lipid and energy metabolism, ATRA modulates adipose tissue/adipocyte-born signalling proteins (adipokines) involved in the control of energy balance and insulin sensitivity such as leptin, resistin and retinol binding protein [17-20]. Direct action of ATRA stimulating oxidative metabolism in cultured white adipocytes [11, 21] and hepatic cells [22] has been demonstrated, however, cell-autonomous effects of ATRA on skeletal myocytes and the possible impact of ATRA on myokine production have been less studied.…”

All- trans -retinoic acid represses chemokine expression in adipocytes and adipose tissue by inhibiting NF-κB signaling

“…To identify the molecular mechanisms involved in ATRA-mediated NF-κB signaling deactivation, we 281 hypothesized the involvement of PGC1α and/or β, since we had recently shown that ATRA induced the expression of PGC1α and PGC1β in 3T3-L1 adipocytes [12], and these transcription factors are known to reduce NF-κB activity in muscle cells [26].…”

“…Notably, the action of ATRA has been linked to increased oxidative metabolism and energy 53 expenditure in different tissues including white adipose tissue (WAT) [10,11], and could be related to the 54 ability of ATRA to impact oxidative phosphorylation (OXPHOS) capacity and mitochondrial content in 55 adipocytes [12].…”