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 ).

Background/Aims: All-trans retinoic acid (ATRA) has protective effects against obesity and metabolic syndrome. We here aimed to gain further insight into the interaction of ATRA with skeletal muscle metabolism and secretory activity as important players in metabolic health. Methods: Cultured murine C2C12 myocytes were used to study direct effects of ATRA on cellular fatty acid oxidation (FAO) rate (using radioactively-labelled palmitate), glucose uptake (using radioactively-labelled 2-deoxy-D-glucose), triacylglycerol levels (by an enzymatic method), and the expression of genes related to FAO and glucose utilization (by RT-real time PCR). We also studied selected myokine production (using ELISA and immunohistochemistry) in ATRA-treated myocytes and intact mice. Results: Exposure of C2C12 myocytes to ATRA led to increased fatty acid consumption and decreased cellular triacylglycerol levels without affecting glucose uptake, and induced the expression of the myokine irisin at the mRNA and secreted protein level in a dose-response manner. ATRA stimulatory effects on FAO-related genes and the Fndc5 gene (encoding irisin) were reproduced by agonists of peroxisome proliferator-activated receptor β/δ and retinoid X receptors, but not of retinoic acid receptors, and were partially blocked by an AMP-dependent protein kinase inhibitor. Circulating irisin levels were increased by 5-fold in ATRA-treated mice, linked to increased Fndc5 transcription in liver and adipose tissues, rather than skeletal muscle. Immunohistochemistry analysis of FNDC5 suggested that ATRA treatment enhances the release of FNDC5/irisin from skeletal muscle and the liver and its accumulation in interscapular brown and inguinal white adipose depots. Conclusion: These results provide new mechanistic insights on how ATRA globally stimulates FAO and enhances irisin secretion, thereby contributing to leaning effects and improved metabolic status.

OBJECTIVE:To assess the influence of supplementation with a moderate dose of vitamin A in early life on adipose tissue development and the response to an obesogenic diet later in life. METHODS: During the suckling period, rat pups received a daily oral dose of retinyl palmitate corresponding to three times the vitamin A ingested daily from maternal milk. Control rats received the vehicle (olive oil). Short-term effects of treatment on gene expression and morphology of white adipose tissue (WAT) were analyzed in animals on the day after weaning (day 21). To study long-term effects, control and vitamin A-treated rats were fed, after weaning, a normal fat or a high-fat (HF) diet for 16 weeks. RESULTS: WAT of vitamin A-treated young rats (day 21) was enriched in small adipocytes with a reduced expression of adipogenic markers (peroxisome proliferator-activated receptor g and lipoprotein lipase) and an increased cell proliferation potential as indicated by increased expression of proliferating cell nuclear antigen. Increased retinoic acid (RA)-induced transcriptional responses were present in the tissues of vitamin A-treated young rats (day 21) including WAT. Vitamin A-treated rats developed higher adiposity than control rats on a HF diet as indicated by body composition analysis and increased WAT depot mass, adipocyte diameter, WAT DNA content, leptinemia and adipose leptin gene expression. Excess adiposity gain in vitamin A-treated rats developed in the absence of changes in body weight and was attributable to excess adipocyte hyperplasia. No differences in adiposity were observed between vitamin A-treated rats and control rats on a normal fat diet. Total retinol levels in WAT of vitamin A-treated rats were elevated at weaning (day 21) and normalized by day 135 of age. CONCLUSION: Vitamin A intake in the early stages of postnatal life favors subsequent HF diet-induced adiposity gain through mechanisms that may relate to changes in adipose tissue development, likely mediated by RA.

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BC is partly absorbed intact by suckling rats, which resembles the situation in humans and suggests that suckling rats may be an appropriate animal model to study BC uptake, metabolism and biological activity, particularly in infants. Vitamin A supplementation with BC or RE in early life differentially affects WAT and may thus entail different outcomes regarding adiposity programming.

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