Retinol saturase promotes adipogenesis and is downregulated in obesity

Schupp, Michael; Lefterova, Martina I.; Janke, Jürgen; Leitner, Kirstin; Cristancho, Ana G.; Mullican, Shannon E.; Qatanani, Mohammed; Szwergold, Nava; Steger, David J.; Curtin, Joshua C.; Kim, Roy J.; Suh, Moo-Jin; Albert, Martin; Engeli, Stefan; Gudas, Lorraine J.; Lazar, Mitchell A.

doi:10.1073/pnas.0812065106

Cited by 87 publications

(106 citation statements)

References 43 publications

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“…In our search to explain how deletion of the same gene could produce a nearly opposite phenotype in two different laboratories, we surveyed expression of genes near the Fabp1 locus and surrounding obesity-related QTLs, including some genes ( Alms1, Retstat, Aqp1 ) that have been implicated in metabolic adaptations and body weight maintenance (28)(29)(30)(31)(32)(33). No evidence was found for gene duplication or altered expression of modifi er genes in this region in our L-Fabp Ϫ / Ϫ mice.…”

Section: Discussionmentioning

confidence: 99%

Decreased body weight and hepatic steatosis with altered fatty acid ethanolamide metabolism in aged L-Fabp mice

Newberry

Kennedy

Luo

et al. 2012

Journal of Lipid Research

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This article is available online at http://www.jlr.org dramatically in the past 20 years, in parallel with the epidemic of obesity. Although environmental factors (caloric excess) and lifestyle choices (lack of exercise) are the primary causes, genetic susceptibility also predisposes individuals to obesity and its metabolic complications. Studies have identifi ed mechanisms by which food consumption is regulated, including release of factors produced within the gastrointestinal tract (CCK, ghrelin, PYY, lipid amides, and palmitoleic acid) that mediate satiety either locally or centrally ( 1 ).Recent studies have identifi ed several lipid messengers that regulate feeding behavior ( 2-5 ). These include the endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (endogenous ligands of the cannabinoid receptors); the fatty acid ethanolamides (FAE), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA); and their biosynthetic precursors, the N -acyl-phosphatidylethanolamines ( 6, 7 ). OEA is an ubiquitous lipid molecule that is synthesized in the proximal small intestine following consumption of dietary fat, and it promotes satiety by binding nuclear peroxisome proliferator-activated receptor-␣ (PPAR ␣ ) and activating vagal efferents ( 8-10 ). Conversely, AEA promotes food consumption through activation of CB 1 cannabinoid receptors both in the brain and peripheral tissues. In addition, AEA regulates systemic energy utilization, infl ammation, apoptosis, and pain ( 11, 12 ). Details of how the balance between opposing satiety and orexigenic factors is maintained are a focus of investigation, but there is increasing evidence for a role of intracellular The prevalence of nonalcoholic fatty liver disease, type II diabetes, and the metabolic syndrome has increased

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Section: Discussionmentioning

confidence: 99%

Decreased body weight and hepatic steatosis with altered fatty acid ethanolamide metabolism in aged L-Fabp mice

Newberry

Kennedy

Luo

et al. 2012

Journal of Lipid Research

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“…RetSat activity has been implicated in the regulation of adipocyte development and differentiation. Ablation of RetSat expression in a cell culture model of adipocyte differentiation inhibited adipogenesis, whereas ectopic expression of RetSat enhanced differentiation ( 24 ). This block in adipocyte differentiation could not be rescued by addition of 13,14-dihydroretinol to the cells, implying that this enzyme may have other, unknown substrates ( 24 ).…”

mentioning

confidence: 95%

“…Ablation of RetSat expression in a cell culture model of adipocyte differentiation inhibited adipogenesis, whereas ectopic expression of RetSat enhanced differentiation ( 24 ). This block in adipocyte differentiation could not be rescued by addition of 13,14-dihydroretinol to the cells, implying that this enzyme may have other, unknown substrates ( 24 ). Mice totally lacking RetSat exhibit increased adiposity, which is associated with an upregulation of PPAR ␥ ( 25 ).…”

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confidence: 98%

Retinol and retinyl esters: biochemistry and physiology

O’Byrne

Blaner

2013

Journal of Lipid Research

282

221

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The different retinoid forms present within the body (see Fig. 1 ) are generated by and large through modifi cations to the terminal polar end group of the molecule. Retinol and retinyl esters are the most abundant retinoid forms present in the body. All-trans -retinol is by defi nition vitamin A. When a fatty acyl group is esterifi ed to the hydroxyl terminus of retinol, a storage form of retinol, the retinyl ester, is formed. The most abundant retinyl esters present in the body are those of palmitic acid, oleic acid, stearic acid, and linoleic acid ( 6, 7 ). Although retinyl acetate can be found in supplements to foods and vitamin formulations, only long-chain acyl groups are esterifi ed to retinol by animals. Retinyl esters have no known biological activity aside from retinol storage and for serving as the substrate for the formation of the visual chromophore 11-cis -retinal, which must be formed from all-trans -retinyl ester through linked hydrolysis and isomerization reactions catalyzed by the enzyme RPE65 ( 3,4,8,9 ). Retinol is a transport form and a precursor form, which is enzymatically activated to retinoic acid via a two-step oxidation process. The primary role of retinal is in the eye where 11-cis -retinal is needed for visual pigment formation. In tissues, retinal serves as an intermediate in the synthesis of retinoic acid from retinol ( 6, 7 ). The literature also suggests a direct role for retinal in adipose tissue, where it was shown to inhibit adipogenesis and suppress peroxisome proliferator-activated receptor-␥ (PPAR ␥ ) and retinoid X receptor (RXR) responses in cell culture models and in mouse models fed high-fat diets ( 10 ).Abstract By defi nition, a vitamin is a substance that must be obtained regularly from the diet. Vitamin A must be acquired from the diet, but unlike most vitamins, it can also be stored within the body in relatively high levels. For humans living in developed nations or animals living in present-day vivariums, stored vitamin A concentrations can become relatively high, reaching levels that can protect against the adverse effects of insuffi cient vitamin A dietary intake for six months, or even much longer. The ability to accumulate vitamin A stores lessens the need for routinely consuming vitamin A in the diet, and this provides a selective advantage to the organism. The molecular processes that underlie this selective advantage include effi cient mechanisms to acquire vitamin A from the diet, effi cient and overlapping mechanisms for the transport of vitamin A in the circulation, a specifi c mechanism allowing for vitamin A storage, and a mechanism for mobilizing vitamin A from these stores in response to tissue needs. These processes are considered in this review. Since the identifi cation of fat-soluble A a century ago ( 1 ), retinoids (vitamin A and its natural and synthetic analogs) have been the most extensively studied of the fatsoluble vitamins. This research has identifi ed essential roles for retinoids in many different aspects of mammalian physiology, includ...

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“…However, the importance of intronic NR response elements has been increasingly recognized (Carroll and Brown 2006;Lefterova et al 2008;Schupp et al 2009). Indeed, we identified two putative Rev-erba monomer-binding sites (ROREs) spaced by 6 base pairs (bp) within the first intron region of the PGC-1a gene and conserved in human and mouse (Fig.…”

Section: Rev-erba Directly Represses Pgc-1a Transcription Via Functiomentioning

confidence: 99%

Negative feedback maintenance of heme homeostasis by its receptor, Rev-erbα

Wu¹,

Yin²,

Hanniman³

et al. 2009

Genes Dev.

Self Cite

102

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Intracellular heme levels must be tightly regulated to maintain proper mitochondrial respiration while minimizing toxicity, but the homeostatic mechanisms are not well understood. Here we report a novel negative feedback mechanism whereby the nuclear heme receptor Rev-erba tightly controls the level of its own ligand. Heme binding to Rev-erba recruits the NCoR/histone deacetylase 3 (HDAC3) corepressor complex to repress the transcription of the coactivator PGC-1a, a potent inducer of heme synthesis. Depletion of Rev-erba derepresses PGC-1a, resulting in increased heme levels. Conversely, increased Rev-erba reduces intracellular heme, and impairs mitochondrial respiration in a heme-dependent manner. Consistent with this bioenergetic impairment, overexpression of Rev-erba dramatically inhibits cell growth due to a cell cycle arrest. Thus, Rev-erba modulates the synthesis of its own ligand in a negative feedback pathway that maintains heme levels and regulates cellular energy metabolism.[Keywords: Rev-erba; PGC-1a; heme homeostasis; mitochondria; energy] Supplemental material is available at http://www.genesdev.org.

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Retinol saturase promotes adipogenesis and is downregulated in obesity

Cited by 87 publications

References 43 publications

Decreased body weight and hepatic steatosis with altered fatty acid ethanolamide metabolism in aged L-Fabp mice

Decreased body weight and hepatic steatosis with altered fatty acid ethanolamide metabolism in aged L-Fabp mice

Retinol and retinyl esters: biochemistry and physiology

Negative feedback maintenance of heme homeostasis by its receptor, Rev-erbα

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