Suppression of PPAR-γ attenuates insulin-stimulated glucose uptake by affecting both GLUT1 and GLUT4 in 3T3-L1 adipocytes

Liao, Wei; Nguyen, Matthew; Yoshizaki, Takeshi; Favelyukis, Svetlana; Patsouris, David; Imamura, Teruhiko; Verma, Inder M.; Olefsky, Jerrold M.

doi:10.1152/ajpendo.00695.2006

Cited by 112 publications

(86 citation statements)

References 56 publications

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“…S1D). There was no obvious phenotypic change or dedifferentiation of the adipocytes within this period as assessed by microscopy and in confirmation of previous reports (19). However, RetSat mRNA decreased by approximately 90% in the PPAR␥ siRNA-treated cells (Fig.…”

Section: Resultssupporting

confidence: 91%

Retinol saturase promotes adipogenesis and is downregulated in obesity

Schupp

Lefterova

Janke

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Adipocyte differentiation is controlled by many transcription factors, but few known downstream targets of these factors are necessary for adipogenesis. Here we report that retinol saturase (RetSat), which is an enzyme implicated in the generation of dihydroretinoid metabolites, is induced during adipogenesis and is directly regulated by the transcription factor peroxisome proliferator activated receptor γ (PPARγ). Ablation of RetSat dramatically inhibited adipogenesis but, surprisingly, this block was not overcome by the putative product of RetSat enzymatic activity. On the other hand, ectopic RetSat with an intact, but not a mutated, FAD/NAD dinucleotide-binding motif increased endogenous PPARγ transcriptional activity and promoted adipogenesis. Indeed, RetSat was not required for adipogenesis when cells were provided with exogenous PPARγ ligands. In adipose tissue, RetSat is expressed in adipocytes but is unexpectedly downregulated in obesity, most likely owing to infiltration of macrophages that we demonstrate to repress RetSat expression. Thiazolidinedione treatment reversed low RetSat expression in adipose tissue of obese mice. Thus, RetSat plays an important role in the biology of adipocytes, where it favors normal differentiation, yet is reduced in the obese state. RetSat is thus a novel target for therapeutic intervention in metabolic disease.

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Section: Resultssupporting

confidence: 91%

Retinol saturase promotes adipogenesis and is downregulated in obesity

Schupp

Lefterova

Janke

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…For example, TZDs, which are high-affinity PPARg ligands, suppress inflammation (40,41). In contrast, PPARg depletion via RNA interference enhances the inflammatory responses of TNFa (42). Consistent with these data, rosiglitazone prevents CLA-mediated insulin resistance and hepatic steatosis in rats (14,15) and delipidation of human adipocytes (13).…”

Section: Discussionmentioning

confidence: 60%

Conjugated linoleic acid-mediated inflammation and insulin resistance in human adipocytes are attenuated by resveratrol

Kennedy

Overman

LaPoint

et al. 2009

Journal of Lipid Research

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Inflammation plays a role in trans-10, cis-12 (10,12)-conjugated linoleic acid (CLA)-mediated delipidation and insulin resistance in adipocytes. Given the anti-inflammatory role of resveratrol (RSV), we hypothesized that RSV would attenuate inflammation and insulin resistance caused by 10,12 CLA in human adipocytes. RSV blocked 10,12 CLA induction of the inflammatory response by preventing activation of extracellular signal-related kinase and induction of inflammatory gene expression (i.e., IL-6, IL-8, IL-1b) within 12 h. Similarly, RSV suppressed 10,12 CLA-mediated activation of the inflammatory prostaglandin pathway involving phospholipase A 2 , cyclooxygenase-2, and PGF 2a . In addition, RSV attenuated 10,12 CLA increase of intracellular calcium and reactive oxygen species associated with cellular stress, and activation of stress-related proteins (i.e., activating transcription factor 3, JNK) within 12 h. 10,12 CLA-mediated insulin resistance and suppression of fatty acid uptake and triglyceride content were attenuated by RSV. Finally, 10,12 CLA-mediated decrease of peroxisome proliferator-activated receptor g (PPARg) protein levels and activation of a peroxisome proliferator response element (PPRE) reporter were prevented by RSV. RSV increased the basal activity of PPRE, suggesting that RSV increases PPARg activity. Collectively, these data demonstrate for the first time that RSV prevents 10,12 CLAmediated insulin resistance and delipidation in human adipocytes by attenuating inflammation and cellular stress and increasing PPARg activity. Feeding a mixture of conjugated linoleic acid (CLA) isomers [i.e., trans-10, cis-12 (10,12) CLA and cis-9, trans-11 (9,11) CLA] reduces adiposity in animals (1) and some humans (2). The triglyceride (TG)-lowering properties of CLA appear to be due exclusively to the 10,12 isomer (3-5), and involve decreased uptake and metabolism of glucose and fatty acids (FA)s (6), and increased lipolysis (7) in adipocytes. These anti-obesity properties of 10,12 CLA are dependent on the activation of mitogen-activated protein kinase kinase/extracellular signal-related kinase (MEK/ERK) (6) and nuclear factor kB (NFkB) (8, 9) in adipocytes. These signaling pathways induced by 10,12 CLA are linked to the induction and secretion of cytokines (8, 9), which are known to antagonize peroxisome proliferator-activated receptor g (PPARg) target gene expression and insulin sensitivity (10-15). Consistent with these data, 10,12 CLA supplementation of humans is associated with hyperglycemia, insulin resistance, elevated levels of inflammatory prostaglandins (PGs) and cytokines, and dyslipidemia (16)(17)(18).Recently, supplementation of mice and 3T3-L1 adipocytes with 10,12 CLA has been shown to activate the integrated stress response (ISR) pathway (19), which is linked to inflammation, insulin resistance, and endoplasmic reticulum (ER) stress (20). Cellular stress can be caused by a relatively disproportional influx of macronutrients that adversely affect organelle function, including the mitoc...

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“…The use of these mouse model systems has shown that PPARg is critical for fat cell development (Rosen et al 1999), and mice with adipose tissue-specific loss of PPARg display decreased fat pad size and insulin resistance in adipose tissue and liver (He et al 2003). Although PPARg is required for adipogenesis, there is evidence to suggest that this nuclear receptor may not be needed to maintain the differentiated state of the cell after adipogenesis (Liao et al 2007). Of note, PPARg heterozygote mice show enhanced insulin sensitivity (Miles et al 2000), suggesting the amount of protein present is highly important.…”

Section: Ppargmentioning

confidence: 99%

Adipogenesis

Sarjeant

Stephens

2012

Cold Spring Harbor Perspectives in Biology

254

236

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SUMMARYAdipose tissue is an important site for lipid storage, energy homeostasis, and whole-body insulin sensitivity. It is important to understand the mechanisms involved in adipose tissue development and function, which can be regulated by the endocrine actions of various peptide and steroid hormones. Recent studies have revealed that white and brown adipocytes can be derived from distinct precursor cells. This review will focus on transcriptional control of adipogenesis and its regulation by several endocrine hormones. The general functions and cellular origins of adipose tissue and how the modulation of adipocyte development pertains to metabolic disease states will also be considered.

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Suppression of PPAR-γ attenuates insulin-stimulated glucose uptake by affecting both GLUT1 and GLUT4 in 3T3-L1 adipocytes

Cited by 112 publications

References 56 publications

Retinol saturase promotes adipogenesis and is downregulated in obesity

Retinol saturase promotes adipogenesis and is downregulated in obesity

Conjugated linoleic acid-mediated inflammation and insulin resistance in human adipocytes are attenuated by resveratrol

Adipogenesis

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