Differential regulation of CIDEA and CIDEC expression by insulin via Akt1/2- and JNK2-dependent pathways in human adipocytes

Ito, Minoru; Nagasawa, Michiaki; Omae, Naoki; Ide, Tomohiro; Akasaka, Yunike; Murakami, Koji

doi:10.1194/jlr.m012427

Cited by 27 publications

(20 citation statements)

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“…Small interfering RNA (siRNA) screening revealed that JNK2 is a regulator of LD homeostasis in HeLa cells ( 33 ). Furthermore, we recently showed that JNK2 is required for insulin-induced LD formation in human adipocytes ( 23 ). These observations implied a role of JNK2 in lipid-related pathologies such as obesity and insulin resistance.…”

Section: Methodsmentioning

confidence: 91%

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A novel JNK2/SREBP-1c pathway involved in insulin-induced fatty acid synthesis in human adipocytes

Ito¹,

Nagasawa²,

Omae³

et al. 2013

Journal of Lipid Research

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cular disease, nonalcoholic steatohepatitis, nephropathy, and several types of cancer ( 1-3 ). WAT mass is determined by the number and size of adipocytes ( 4, 5 ) regulated by cell differentiation, apoptosis, and lipid droplet (LD) formation (6)(7)(8). Insulin is known to inhibit apoptosis ( 9, 10 ) and increase LD formation ( 11,12 ) in adipocytes. Hyperinsulinemia is associated with weight gain in humans ( 13 ). Insulin signaling in adipocytes is critical for the development of obesity ( 14,15 ). Therefore, it has been suggested that insulin is one of the determinants involved in increasing the WAT mass.Our previous study showed that insulin decreases cell death-inducing DNA fragmentation factor-␣ -like effector (CIDE)A expression and increases CIDEC expression, both of which belong to the CIDE family and play critical roles in apoptosis ( 16,17 ) and LD formation ( 18-21 ), and the differential regulation of these genes is related, at least in part, to insulin-induced anti-apoptosis and LD formation in human adipocytes ( 22 ). Our recent study also showed that insulin regulates CIDEA and CIDEC expression via phosphatidylinositol 3-kinase (PI3K), and regulates expression of each protein via Akt1/2-and c-Jun N-terminal kinase (JNK)2-dependent pathways downstream of PI3K, respectively ( 23 ). These results suggest that insulin regulation of CIDEA and CIDEC contribute separately via different signaling pathways to insulin-induced antiapoptosis and LD formation, leading to increases in the number and size of adipocytes. Adipocyte size is determined by LD formation regulated by glucose uptake, de novo fatty acid synthesis, triacylglycerol synthesis, and lipolysis ( 24,25 ). Previous studies suggested that regulation of CIDEC expression contributes to LD maintenance by modulating lipolysis. However, regulation of other genes Press, March 19, 2013 DOI 10.1194 A novel JNK2/SREBP-1c pathway involved in insulininduced fatty acid synthesis in human adipocytes Abbreviations: ACC1, acetyl-CoA carboxylase 1; ACLY, ATP citrate lyase; CIDE, cell death-inducing DNA fragmentation factor-␣ -like effector; DAPI, 4 ′ ,6 ′ -diamidino-2-phenylindole; Dex, dexamethasone; FAS, fatty acid synthase; IPA, Ingenuity Pathway Analysis; JNK, c-Jun N-terminal kinase; LD, lipid droplet; n-SREBP-1c , nuclear form of sterol regulatory element binding protein-1c; PI3K, phosphatidylinositol 3-kinase; pre-SREBP-1c, precursor form of sterol regulatory element binding protein-1c; siJNK, JNK siRNA; siRNA, small interfering RNA; siSREBP-1, SREBP-1 siRNA; SREBP, sterol regulatory element binding protein; WAT, white adipose tissue. Published, JLR Papers in

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Section: Methodsmentioning

confidence: 91%

“…Our recent study showed that JNK2, but not JNK1, mediates regulation of CIDEC expression by insulin in human adipocytes ( 23 ).…”

Section: Jnk2 Mediates Insulin-induced Upregulation Of Lipogenic Enzymentioning

confidence: 99%

A novel JNK2/SREBP-1c pathway involved in insulin-induced fatty acid synthesis in human adipocytes

Ito¹,

Nagasawa²,

Omae³

et al. 2013

Journal of Lipid Research

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“…Insulin is a major regulator of adipogenesis by regulating gene transcription of numerous adipocyte genes, including regulators of cell survival and of lipid droplet formation such as CIDEA and CIDEC 8 and consequently promotes both lipid uptake and differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…8 Thus insulin promotes adipogenesis through indirect activation of lipogenesis and cell survival. In adipocytes lipogenesis results from a rapid uptake of fatty acids (FA) stored in lipid droplets which increase in size and finally fuse into a unique and large droplet in mature adipocytes.…”

Section: Cell and Tissue Imagingmentioning

confidence: 99%

“…lipid accumulation into specific droplets, requires numerous proteins including the cell deathinducing DFFA-like effectors a and c CIDEA and CIDEC to increase in size and for the fusion into larger ones. 6 Both adipogenesis and lipogenesis are stimulated by insulin which increases adipocyte cell size 7 through transcriptional inhibition of apoptosis and activation of lipid droplet synthesis 8 but also controls the transcription and/or secretion of numerous secreted factors such as adiponectin. 9 Lipid uptake by adipocytes is performed through interaction with intracellular fatty acid binding proteins FABP1 and FABP4, with fatty acid translocase FAT/CD36, lipoprotein receptor heparan sulfate proteoglycans HSPG but also G-protein coupled receptors, then accumulation as triglycerides in lipid droplets, [10][11][12][13][14][15][16][17][18] however their respective functions in fatty acid storage and intracellular signaling need further investigations.…”

Section: Introductionmentioning

confidence: 99%

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Pathways commonly dysregulated in mouse and human obese adipose tissue: FAT/CD36 modulates differentiation and lipogenesis

et al. 2015

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Obesity is linked to adipose tissue hypertrophy (increased adipocyte cell size) and hyperplasia (increased cell number). Comparative analyses of gene datasets allowed us to identify 1426 genes which may represent common adipose phenotype in humans and mice. Among them we identified several adipocyte-specific genes dysregulated in obese adipose tissue, involved in either fatty acid storage (acyl CoA synthase ACSL1, hormone-sensitive lipase LIPE, aquaporin 7 AQP7, perilipin PLIN) or cell adhesion (fibronectin FN1, collagens COL1A1, COL1A3, metalloprotein MMP9, or both (scavenger receptor FAT/CD36). Using real-time analysis of cell surface occupancy on xCELLigence system we developed a new method to study lipid uptake and differentiation of mouse 3T3L1 fibroblasts and human adipose stem cells. Both processes are regulated by insulin and fatty acids such as oleic acid. We showed that fatty acid addition to culture media increased the differentiation rate and was required for full differentiation into unilocular adipocytes. Significant activation of lipogenesis, i.e. lipid accumulation, by either insulin or oleic acid was monitored in times ranging from 1 to 24 h, depending on differentiation state, whereas significant effects on adipogenesis, i.e., surperimposed lipid accumulation and gene transcriptional regulations were measured after 3 to 4 d. Combination of selected times for analysis of lipid contents, cell counts, size fractionations, and gene transcriptional regulations showed that FAT/CD36 specific inhibitor AP5258 significantly increased cell survival of oleic acid-treated mouse and human adipocytes, and partially restored the transcriptional response to oleic acid in the presence of insulin through JNK pathway. Taken together, these data open new perspectives to study the molecular mechanisms commonly dysregulated in mouse and human obesity at the level of lipogenesis linked to hypertrophy and adipogenesis linked to hyperplasia

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Is Mitogen‐Activated Protein Kinase Phosphatase 5 a Solution to the Puzzle of the Mitogen‐Activated Protein Kinase Signal in Steatohepatitis?

Miura

Yamamoto

2019

Hepatol Commun

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Differential regulation of CIDEA and CIDEC expression by insulin via Akt1/2- and JNK2-dependent pathways in human adipocytes

Cited by 27 publications

References 57 publications

A novel JNK2/SREBP-1c pathway involved in insulin-induced fatty acid synthesis in human adipocytes

A novel JNK2/SREBP-1c pathway involved in insulin-induced fatty acid synthesis in human adipocytes

Pathways commonly dysregulated in mouse and human obese adipose tissue: FAT/CD36 modulates differentiation and lipogenesis

Is Mitogen‐Activated Protein Kinase Phosphatase 5 a Solution to the Puzzle of the Mitogen‐Activated Protein Kinase Signal in Steatohepatitis?

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