Hormonal regulation of malic enzyme and glucose‐6‐phosphate‐dehydrogenase expression in fetal brown‐adipocyte primary cultures under non‐proliferative conditions

Valverde, Ángela M.; Benito, Manuel; Lorenzo, Margarita

doi:10.1111/j.1432-1033.1992.tb19861.x

Cited by 25 publications

(12 citation statements)

References 28 publications

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“…However, NADPH may be produced both via Glc-6-phosphate dehydrogenase in the pentose phosphate pathway and via malic enzyme. Brown adipocyte differentiation induces increases in both of these enzymes, and thus both may play a role in generating NADPH for lipogenesis (31,32). As shown here, isotopic tools, including ISA, may be applied to further explore and quantify lipogenic fluxes in brown adipose cells.…”

Section: Physiology Of Lipogenesis In Brown Adipose Cellsmentioning

confidence: 83%

Quantifying carbon sources for de novo lipogenesis in wild-type and IRS-1 knockout brown adipocytes

Yoo

Stephanopoulos

Kelleher

2004

Journal of Lipid Research

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Studies were conducted to evaluate the flux of various carbon sources to lipogenesis during brown adipocyte differentiation. 13 C labeling and isotopomer spectral analysis quantified the contribution of metabolites to de novo lipogenesis in wild-type (WT) and insulin receptor substrate-1 knockout (KO) brown adipocytes. Both glucose (Glc) and glutamine (Gln) provided substantial fractions of the lipogenic acetyl CoA for both WT and KO cells in standard media, together contributing 60%. Adding acetoacetate (AcAc; 10 mM) to the medium resulted in a large flux of AcAc to lipid, representing 70% of the lipogenic acetyl CoA and decreasing the contribution of Glc plus Gln to 30%. For WT cells, the fractional synthesis of new fatty acids during 4 days of differentiation was 80% of the total. Similarly, 80% of the lipidic glycerol was derived from Glc in the medium; Gln was not a precursor for glycerol. When Gln was removed from the medium, the contribution of Glc to fatty acid synthesis doubled, replacing most of the contribution of Gln and maintaining total lipogenesis. Conversely, removal of Glc dramatically decreased lipogenesis. These results indicate that Glc's distinct role in lipid synthesis during differentiation cannot be replaced by other carbon sources, consistent with the role of Glc supplying NADPH and/or glycerol for triglyceride synthesis. The differentiation of brown adipocyte cells from a fibroblast-like precursor is evolutionarily related to prehibernation fat accumulation and thus linked to total body energy metabolism (1). Adipogenesis occurs under conditions of excess nutrients and accompanying hormones and involves changes in gene expression and cell signaling, leading to a substantial increase in de novo synthesis and storage of triglyceride. Cell surface receptors, especially for insulin and insulin-like growth factor-1, provide a mechanism for hormonal response to nutrient abundance. Recent investigations of adipogenesis have focused on gene expression and cell signaling events associated with this conversion (2-4). The importance of the insulin receptor substrate-1 (IRS-1) signaling pathway for differentiation has been demonstrated by the finding that an IRS-1 knockout (KO) preadipocyte cell line is unable to differentiate under the standard condition in which wildtype (WT) cells accumulate triglyceride and express adipocyte-specific genes, including UCP-1 and fatty acid synthase (5). A consequence of the IRS-1 KO is that these cells are deficient in insulin-stimulated glucose (Glc) uptake via the Glc transporter GLUT4. The studies of in vitro adipogenesis are normally conducted under constant nutrient conditions using cell culture media in which Glc (25 mM) and glutamine (Gln; 2-4 mM) provide the major carbon sources for cell metabolism. In the work presented here, we investigate the role of the nutrient and hormonal environment on the process of lipogenesis accompanying brown adipocyte differentiation.Animal studies support the concept that Glc is a major carbon source for brown adip...

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Section: Physiology Of Lipogenesis In Brown Adipose Cellsmentioning

confidence: 83%

Quantifying carbon sources for de novo lipogenesis in wild-type and IRS-1 knockout brown adipocytes

Yoo

Stephanopoulos

Kelleher

2004

Journal of Lipid Research

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“…In these cells insulin and IGF-I, acting independently, up-regulate the expression of adipogenic-related genes (fatty acid synthase, glycerol-3-phosphate dehydrogenase, malic enzyme, glucose-6-phosphate dehydrogenase) in a dose and time-dependent manner at the transcriptional level, resulting in an increase of cytosolic lipid content [20,40].…”

Section: Role Of Insulin/igf-i In Brown Adipocyte Differentiation: Momentioning

confidence: 99%

The Brown Adipose Cell: A Unique Model for Understanding the Molecular Mechanism of Insulin Resistance

Valverde

Benito²

2005

MRMC

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Type 2 diabetes mellitus (NIDDM) is a complex metabolic disease that occurs when insulin secretion can no longer compensate insulin resistance in peripheral tissues. At the molecular level, insulin resistance correlates with impaired insulin signaling. This review provides new insights into the molecular mechanisms of insulin action and resistance in brown adipose tissue (BAT) and pinpoints the role of BAT in the control of glucose homeostasis.

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“…In these cells, insulin and IGF-I, acting independently, up-regulate the expression of adipogenic-related genes in a dose and timedependent manner at the transcriptional level, resulting in an increase of cytosolic lipid content (Valverde et al 1992. In these cells, insulin and IGF-I, acting independently, up-regulate the expression of adipogenic-related genes in a dose and timedependent manner at the transcriptional level, resulting in an increase of cytosolic lipid content (Valverde et al 1992.…”

Section: The Insulin/igf-i Signalling Cascade In Brown Adipocytes Difmentioning

confidence: 99%

The brown adipose cell: a model for understanding the molecular mechanisms of insulin resistance

Valverde

Benito

Lorenzo

2005

Acta Physiologica Scandinavica

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Type 2 diabetes mellitus is a complex metabolic disease that occurs when insulin secretion can no longer compensate insulin resistance in peripheral tissues. At the molecular level, insulin resistance correlates with impaired insulin signalling. This review provides new insights into the molecular mechanisms of insulin action and resistance in brown adipose tissue and pinpoints the role of this tissue in the control of glucose homeostasis. Brown adipocytes are target cells for insulin and IGF-I action, especially during late foetal development when insulin supports survival and promotes both adipogenic and thermogenic differentiation. The main pathway involved in insulin induction of adipogenic differentiation, monitored by fatty acid synthase expression, is the cascade insulin receptor substrate (IRS)-1/phosphatidylinositol 3-kinase (PI3K)/Akt. Glucose transport in these cells is maintained mainly by the activity of GLUT4. Acute insulin treatment stimulates glucose transport largely by mediating translocation of GLUT4 to the plasma membrane, involving the activation of IRS-2/PI3K, and the downstream targets Akt and protein kinase C zeta. Tumour necrosis factor (TNF-alpha) caused insulin resistance on glucose uptake by impairing insulin signalling at the level of IRS-2. Activation of stress kinases and phosphatases by this cytokine contribute to insulin resistance. Furthermore, brown adipocytes are also target cells for rosiglitazone action since they show a high expression of peroxisome proliferator activated receptor gamma, and rosiglitazone increased the expression of the thermogenic uncoupling protein 1. Rosiglitazone ameliorates insulin resistance provoked by TNF-alpha, completely restoring insulin-stimulated glucose uptake in parallel to the insulin signalling cascade. Accordingly, foetal brown adipocytes represent a model for investigating insulin action, as well as for the mechanism by which rosiglitazone increase insulin sensitivity under situations that mimic insulin resistance.

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Hormonal regulation of malic enzyme and glucose‐6‐phosphate‐dehydrogenase expression in fetal brown‐adipocyte primary cultures under non‐proliferative conditions

Cited by 25 publications

References 28 publications

Quantifying carbon sources for de novo lipogenesis in wild-type and IRS-1 knockout brown adipocytes

Quantifying carbon sources for de novo lipogenesis in wild-type and IRS-1 knockout brown adipocytes

The Brown Adipose Cell: A Unique Model for Understanding the Molecular Mechanism of Insulin Resistance

The brown adipose cell: a model for understanding the molecular mechanisms of insulin resistance

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