MicroRNA Expression in Human Omental and Subcutaneous Adipose Tissue

Klöting, Nora; Berthold, Susan; Kovacs, Peter; Schön, Michael P.; Faßhauer, Mathias; Ruschke, Karen; Stümvoll, Michael; Blüher, Matthias

doi:10.1371/journal.pone.0004699

Cited by 304 publications

(289 citation statements)

References 25 publications

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“…All data are representative of three independent experiments. *P < 0.05; **P < 0.01; ***P < 0.001. sion of certain miRNAs and circulating leptin (25). In this study, we show that leptin could suppress the expressions of a panel of miRNAs to mediate induction of gene expressions in B cells.…”

Section: Discussionmentioning

confidence: 56%

Leptin signaling maintains B-cell homeostasis via induction of Bcl-2 and Cyclin D1

Lam

Wang

et al. 2010

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

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Regulation of apoptosis and cell cycle progression plays an essential role in the maintenance of B-cell homeostasis, because a fine balance of survival and expansion is critical for preventing lymphocytic disorders. Although remarkable progress in understanding B-cell development has been achieved, much less is known concerning niches that are critical to the maintenance of B-cell homeostasis. Leptin has recently been recognized to be important for modulating the immune responses, but it has remained unclear how leptin signaling influences B-cell physiology. A variety of lymphocytic malignancies have been reported to be linked to leptin, and therefore it is necessary to elucidate the mechanisms involved. Here we demonstrate that leptin promotes B-cell homeostasis by inhibiting apoptosis and by inducing cell cycle entry through the activation of expressions of B-cell CLL/lymphoma 2 (Bcl-2) and cyclin D1. We further show that leptin can induce Bcl-2 and cyclin D1 expression by two pathways, including the direct activation of their promoters and suppression of microRNAs (miRNAs) that target their putative 3′untranslated regions. Amplification of these leptin-modulated miRNAs inhibited B lymphoma cell growth. These findings provide insights into mechanisms for leptin regulation of the humoral immune system and suggest new therapeutic strategies for leptin receptor expressing malignancies.B cell survival | apoptosis | proliferation | microRNA A poptosis plays an essential role in the maintenance of B-cell homeostasis, a process that is regulated by a fine balance between the continual generation of new B lymphocytes and their elimination through multiple checkpoints in both bone marrow (BM) and secondary lymphoid organs (1). The balance between B cell survival and death is critical because excessive apoptosis may lead to immunodeficiencies whereas insufficient apoptosis may result in autoimmunity and even lymphoid malignancies (2). B cells that are optimally activated escape apoptosis and transit through different cell cycle checkpoints. B-cell CLL/lymphoma 2 (Bcl-2) family proteins, which function to preserve or disturb mitochondrial integrity, are required for the maintenance of immune homeostasis (2, 3). Targeted loss of the antiapoptotic member gene Bcl-2 has led to massive apoptosis of lymphocytes, whereas overexpression of Bcl-2 has caused the accumulation of B cells (4, 5). D-type cyclins are key players in the G 1 checkpoint control mechanism and are critical for cell proliferation (6). Both Bcl-2 and D-type cyclins are prime targets for novel therapeutics because their overexpression is common in many hematological diseases and many types of cancers (7,8). MicroRNAs (miRNAs) are increasingly recognized for their prominent role in immune homeostasis, while the accumulating evidence for aberrant miRNA expression in B-cell-derived tumors underscores miRNAs as potential targets for cancer therapeutics (9). Therefore, elucidation of the regulatory mechanisms of miRNAs in peripheral B cells will contribute to a fu...

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Section: Discussionmentioning

confidence: 56%

Leptin signaling maintains B-cell homeostasis via induction of Bcl-2 and Cyclin D1

Lam

Wang

et al. 2010

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

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“…Namely, miR-134 is related to insulin sensitivity and chronic hyperglycemia, whereas miR-132 is linked to obesityinduced adipose tissue inflammation in humans. 30 HFD-fed NOX4-deficient mice showed increased miR-134 and miR-132 expression compared with WT mice on the same regime (Figure 3o). Upregulation of miR-143 was associated with HFD-induced obesity, and miR-21 has been shown to regulate adipogenic differentiation of mesenchymal stem cells.…”

Section: Resultsmentioning

confidence: 92%

Deficiency in the NADPH oxidase 4 predisposes towards diet-induced obesity

Mouche

Sajic

et al. 2012

Int J Obes

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OBJECTIVE: NADPH oxidase 4 (NOX4) is a reactive oxygen species (ROS) producing NADPH oxidase that regulates redox homeostasis in diverse insulin-sensitive cell types. In particular, NOX4-derived ROS is a key modulator of adipocyte differentiation and mediates insulin receptor signaling in mature adipocytes in vitro. Our study was aimed at investigating the role of NOX4 in adipose tissue differentiation, whole body metabolic homeostasis and insulin sensitivity in vivo. DESIGN: Mice with genetic ablation of NOX4 (NOX4-deficient mice) were subjected to chow or high-fat-containing diet for 12 weeks. Body weight gain, adiposity, insulin sensitivity, and adipose tissue and liver gene and protein expression were analyzed and compared with similarly treated wild-type mice. RESULTS: Here, we report that NOX4-deficient mice display latent adipose tissue accumulation and are susceptible to diet-induced obesity and early onset insulin resistance. Obesity results from accelerated adipocyte differentiation and hypertrophy, and an increase in whole body energy efficiency. Insulin resistance is associated with increased adipose tissue hypoxia, inflammation and adipocyte apoptosis. In the liver, more severe diet-induced steatosis was observed due to the lack of proper upregulation of mitochondrial fatty acid b-oxidation. CONCLUSION: These findings identify NOX4 as a regulator of metabolic homeostasis. Moreover, they indicate an anti-adipogenic role for NOX4 in vivo and reveal its function as a protector against the development of diet-induced obesity, insulin resistance and hepatosteatosis.

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“…111 The expression of miR-27 decreases during adipogenesis and, interestingly, was found to be increased in adipose tissue of obese mouse. Finally, significant correlation of the levels of differents miRNAs with metabolic parameters such as fasting plasma glucose or circulating leptin and adiponectin has also been reported, 112 highlighting the importance of these factors in the regulation of metabolism.…”

Section: Differentiation Of Preadipocytesmentioning

confidence: 88%