Agouti Expression in Human Adipose Tissue

Smith, Steven R.; Gawrońska‐Kozak, Barbara; Janderová, Lenka; Nguyen, Taylor M.; Murrell, Angela; Stephens, Jacqueline M.; Mynatt, Randall L.

doi:10.2337/diabetes.52.12.2914

Cited by 69 publications

(55 citation statements)

References 48 publications

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“…Such studies, together with a number of attempts to document the tissue distribution of melanocortin receptor mRNAs (36,38), have concluded that the MC2-R is not present in human adipocytes, and this lack of expression might be explained by the absence of an equivalent PPRE-like sequence in the proximal promoter of the human mc2-r. However, an analysis of the distal human promoter sequence revealed the presence of at least three putative PPRE-like elements, 2 and recent work using both human subcutaneous adipose tissue and human embryonic stem cell line capable of undergoing adipogenesis demonstrated the expression of mc2-r mRNA in the human adipocyte (39). Interestingly, the cell line used in this study is analogous to the 3T3-L1 cell line, being of embryonic mesenchymal origin.…”

Section: The Mmc2-r Promoter Responds To Rxr␣/ppar␥2 In Preadipocytesmentioning

confidence: 58%

A Peroxisome Proliferator-response Element in the Murine mc2-r Promoter Regulates Its Transcriptional Activation during Differentiation of 3T3-L1 Adipocytes

Noon

Clark

King

2004

Journal of Biological Chemistry

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Adrenocorticotropic hormone can stimulate lipolysis and suppress leptin expression in murine adipocytes. These effects are mediated via the melanocortin 2 receptor (MC2-R), which is expressed when 3T3-L1 cells are induced to undergo adipogenesis. In this study, we have characterized the mc2-r promoter in the murine adipocyte, one of the few extra-adrenal sites of expression and a cell type that lacks steroidogenic factor 1 (SF-1), a transcription factor that is required for mc2-r expression in adrenal cells. Transcriptional regulation of the mc2-r in the absence of SF-1 was investigated by 5 deletion analysis of the murine mc2-r promoter in both undifferentiated and differentiated 3T3-L1 cells. The results revealed the presence of a 59-base pair regulatory region within the promoter containing an adipocytespecific enhancer. The ability of this region to confer enhanced activity in the adipocyte was mapped to a peroxisome proliferator-response element (PPRE)-like sequence that bound to peroxisome proliferator-activated receptor ␥ (PPAR␥) and its heterodimeric partner retinoid X receptor ␣ (RXR␣) in adipocyte nuclear extracts. Co-transfection of PPAR␥2/RXR␣ with the pMC2-R(؊112/؉105)GL3 reporter resulted in transcriptional activation in preadipocytes, and this response required an intact PPRE. Mutation of the PPRE to prevent PPAR␥/RXR␣ binding resulted in a complete abrogation of the pMC2-R(؊112/؉105)GL3 reporter activity in day 3 differentiated 3T3-L1 cells, demonstrating a key role played by this site in regulating MC2-R expression in the murine adipocyte. These data highlight a novel mechanism for mc2-r transcription, which may have significance in both adrenal and extra-adrenal sites of expression.The melanocortin 2 receptor (MC2-R) 1,2 is a seven-transmembrane G-protein coupled receptor best known for its role in the adrenal cortex where it couples the actions of adrenocorticotropic hormone (ACTH) to steroidogenesis and increased glucocorticoid output (1). Although the key role of MC2-R in the hypothalamo-pituitary-adrenal axis has been the focus of the majority of publications to date, it is also expressed in a number of extra-adrenal sites including the murine adipocyte, fetal testis, human skin, and sympathetic ganglia (2-5).Early studies using the murine 3T3-L1 cell line, a widely used model of adipogenesis, demonstrated the appearance of high affinity ACTH binding sites following treatment of growth-arrested cells with a mixture of adipogenic agents including insulin, dexamethasone, and 3-isobutyl-1-methyl-xanthine (6). Subsequent characterization of the melanocortin receptors expressed by 3T3-L1 adipocytes revealed the presence of both the MC2 and MC5-R. However, a pharmacological analysis showed that the actions of ACTH were mediated solely through the MC2-R in this cell line (2). ACTH exerts a potent lipolytic effect on the murine adipocyte via the cAMP pathway (7, 8) and has more recently been shown to suppress the expression and secretion of the appetite regulating hormone leptin in differentiated 3...

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Section: The Mmc2-r Promoter Responds To Rxr␣/ppar␥2 In Preadipocytesmentioning

confidence: 58%

A Peroxisome Proliferator-response Element in the Murine mc2-r Promoter Regulates Its Transcriptional Activation during Differentiation of 3T3-L1 Adipocytes

Noon

Clark

King

2004

Journal of Biological Chemistry

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“…Subcutaneous adipose tissue biopsies were obtained from diabetic and nondiabetic subjects using a Bergstrom needle as previously described (22). RNA and DNA extraction.…”

Section: Methodsmentioning

confidence: 99%

Pioglitazone Induces Mitochondrial Biogenesis in Human Subcutaneous Adipose Tissue In Vivo

et al. 2005

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“…In ex vivo experiments with human adipocytes from obese subjects, high expression levels of MC1R, but only low levels of MC2R, have been detected (Smith et al 2003). Nevertheless, MC2R is expressed in human mesenchymal cells (MSC) during adipogenic induction (Smith et al 2003), suggesting that MC2R may have a role as a differentiating factor as in 3T3-L1 cells, but not in fully differentiated cells (Smith et al 2003, Betz et al 2012.…”

Section: Acth and Adipocyte Functionalitymentioning

confidence: 99%

60 YEARS OF POMC: Adrenal and extra-adrenal functions of ACTH

Gallo‐Payet

2016

Journal of Molecular Endocrinology

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The pituitary adrenocorticotropic hormone (ACTH) plays a pivotal role in homeostasis and stress response and is thus the major component of the hypothalamo–pituitary–adrenal axis. After a brief summary of ACTH production from proopiomelanocortin (POMC) and on ACTH receptor properties, the first part of the review covers the role of ACTH in steroidogenesis and steroid secretion. We highlight the mechanisms explaining the differential acute vs chronic effects of ACTH on aldosterone and glucocorticoid secretion. The second part summarizes the effects of ACTH on adrenal growth, addressing its role as either a mitogenic or a differentiating factor. We then review the mechanisms involved in steroid secretion, from the classical Cyclic adenosine monophosphate second messenger system to various signaling cascades. We also consider how the interaction between the extracellular matrix and the cytoskeleton may trigger activation of signaling platforms potentially stimulating or repressing the steroidogenic potency of ACTH. Finally, we consider the extra-adrenal actions of ACTH, in particular its role in differentiation in a variety of cell types, in addition to its known lipolytic effects on adipocytes. In each section, we endeavor to correlate basic mechanisms of ACTH function with the pathological consequences of ACTH signaling deficiency and of overproduction of ACTH.

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Agouti Expression in Human Adipose Tissue

Cited by 69 publications

References 48 publications

A Peroxisome Proliferator-response Element in the Murine mc2-r Promoter Regulates Its Transcriptional Activation during Differentiation of 3T3-L1 Adipocytes

A Peroxisome Proliferator-response Element in the Murine mc2-r Promoter Regulates Its Transcriptional Activation during Differentiation of 3T3-L1 Adipocytes

Pioglitazone Induces Mitochondrial Biogenesis in Human Subcutaneous Adipose Tissue In Vivo

60 YEARS OF POMC: Adrenal and extra-adrenal functions of ACTH

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