Interviews with outstanding authors. Authors' experiences and opinions. Andrei V. His area of general research interest includes drug discovery, gene discovery, molecular targets for cancer treatment. Mikhail V. Blagosklonny, M. Blagosklonny is the author of over articles in peer-reviewed journals. His research interests range from molecular and cellular biology to clinical investigations.
Recently, he extended the study of signal transduction pathways from cancer to aging, revealing potential targets for slowing down aging and age-related diseases. Frederick W. Alt, Ph. Editorial Boards: Mol. Dafna Bar-Sagi, Ph. Bar-Sagi has published over peer-reviewed articles in leading scientific journals.
Jiri Bartek, MD. He received his M. His main research interests include the molecular mechanisms of mammalian cell-cycle control and responses to DNA damage, and the cancer-predisposing aberrations of these regulatory pathways. Jiri Bartek has a total of more than publications in peer reviewed journals about in Nature, Science and Cell , with over He is currently member of the editorial boards of 10 high-medium impact biomedical journals and has won a number of awards including: , Czech Medical Association Award, Elected EMBO member, A. Stephen B. Baylin, M. Baylin is professor of oncology and medicine, director of the cancer biology program at the oncology center, and the Virginia and D.
For the last 20 years, Dr. Baylin has studied the role of epigenetic gene silencing in the initiation and progression of human cancer. Joseph R. Bertino, M. He has been an American Cancer Society professor since From to , Dr. Bertino served as director of the Yale Comprehensive Cancer Center, including director of the center and associate director for clinical research. Bertino has been internationally recognized for his role in finding curative treatments for leukemia and lymphoma.
He was the founding editor of the Journal of Clinical Oncology. Currently, he is the associate editor for Cancer Research and Clinical Cancer Research and also the editor of the Encyclopedia of Cancer. Bertino served as president for the American Society of Clinical Oncology in , and president of the American Association for Cancer Research in Bertino is the author and co-author of more than scientific publications. Mina J. Mina Bissell has been recognized for her lifetime contributions to the fields of breast cancer research, the enhanced role of extracellular matrix ECM and the nucleus environment to gene expression in normal and malignant tissues.
These works have ushered and have changed some central paradigms that have strengthened the importance of context in the development of cancer. In rodents, glucocorticoids have been shown to reduce the thermogenic activity of brown adipocytes. However, in human acute glucocorticoid exposure, glucocorticoids act to promote thermogenesis. In this article, we will review the recent studies on the mechanisms underlying the complex metabolic functions of GR in adipocytes.
Glucocorticoid Receptor and Adipocyte Biology
These include studies of the metabolic outcomes of adipocyte specific GR knockout mice and identification of novel GR primary target genes that mediate glucocorticoid action in adipocytes. Glucocorticoids are steroid hormones that convey their signals through the intracellular glucocorticoid receptor GR , which is a transcriptional regulator. Before binding to hormones or ligands, the majority of GR is localized in the cytosol and associates with the heat shock protein 90 hsp90 -containing chaperone complex [ 1 — 4 ].
Upon binding to hormones or ligands, the heterocomplex of GR-hspcontaining chaperone complex can passage through the nuclear pore [ 1 — 4 ].
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In the nucleoplasmic region, GR is dissociated from hspcontaining chaperone complex and associates with genomic glucocorticoid response elements GREs to regulate the transcriptional rate of nearby genes. GR usually binds to GREs as a homodimer, though it could also modulate the transcription as a monomer through binding to the DNA [ 5 ] or interaction with other transcription factors [ 6 ]. Glucocorticoids play critical roles in the regulation of metabolic homeostasis.
Upon stress, such as fasting and starvation, glucocorticoids exert their metabolic functions through multiple cell types to maintain plasma glucose levels, which is the major energy source for brain. Glucocorticoid excess does not need to be systemic to result in metabolic syndrome. In fact, patients with metabolic syndrome do not have elevated glucocorticoid levels but are thought to have elevated local levels of glucocorticoids in adipose tissue. It is important to note that reducing glucocorticoid signaling in animal models of metabolic disorders usually improves their metabolic profiles and insulin sensitivity [ 13 — 15 ].
However, not surprisingly, reducing glucocorticoid signaling universally would result in undesired adverse effects.
Adipose tissue plays a key role in whole body metabolic homeostasis. Glucocorticoids affect multiple aspects of adipocyte biology. First, glucocorticoids are included in almost all differentiation media for adipogenesis in vitro. However, the exact role of glucocorticoids and GR in adipose tissue development in vivo has not been established. Second, glucocorticoids exert complex effects on lipid metabolism in adipose tissues. Upon fasting, glucocorticoids increase lipolysis in white adipose tissues, generating glycerol and fatty acids.
The former is the precursor for hepatic gluconeogenesis whereas the latter is an energy source during fasting [ 16 , 17 ]. However, in pathological states, glucocorticoid effects on lipid metabolism in adipose tissue are more complicated. The molecular basis of these fat depot specific effects of glucocorticoids is unclear.
One possibility is depot-specific balance between lipogenic and lipolytic gene expression, which has been investigated in human visceral and subcutaneous adipose derived stem cells [ 20 ] as well as in adipose tissue harvested from obese individuals [ 21 ]. In fact, in rodents, chronic glucocorticoid exposure augments adiposity but is usually not restricted to visceral fat depots [ 22 ]. Third, glucocorticoids suppress insulin-stimulated glucose uptake in adipocytes, which might contribute to the modulation of whole body glucose homeostasis and insulin sensitivity [ 23 — 25 ].
The mechanism underlying glucocorticoid-induced insulin resistance in adipocytes is not entirely clear. Notably, certain studies find that glucocorticoids enhance, rather than suppress, insulin actions in human primary adipocytes [ 26 , 27 ]. Finally, glucocorticoids have been shown to repress the thermogenic activity of brown and beige adipocytes in rodents [ 28 — 31 ].
However, recent studies show that acute glucocorticoid exposure enhances the thermogenic activity of human brown adipose tissue [ 32 ]. The reason for such species-specific effects is unknown. Studies over the last several years have made significant contributions to our understanding of glucocorticoid functions in various aspects of adipocyte biology.
We will review and discuss these new developments below. Glucocorticoids are included in most differentiation protocols that are used to induce adipogenesis in vitro. Transcriptional coregulators of GR [ 35 ] and some GR primary target genes are found to be required for adipocyte differentiation in vitro [ 36 — 38 ].
However, the exact role of GR in adipose tissue development had not been explored until two recent publications. There was no apparent difference in brown adipose tissue development between these mice and wild type mice. This suggests that GR is not required for brown adipose tissue development in vivo. Preadipocytes isolated from brown adipose tissue of brown fat specific GR knockout mice showed immature adipocytes at day seven of differentiation compared to those differentiated from preadipocytes of wild type mice.
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However, the number of mature adipocytes were comparable at day 14 and day 21 of differentiation [ 39 ]. These results demonstrate that GR is dispensable but can accelerate both white and brown adipocyte differentiation.
In another study, several approaches were used to test the role of GR and endogenous glucocorticoids in adipose tissue development. However, GR-null fat pads and their associated adipocyte areas were smaller than those in controls [ 40 ].
Second, eliminating circulating corticosterone by adrenalectomy does not block the formation of de novo fat pads in mice, though the fat pads formed in adrenalectomized mice were smaller than those in control mice [ 40 ].