Oncostatin M modulation of lipid storage

© 2015 by the authors; licensee MDPI, Basel, Switzerland. Oncostatin M (OSM) is a cytokine belonging to the gp130 family, whose members serve pleiotropic functions. However, several actions of OSM are unique from those of other gp130 cytokines, and these actions may have critical roles in inflammatory mechanisms influencing several metabolic and biological functions of insulin-sensitive tissues. In this review, the actions of OSM in adipose tissue and liver are discussed, with an emphasis on lipid metabolism

The Fat Controller: Adipocyte Development

Obesity is a condition characterized by excess adipose tissue that results from positive energy balance and is the most common metabolic disorder in the industrialized world. The obesity epidemic shows no sign of slowing, and it is increasingly a global problem. Serious clinical problems associated with obesity include an increased risk for type 2 diabetes, atherosclerosis, and cancer. Hence, understanding the origin and development of adipocytes and adipose tissue will be critical to the analysis and treatment of metabolic diseases. Historically, albeit incorrectly, adipocytes were thought to be inert cells whose singular function was lipid storage. It is now known that adipocytes have other critical functions; the most important include sensitivity to insulin and the ability to produce and secrete adipocyte-specific endocrine hormones that regulate energy homeostasis in other tissues. Today, adipocytes are recognized as critical regulators of whole-body metabolism and known to be involved in the pathogenesis of a variety of metabolic diseases. All cells come from other cells and many cells arise from precursor cells. Adipocytes are not created from other adipocytes, but they arise from precursor cells. In the last two decades, scientists have discovered the function of many proteins that influence the ability of precursor cells to become adipocytes. If the expansion of the adipose tissue is the problem, it seems logical that adipocyte development inhibitors could be a viable anti-obesity therapeutic. However, factors that block adipocyte development and limit adipocyte expansion also impair metabolic health. This notion may be counterintuitive, but several lines of evidence support the idea that blocking adipocyte development is unhealthy. For this reason it is clear that we need a better understanding of adipocyte development. © 2012 Jacqueline M

Induction of SOCS-3 is insufficient to confer IRS-1 protein degradation in 3T3-L1 adipocytes

Insulin receptor substrate (IRS)-1 is a key protein in insulin signaling. Several studies have shown that the expression of IRS-1 can be modulated by protein degradation via the proteasome and the degradation of IRS-1 can be related to insulin-resistant states. The degradation of IRS-1 has been shown to be induced by SOCS-1 and SOCS-3 via the ubiquitin pathway. The goal of our study was to determine if the induction of SOCS-3 correlated with increased IRS-1 degradation in cultured 3T3-L1 adipocytes. Interestingly, our studies have shown that there is little correlation between the induction in SOCS-3 expression and the degradation of IRS-1 in mature 3T3-L1 adipocytes. Our results clearly demonstrate that treatment with leukemia inhibitory factor (LIF) or cardiotrophin (CT)-1 strongly induces the expression of SOCS-3 in mature 3T3-L1 adipocytes, but does not affect the degradation of IRS-1. On the contrary, tumor necrosis factor (TNF) α and insulin, which very weakly induce SOCS-3 expression, have profound effects on IRS-1 degradation. In summary, our results indicate that the expression of SOCS-3 does not correlate with the degradation of IRS-1 proteins in fat cells. © 2006 Elsevier Inc. All rights reserved

Adipogenesis

Adipose tissue is an important site for lipid storage, energy homeostasis, and whole-body insulin sensitivity. It is important to understand the mechanisms involved in adipose tissue development and function, which can be regulated by the endocrine actions of various peptide and steroid hormones. Recent studies have revealed that white and brown adipocytes can be derived from distinct precursor cells. This review will focus on transcriptional control of adipogenesis and its regulation by several endocrine hormones. The general functions and cellular origins of adipose tissue and how the modulation of adipocyte development pertains to metabolic disease states will also be considered. © 2012 Cold Spring Harbor Laboratory Press; all rights reserved

Diosgenin, 4-hydroxyisoleucine, and fiber from fenugreek: Mechanisms of actions and potential effects on metabolic syndrome

© 2015 American Society for Nutrition. Metabolic syndrome and its complications continue to rise in prevalence and show no signs of abating in the immediate future. Therefore, the search for effective treatments is a high priority in biomedical research. Products derived from botanicals have a time-honored history of use in the treatment of metabolic diseases including type 2 diabetes. Trigonella foenum-graecum, commonly known as fenugreek, is an annual herbaceous plant that has been a staple of traditional herbal medicine in many cultures. Although fenugreek has been studied in both clinical and basic research settings, questions remain about its efficacy and biologic mechanisms of action. Diosgenin, 4-hydroxyisoleucine, and the fiber component of the plant are the most intensively studied bioactive constituents present in fenugreek. These compounds have been demonstrated to exert beneficial effects on several physiologic markers including glucose tolerance, inflammation, insulin action, liver function, blood lipids, and cardiovascular health. Although insights into the molecular mechanisms underlying the favorable effects of fenugreek have been gained, we still do not have definitive evidence establishing its role as a therapeutic agent in metabolic disease. This review aims to summarize the currently available evidence on the physiologic effects of the 3 best-characterized bioactive compounds of fenugreek, with particular emphasis on biologic mechanisms of action relevant in the context of metabolic syndrome

2-deoxyglucose inhibits induction of chemokine expression in 3T3-L1 adipocytes and adipose tissue explants

© 2016 The Obesity Society Objective: To determine the influence of glycolytic inhibition on the adipocyte inflammatory response. Methods: To determine the effect of 2-deoxyglucose (2-DOG) on the inflammatory response, mature 3T3-L1 adipocytes were co-treated with 2-DOG and LPS or TNF. To determine the effect of endoplasmic reticulum stress on TNF-induced induction of chemokines, adipocytes were pretreated with thapsigargin or salubrinal. Chemokine mRNA levels were determined using quantitative real-time PCR, and secretion of CCL2 was determined by Western blot. Results: 2-DOG treatment reduced the ability of LPS and TNF to induce CCL2 mRNA levels and reduced secreted CCL2 protein levels in a dose-dependent manner. A similar pattern of mRNA regulation was observed for other chemokines. The attenuation of TNF-induced CCL2 mRNA levels occurred regardless of whether glucose or pyruvate was present in the media, suggesting that mechanisms other than glycolysis might mediate the observed effects. Treatment with the endoplasmic reticulum stressor thapsigargin and the endoplasmic reticulum signaling activator salubrinal reduced chemokine mRNA levels similarly to 2-DOG. Conclusions: Collectively, our data indicate that 2-DOG suppresses inflammatory chemokine induction in adipocytes. The effects of 2-DOG do not seem to be linked to glycolysis but correlate with endoplasmic reticulum stress activation

Effects of leukemia inhibitory factor on 3T3-L1 adipocytes

Leukemia inhibitory factor (LIF) is a member of the gp130 cytokine family and signals through the receptor complex of gp130 and the LIF receptor (LIFR) to activate the JAK/STAT signaling cascade. Since LIF activates STATs 1 and 3 in adipocytes, we examined the effects of LIF on 3T3-L1 adipocytes. Our studies clearly demonstrate that LIF treatment had minimal effects on adipocyte differentiation as judged by marker gene expression, but did inhibit triacylglyceride (TAG) accumulation during adipogenesis. Acute treatment with LIF resulted in increased expression of suppressors of cytokine signaling-3 (SOCS3) and CCAAT/enhancer-binding protein-δ (C/EBPδ) mRNA in 3T3-L1 adipocytes. Moreover, the upregulation of C/EBPδ correlated with binding to three sites in the C/EBPδ promoter by LIF-activated protein complexes that contained STAT1 and not STAT3. Chronic treatment with LIF resulted in decreased protein levels of sterol regulatory element binding protein-1 (SREBP1) and fatty acid synthase (FAS), but had no effect on the expression of other adipocyte marker proteins or on TAG levels in mature 3T3-L1 adipocytes. LIF had a small effect on insulin-stimulated glucose uptake in 3T3-L1 adipocytes, but did not cause insulin resistance following chronic treatment. These findings indicate that LIF has similar and distinct effects in comparison with the effects of other gp130 cytokines on cultured fat cells. In summary, our results support a role for LIF in the regulation of proteins involved in lipid synthesis and in the modulation of signal transduction pathways in 3T3-L1 adipocytes. © 2005 Society for Endocrinology

Modulation and lack of cross-talk between signal transducer and activator of transcription 5 and suppressor of cytokine signaling-3 in insulin and growth hormone signaling in 3T3-L1 adipocytes

Objective: To examine the role of signal transducer and activator of transcription (STAT) 5 and suppressor of cytokine signaling (SOCS)-3 in the cross-talk between growth hormone and insulin (INS) signaling in fat cells. Research Methods and Procedures: Fully differentiated 3T3-L1 adipocytes were exposed to INS, growth hormone (GH), or both of these growth factors, and the activation of STAT5 proteins and mitogen-activated protein kinase was examined using phospho-specific antibodies. The induction of SOCS-3 mRNA was assessed by Northern blot analysis. INS-stimulated glucose transport was also measured. Results: We observed that GH, not INS, induced STAT5 activation in adipocytes in a manner that was independent of extracellular signal-regulated kinase (ERK) activation or new protein synthesis. GH strongly induced SOCS-3 mRNA expression, whereas INS had a much less potent effect on SOCS-3 mRNA expression. Because SOCS-3 has been implicated in the attenuation of GH and INS signaling, we examined the cross-talk between these signaling pathways. GH pretreatment of adipocytes inhibited GH signaling. Similarly, INS pretreatment inhibited INS signaling. However, INS did not block the GH-induced activation of STAT5, and GH did not block the INS induction of ERK activity or of increased glucose uptake. We observed that neither new protein synthesis nor activation of ERKs 1 and 2 were required for the inhibition of GH signaling. Discussion: These results demonstrate that blocking the induction of the SOCS-3 protein has no effect on the attenuation of GH signaling and support recent studies suggesting that SOCS proteins have additional functions. In addition, these studies demonstrate that GH-induced SOCS-3 expression is insufficient to inhibit INS-induced glucose uptake in adipocytes. Copyright © 2006 NAASO

Controlling a master switch of adipocyte development and insulin sensitivity: Covalent modifications of PPARγ

Adipocytes are highly specialized cells that play a central role in lipid homeostasis and the maintenance of energy balance. Obesity, an excessive accumulation of adipose tissue, is a major risk factor for the development of Type 2 diabetes mellitus (T2DM), cardiovascular disease, and hypertension. A variety of studies suggest that obesity and T2DM can be linked to a breakdown in the regulatory mechanisms that control the expression and transcriptional activity of PPARγ. PPARγ is a nuclear hormone receptor that functions as a master switch in controlling adipocyte differentiation and development. Also important in controlling glucose homeostasis and insulin sensitivity, PPARγ is a ligand-dependent transcription factor that is the functional receptor for the anti-diabetic thiazolidinediones (TZDs). In the last fifteen years, a variety of covalent modifications of PPARγ activity have been identified and studied. These covalent modifications include phosphorylation, ubiquitylation, O-GlcNAcylation and SUMOylation. Covalent modifications of PPARγ represent key regulatory mechanisms that control both PPARγ protein stability and transcriptional activity. A variety of PPARγ transgenic models, including mice heterozygous for PPARγ, have demonstrated the importance of PPARγ expression in glucose homeostasis and insulin resistance. In the following review, we have highlighted the regulation of PPARγ by covalent modifications, the interplay between these interactions and how these post-translational modifications impact metabolic disease states. © 2012 Elsevier B.V