Trends in endocrinology and metabolism

Insulin signaling - mathematical modeling comes of age.

Publication Date: 2012 Jan 27 PMID: 22285743
Authors: Nyman, E. - Cedersund, G. - Stralfors, P.
Journal: Trends Endocrinol Metab

Signaling pathways that only a few years ago appeared simple and understandable, albeit far from complete, have evolved into very complex multi-layered networks of cellular control mechanisms, which in turn are integrated in a similarly complex whole-body level of control mechanisms. This complexity sets limits for classical biochemical reasoning, such that a correct and complete analysis of experimental data while taking the full complexity into account is not possible. In this Opinion we propose that mathematical modeling can be used as a tool in insulin signaling research, and we demonstrate how recent developments in modeling - and the integration of modeling in the experimental process - provide new possibilities to approach and decipher complex biological systems more efficiently.

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AMPK functions as an adenylate charge-regulated protein kinase.

Publication Date: 2012 Jan 25 PMID: 22284532
Authors: Oakhill, J. S. - Scott, J. W. - Kemp, B. E.
Journal: Trends Endocrinol Metab

The energy sensor AMP-activated protein kinase (AMPK) is activated by metabolic stress and restores ATP levels in cells by switching off anabolic and switching on catabolic pathways. Recent discoveries demonstrate that AMPK is activated primarily by rising ADP levels and not, as previously thought, by AMP. AMPK activation is dependent on ADP-controlled phosphorylation of Thr172 on its activation loop, a mechanism of protein regulation that represents an example of an allosterically regulated modification (ARM). AMPK embodies many features of an adenylate charge regulatory system envisaged by Atkinson, where anabolic and catabolic pathway regulation is modulated by adenine nucleotide ratios. Here we discuss the current state of AMPK regulation by adenine nucleotides and we propose that AMPK functions as an adenylate charge-regulated protein kinase.

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Insulin-sensitive obesity in humans - a 'favorable fat' phenotype?

Publication Date: 2012 Jan 25 PMID: 22284531
Authors: Samocha-Bonet, D. - Chisholm, D. J. - Tonks, K. - Campbell, L. V. - Greenfield, J. R.
Journal: Trends Endocrinol Metab

In most humans, obesity and insulin resistance coexist. However, a unique group of obese individuals, who exhibit better insulin sensitivity than expected for their adiposity, has been the focus of recent research interest. We critically examine cross-sectional and lifestyle intervention studies in obese humans classified as 'insulin-sensitive' versus 'insulin-resistant' and review the few longitudinal studies comparing rates of cardiovascular disease, type 2 diabetes and all-cause mortality in these groups of individuals. We suggest that reduced deposition of fat, particularly of bioactive lipid intermediates, in muscle and liver is potentially protective. We propose that dynamic interventional studies in insulin-sensitive obese humans may increase understanding of the metabolic factors that play a role in obesity-associated insulin resistance in humans.

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CTRP family: linking immunity to metabolism.

Publication Date: 2012 Jan 17 PMID: 22261190
Authors: Schaffler, A. - Buechler, C.
Journal: Trends Endocrinol Metab

It is well known that infectious and inflammatory diseases such as sepsis and severe inflammatory response syndrome are accompanied by metabolic alterations such as insulin resistance. Conversely, metabolic diseases such as visceral obesity and type 2 diabetes are characterized by high levels of proinflammatory cytokines. Metabolism and immunity are linked by proteins of dual function. Adiponectin, a member of the C1q/TNF-related protein (CTRP) family, has attracted much interest because of its anti-inflammatory and insulin-sensitizing effects. To date, 15 additional CTRP family members have been identified that might also play a role in metabolism and immunity. This review focuses on the biochemistry and pleiotropic physiological functions of CTRPs as new molecular mediators connecting inflammatory and metabolic diseases.

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ERalpha, microRNAs, and the epithelial-mesenchymal transition in breast cancer.

Publication Date: 2012 Jan 16 PMID: 22257677
Authors: Guttilla, I. K. - Adams, B. D. - White, B. A.
Journal: Trends Endocrinol Metab

The most common form of breast cancer, luminal A, is estrogen receptor alpha (ERalpha)-positive and epithelial, but nevertheless can metastasize. The process of epithelial-mesenchymal transition (EMT) is probably the first step in the metastasis of epithelial cancers. We discuss the characteristics of EMT, including factors that induce EMT, and the relationship of EMT to cancer stem cells (CSCs). Estrogen/ERalpha signaling maintains an epithelial phenotype and suppresses EMT. An overview of microRNAs in breast cancer is presented, including how microRNA biogenesis is altered in cancer and regulated by ERalpha. We also discuss the role of the miR-200 family in opposing EMT. Finally, we discuss specific microRNAs that target ERalpha and regulate EMT in breast cancer, and the role of these microRNAs in breast cancer progression.

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Insulin resistance in the nervous system.

Publication Date: 2012 Jan 13 PMID: 22245457
Authors: Kim, B. - Feldman, E. L.
Journal: Trends Endocrinol Metab

Metabolic syndrome is a cluster of cardiovascular risk factors including obesity, diabetes and dyslipidemia. Insulin resistance (IR) is at the core of metabolic syndrome. In adipose tissue and muscle, IR results in decreased insulin signaling, primarily affecting downstream phosphatidylinositol 3-kinase (PI3K)/Akt signaling. It was recently proposed that neurons can develop hyperinsulinemia-induced IR, which in turn results in injury to the peripheral and central nervous systems and is probably pathogenic in common neurological disorders such as diabetic neuropathy and Alzheimer's disease (AD). This review presents evidence indicating that, similarly to insulin-dependent metabolically active tissues such as fat and muscle, neurons also develop IR and thus cannot respond to the neurotrophic properties of insulin, resulting in neuronal injury, subsequent dysfunction and disease states.

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Oxysterols as non-genomic regulators of cholesterol homeostasis.

Publication Date: 2012 Jan 11 PMID: 22244444
Authors: Bielska, A. A. - Schlesinger, P. - Covey, D. F. - Ory, D. S.
Journal: Trends Endocrinol Metab

Tight regulation of cellular and plasma cholesterol is crucial to proper cellular functioning because excess free cholesterol is toxic to cells and is associated with atherosclerosis and heart disease. Cellular cholesterol homeostasis is regulated by enzymatically formed oxygenated cholesterol derivatives termed oxysterols. Although the effects of oxysterols on transcriptional pathways are well described, the non-transcriptional mechanisms through which oxysterols acutely modulate cellular cholesterol levels are less well understood. We present emerging evidence suggesting that the membrane biophysical properties of oxysterols underlie their acute cholesterol-regulatory functions and discuss the relevance of these acute effects to cholesterol overload in physiological and pathophysiological states.

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