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WIREs Syst Biol Med
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Systems biology of adipose tissue metabolism: regulation of growth, signaling and inflammation

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Abstract Adipose tissue (AT) depots actively regulate whole body energy homeostasis by orchestrating complex communications with other physiological systems as well as within the tissue. Adipocytes readily respond to hormonal and nutritional inputs to store excess nutrients as intracellular lipids or mobilize the stored fat for utilization. Co‐ordinated regulation of metabolic pathways balancing uptake, esterification, and hydrolysis of lipids is accomplished through positive and negative feedback interactions of regulatory hubs comprising several pleiotropic protein kinases and nuclear receptors. Metabolic regulation in adipocytes encompasses biogenesis and remodeling of uniquely large lipid droplets (LDs). The regulatory hubs also function as energy and nutrient sensors, and integrate metabolic regulation with intercellular signaling. Over‐nutrition causes hypertrophic expansion of adipocytes, which, through incompletely understood mechanisms, initiates a cascade of metabolic and signaling events leading to tissue remodeling and immune cell recruitment. Macrophage activation and polarization toward a pro‐inflammatory phenotype drives a self‐reinforcing cycle of pro‐inflammatory signals in the AT, establishing an inflammatory state. Sustained inflammation accelerates lipolysis and elevates free fatty acids in circulation, which robustly correlates with development of obesity‐related diseases. The adipose regulatory network coupling metabolism, growth, and signaling of multiple cell types is exceedingly complex. While components of the regulatory network have been individually studied in exquisite detail, systems approaches have rarely been utilized to comprehensively assess the relative engagements of the components. Thus, need and opportunity exist to develop quantitative models of metabolic and signaling networks to achieve a more complete understanding of AT biology in both health and disease. WIREs Syst Biol Med 2013, 5:425–447. doi: 10.1002/wsbm.1213 This article is categorized under: Biological Mechanisms > Metabolism Physiology > Mammalian Physiology in Health and Disease Biological Mechanisms > Regulatory Biology

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Regulatory hubs in adipocyte metabolism. The signaling pathways anchored by adenosine monophosphate‐activated protein kinase (AMPK) and mTORC1 and nuclear receptor PPARγ afford multiple layers of control over fatty acid flux through regulation of different enzymes in overlapping pathways.

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Chronic over‐nutrition leads to adipocyte hypertrophy, tissue remodeling, angiogenesis, and possibly hyperplasia (through precursor cell proliferation and adipogenesis). Hypertrophic adipocytes generate paracrine signals to recruit circulating immune cells and activate tissue‐resident macrophages. Polarization toward a pro‐inflammatory M1 phenotype induces secretion of additional pro‐inflammatory cytokines that establish a self‐reinforcing inflammatory signaling loop with adipocytes, and elicit enhanced lipolysis and possible cell death, further exacerbating the inflammatory state. An additional source inflammation is enhanced absorption of gut microbiota derived lipopolysaccharide (LPS) due to dysbiosis and impaired gut barrier function resulting from over‐nutrition. For clarity, only representative signaling factors are shown.

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Inflammatory signaling between adipocytes and macrophages. Macrophage‐derived TNFα induces production of pro‐inflammatory cytokines and lipolysis in adipocytes, suppresses expression of adiponectin, and impairs insulin signaling. Lipolysis releases saturated fatty acids (SFAs), which stimulate expression of inflammatory genes in macrophages through the NF‐κB pathway. The positive feedback toward a pro‐inflammatory state may be counterbalanced by a negative control mechanism. In addition to adiponectin, adipocytes also produce anti‐inflammatory cytokines IL‐13 and IL‐4, which increases PPARδ expression in macrophages and promotes polarization toward the M2 phenotype.

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Multi‐functional regulators of adipocyte metabolism and AT signaling. Transcriptional activators and protein kinases that regulate major metabolic pathways in adipocytes also mediate the production of cell–cell signaling factors. The regulatory molecules are shown in the third column (from the left), with signaling and metabolic function modules shown to the left and right, respectively. Lines with the same color refer to a common regulatory molecule. The lines between Angiogenesis and VEGF‐A, Immune cell recruitment and MCP‐1, Immune cell recruitment and Macrophage priming, and Hypoxia‐induced production of HIF‐a targets and NF‐kB should appear darker. The lines connecting the first and second columns should all be black, and the line connecting Hypoxia‐induced production of HIF‐a targets to NF‐kB should be purple, just as the other lines extending from NF‐kB. Also, there should be a yellow line from FOXC2 to Mitochondrial oxidation. Black lines indicate functional activation.

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Negative and positive feedback mechanisms regulating lipogenesis and lipolysis. (a) Reesterification of fatty acids (FAs) increases the cellular AMP/ATP ratio, and activates the adenosine monophosphate‐activated protein kinase (AMPK) signaling pathway. Activated AMPK inhibits mTORC1, attenuating reesterification. Additionally, AMPK phosphorylation inactivates Acetyl‐CoA carboxylase (ACC) to suppress FA synthesis. (b) Activation of PPARγ induces the expression of lipolytic enzymes, generating FFAs from TG hydrolysis. The free fatty acids (FFAs) as well as other intermediates of the lipolysis pathway can be converted into PPARγ ligands, which could further increase lipolysis through positive feedback. Uncontrolled FFA efflux is prevented by a parallel upregulation of lipogenesis. Further, modulation of lipolysis is possible through additional regulators such as FOXO1, which stimulates lipolysis, but also inhibits transcriptional activation by PPARγ.

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Physiology > Mammalian Physiology in Health and Disease
Biological Mechanisms > Regulatory Biology
Biological Mechanisms > Metabolism

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