Flux profile and modularity analysis of time-dependent metabolic changes of de novo adipocyte formation

Si, Yaguang; Yoon, Jeongah; Lee, Kyongbum

doi:10.1152/ajpendo.00670.2006

Cited by 30 publications

(40 citation statements)

References 48 publications

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“…Induction of several antioxidant enzymes [77][78][79] and increased NADPH generation 80 may protect adipocytes against ER stress caused by inflammatory cytokines, because these cytokines cause ER stress via production of reactive oxygen species. 27,81,82 Our conclusions differ from conclusions drawn in other studies, which suggest that TNF-a, 83 free fatty acids, [84][85][86][87] and cholesterol 88 induce ER stress in adipocytes in vitro.…”

Section: Discussionmentioning

confidence: 99%

Glucose starvation and hypoxia, but not the saturated fatty acid palmitic acid or cholesterol, activate the unfolded protein response in 3T3-F442A and 3T3-L1 adipocytes

Mihai

Schröder

2015

Adipocyte

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Obesity is associated with endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) in adipose tissue. In this study we identify physiological triggers of ER stress and of the UPR in adipocytes in vitro. We show that two markers of adipose tissue remodelling in obesity, glucose starvation and hypoxia, cause ER stress in 3T3-F442A and 3T3-L1 adipocytes. Both conditions induced molecular markers of the IRE1a and PERK branches of the UPR, such as splicing of XBP1 mRNA and CHOP, as well as transcription of the ER stress responsive gene BiP. Hypoxia also induced an increase in phosphorylation of the PERK substrate eIF2a. By contrast, physiological triggers of ER stress in many other cell types, such as the saturated fatty acid palmitic acid, cholesterol, or several inflammatory cytokines including TNF-a, IL-1b, and IL-6, do not cause ER stress in 3T3-F442A and 3T3-L1 adipocytes. Our data suggest that physiological changes associated with remodelling of adipose tissue in obesity, such as hypoxia and glucose starvation, are more likely physiological ER stressors of adipocytes than the lipid overload or hyperinsulinemia associated with obesity.

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Section: Discussionmentioning

confidence: 99%

Glucose starvation and hypoxia, but not the saturated fatty acid palmitic acid or cholesterol, activate the unfolded protein response in 3T3-F442A and 3T3-L1 adipocytes

Mihai

Schröder

2015

Adipocyte

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“…Adipocyte metabolism increases dramatically with differentiation. 16 Therefore, the medium concentrations of major nutrients, such as glucose, are expected to be lower near the source channel, rather than the sink channel. One last possible explanation is migration of differentiated adipocytes from the source channel to the sink channel.…”

Section: Discussionmentioning

confidence: 99%

Adipocyte Induction of Preadipocyte Differentiation in a Gradient Chamber

Lai

Sims²,

Jeon³

et al. 2012

Tissue Engineering Part C: Methods

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Adipose tissue expansion involves enlargement of mature adipocytes and the formation of new adipocytes through the differentiation of locally resident preadipocytes. Factors released by the enlarged adipocytes are potential cues that induce the differentiation of the preadipocytes. Currently, there are limited options to investigate these cues in isolation from confounding systemic influences. A gradient generating microfluidic channel-based cell culture system was designed to enable solution patterning, while supporting long-term culture and differentiation of preadipocytes. Solution patterning was confirmed by selectively staining a fraction of uniformly seeded preadipocytes. An adipogenic cocktail gradient was used to induce the differentiation of a fraction of uniformly seeded preadipocytes and establish a spatially defined coculture of adipocytes and preadipocytes. Varying the adipogenic cocktail gradient generated cocultures of preadipocytes and adipocytes with different compositions. Transient application of the cocktail gradient, followed by basal medium treatment showed a biphasic induction of differentiation. The two phases of differentiation correlated with a spatial gradient in adipocyte size. Our results provide in vitro data supporting the size-dependent release of preadipocyte differentiation factors by enlarged adipocytes. Prospectively, the coculture system developed in this study could facilitate controlled, yet physiologically meaningful studies on paracrine interactions between adipocytes and preadipocytes during adipose tissue development.

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“…In the fully mature adipocyte, the malate cycle quantitatively contributes to the pool of reducing co-factors required for lipogenesis (Flatt, 1970). Measurements on intracellular TG (Si et al, 2007) showed continued increase in lipid loading through day 16, which is presumably reflected in the completion of the malate cycle. The modules for days 12 and 16 were identical.…”

Section: Physiological Perturbationsmentioning

confidence: 95%

“…The first model described the impact of fasting and whole body inflammation on the energy metabolism of the rat liver (Lee et al, 2003). The second model represented the metabolic changes underlying de novo adipose tissue formation (Si et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Modular decomposition of metabolic reaction networks based on flux analysis and pathway projection

Yoon

Nolan

et al. 2007

Bioinformatics

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Motivation: The rational decomposition of biochemical networks into sub-structures has emerged as a useful approach to study the design of these complex systems. A biochemical network is characterized by an inhomogeneous connectivity distribution, which gives rise to several organizational features, including modularity. To what extent the connectivity-based modules reflect the functional organization of the network remains to be further explored. In this work, we examine the influence of physiological perturbations on the modular organization of cellular metabolism. Results: Modules were characterized for two model systems, liver and adipocyte primary metabolism, by applying an algorithm for topdown partition of directed graphs with non-uniform edge weights. The weights were set by the engagement of the corresponding reactions as expressed by the flux distribution. For the base case of the fasted rat liver, three modules were found, carrying out the following biochemical transformations: ketone body production, glucose synthesis and transamination. This basic organization was further modified when different flux distributions were applied that describe the liver's metabolic response to whole body inflammation. For the fully mature adipocyte, only a single module was observed, integrating all of the major pathways needed for lipid storage.

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Flux profile and modularity analysis of time-dependent metabolic changes of de novo adipocyte formation

Cited by 30 publications

References 48 publications

Glucose starvation and hypoxia, but not the saturated fatty acid palmitic acid or cholesterol, activate the unfolded protein response in 3T3-F442A and 3T3-L1 adipocytes

Glucose starvation and hypoxia, but not the saturated fatty acid palmitic acid or cholesterol, activate the unfolded protein response in 3T3-F442A and 3T3-L1 adipocytes

Adipocyte Induction of Preadipocyte Differentiation in a Gradient Chamber

Modular decomposition of metabolic reaction networks based on flux analysis and pathway projection

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