Enhanced glycogen metabolism in adipose tissue decreases triglyceride mobilization

Markan, Kathleen R.; Jurczak, Michael J.; Allison, Margaret B.; Ye, Honggang; Sutanto, Maria M.; Cohen, Ronald N.; Brady, Matthew J.

doi:10.1152/ajpendo.00741.2009

Cited by 12 publications

(10 citation statements)

References 37 publications

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“…Basal adipocyte metabolism was unaffected by glycogen accumulation since similar cellular respiratory rates, metabolic gene expression and lactate release were observed in glycogen-loaded adipocytes and control cells ( Figure S4 ). Nevertheless, an increase in the sensitivity to the lipolytic agents isoproterenol and CL-316243 was evident in glycogen-loaded adipocytes ( Figure 2 H), supporting the metabolic link proposed previously between lipid and carbohydrate metabolism [16] , [32] .…”

Section: Resultssupporting

confidence: 87%

“…Interestingly, although adipocyte function appeared to be maintained in these animals, leptin, but not adiponectin, protein content in adipose tissue was increased, and the associated hyperleptinemia was independent of fat mass [15] . Further studies showed that upon caloric excess-induced expansion of adipose tissue mass, the elevated levels of glycogen in this model inhibited the mobilization of triglyceride and impeded weight loss following the return to chow feeding [16] .…”

Section: Introductionmentioning

confidence: 83%

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Adipose tissue glycogen accumulation is associated with obesity-linked inflammation in humans

Ceperuelo-Mallafré

Ejarque

Serena

et al. 2016

Molecular Metabolism

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ObjectiveGlycogen metabolism has emerged as a mediator in the control of energy homeostasis and studies in murine models reveal that adipose tissue might contain glycogen stores. Here we investigated the physio(patho)logical role of glycogen in human adipose tissue in the context of obesity and insulin resistance.MethodsWe studied glucose metabolic flux of hypoxic human adipoctyes by nuclear magnetic resonance and mass spectrometry-based metabolic approaches. Glycogen synthesis and glycogen content in response to hypoxia was analyzed in human adipocytes and macrophages. To explore the metabolic effects of enforced glycogen deposition in adipocytes and macrophages, we overexpressed PTG, the only glycogen-associated regulatory subunit (PP1-GTS) reported in murine adipocytes. Adipose tissue gene expression analysis was performed on wild type and homozygous PTG KO male mice. Finally, glycogen metabolism gene expression and glycogen accumulation was analyzed in adipose tissue, mature adipocytes and resident macrophages from lean and obese subjects with different degrees of insulin resistance in 2 independent cohorts.ResultsWe show that hypoxia modulates glucose metabolic flux in human adipocytes and macrophages and promotes glycogenesis. Enforced glycogen deposition by overexpression of PTG re-orients adipocyte secretion to a pro-inflammatory response linked to insulin resistance and monocyte/lymphocyte migration. Furthermore, glycogen accumulation is associated with inhibition of mTORC1 signaling and increased basal autophagy flux, correlating with greater leptin release in glycogen-loaded adipocytes. PTG-KO mice have reduced expression of key inflammatory genes in adipose tissue and PTG overexpression in M0 macrophages induces a pro-inflammatory and glycolytic M1 phenotype. Increased glycogen synthase expression correlates with glycogen deposition in subcutaneous adipose tissue of obese patients. Glycogen content in subcutaneous mature adipocytes is associated with BMI and leptin expression.ConclusionOur data establish glycogen mishandling in adipose tissue as a potential key feature of inflammatory-related metabolic stress in human obesity.

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Section: Resultssupporting

confidence: 87%

Section: Introductionmentioning

confidence: 83%

Adipose tissue glycogen accumulation is associated with obesity-linked inflammation in humans

Ceperuelo-Mallafré

Ejarque

Serena

et al. 2016

Molecular Metabolism

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“…An induction of adipose tissue lipogenesis (rather than hepatic lipogenesis) could mirror an increased efficiency of lipid storage during HFO, as reflected by the reduced fasting plasma NEFA and triacylglycerol levels observed in the young men after HFO. Moreover, the finding that genes involved in glycogen synthesis (GYS1 and GYS2) were among those most strongly upregulated by HFO is consistent with the suggestion that adipose glycogen turnover may help coordinate glucose and lipid metabolism in adipose tissue [35].…”

Section: Discussionsupporting

confidence: 83%

Adipose tissue transcriptomics and epigenomics in low birthweight men and controls: role of high-fat overfeeding

et al. 2016

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Aims/hypothesis Individuals who had a low birthweight (LBW) are at an increased risk of insulin resistance and type 2 diabetes when exposed to high-fat overfeeding (HFO). We studied genome-wide mRNA expression and DNA methylation in subcutaneous adipose tissue (SAT) after 5 days of HFO and after a control diet in 40 young men, of whom 16 had LBW. Methods mRNA expression was analysed using Affymetrix Human Gene 1.0 ST arrays and DNA methylation using Illumina 450K BeadChip arrays. Results We found differential DNA methylation at 53 sites in SAT from LBW vs normal birthweight (NBW) men (false discovery rate <5%), including sites in the FADS2 and CPLX1 genes previously associated with type 2 diabetes. When we used reference-free cell mixture adjustments to potentially adjust for cell composition, 4,323 sites had differential methylation in LBW vs NBW men. However, no differences in SAT gene expression levels were identified between LBW and NBW men. In the combined group of all 40 participants, 3,276 genes (16.5%) were differentially expressed in SAT after HFO (false discovery rate <5%) and there was no difference between LBW men and controls. The most strongly upregulated genes were ELOVL6, FADS2 and NNAT; in contrast, INSR, IRS2 and the SLC27A2 fatty acid transporter showed decreased expression after HFO. Interestingly, SLC27A2 expression correlated negatively with diabetes-and obesity-related traits in a replication cohort of 142 individuals. DNA methylation at 652 CpG sites (including in CDK5, IGFBP5 and SLC2A4) was altered in SAT after overfeeding in this and in another cohort. Conclusions/interpretation Young men who had a LBW exhibit epigenetic alterations in their adipose tissue that potentially influence insulin resistance and risk of type 2 diabetes. Short-term overfeeding influences gene transcription and, to some extent, DNA methylation in adipose tissue; there was no major difference in this response between LBW and control participants.

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“…The relationship between the over-accumulation of glycogen and improved lipid retention was demonstrated by prior investigations that manipulated glycogen dynamics through use of a transgenic mouse model, which resulted in the marked, permanent over-accumulation of glycogen in EPI and IBAT. Persistent elevation of WAT glycogen levels slowed weight loss following a transition from high-fat diet to normal chow diet through the enhanced retention of free fatty acids in adipocytes [36], [63]. During the present study glycogen over-accumulation in the major WAT and BAT adipose depots may have enabled a similar lipid-retention effect.…”

Section: Discussionsupporting

confidence: 52%

Refeeding-Induced Brown Adipose Tissue Glycogen Hyper-Accumulation in Mice Is Mediated by Insulin and Catecholamines

Carmean

Bobe

et al. 2013

PLoS ONE

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Brown adipose tissue (BAT) generates heat during adaptive thermogenesis through a combination of oxidative metabolism and uncoupling protein 1-mediated electron transport chain uncoupling, using both free-fatty acids and glucose as substrate. Previous rat-based work in 1942 showed that prolonged partial fasting followed by refeeding led to a dramatic, transient increase in glycogen stores in multiple fat depots. In the present study, the protocol was replicated in male CD1 mice, resulting in a 2000-fold increase in interscapular BAT (IBAT) glycogen levels within 4–12 hours (hr) of refeeding, with IBAT glycogen stores reaching levels comparable to fed liver glycogen. Lesser effects occurred in white adipose tissues (WAT). Over the next 36 hr, glycogen levels dissipated and histological analysis revealed an over-accumulation of lipid droplets, suggesting a potential metabolic connection between glycogenolysis and lipid synthesis. 24 hr of total starvation followed by refeeding induced a robust and consistent glycogen over-accumulation similar in magnitude and time course to the prolonged partial fast. Experimentation demonstrated that hyperglycemia was not sufficient to drive glycogen accumulation in IBAT, but that elevated circulating insulin was sufficient. Additionally, pharmacological inhibition of catecholamine production reduced refeeding-induced IBAT glycogen storage, providing evidence of a contribution from the central nervous system. These findings highlight IBAT as a tissue that integrates both canonically-anabolic and catabolic stimulation for the promotion of glycogen storage during recovery from caloric deficit. The preservation of this robust response through many generations of animals not subjected to food deprivation suggests that the over-accumulation phenomenon plays a critical role in IBAT physiology.

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Enhanced glycogen metabolism in adipose tissue decreases triglyceride mobilization

Cited by 12 publications

References 37 publications

Adipose tissue glycogen accumulation is associated with obesity-linked inflammation in humans

Adipose tissue glycogen accumulation is associated with obesity-linked inflammation in humans

Adipose tissue transcriptomics and epigenomics in low birthweight men and controls: role of high-fat overfeeding

Refeeding-Induced Brown Adipose Tissue Glycogen Hyper-Accumulation in Mice Is Mediated by Insulin and Catecholamines

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