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

Abstract

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.

Characterization of the CLASP2 Protein Interaction Network Identifies SOGA1 as a Microtubule-Associated Protein

“…These previous findings highlight the importance of our discovery that glycogen synthase (GYS1), the key biosynthetic enzyme for the synthesis of glycogen (103), is enriched in the SOGA1 interactome. While the role of glycogen autophagy in adipocytes was only recently examined (104), it is possible to hypothesize that SOGA1 may regulate glucose and glycogen metabolism by directly cooperating with glycogen synthase and the glycogen synthase-associated protein glycogenin, which was also detected in the SOGA1…”

Crohn's Disease Disturbs the Immune Properties of Human Adipose-Derived Stem Cells Related to Inflammasome Activation

“…To prevent spontaneous differentiation, primary cultures of ASCs at passage 0 (P0) were grown to 90% confluence and harvested with trypsin-EDTA, and aliquots (1 × 10 6 cells) were cryopreserved in liquid nitrogen until required ( Pachon-Pena et al., 2011 ). ATMs were also isolated from the stromal vascular fraction of AT biopsies as described previously ( Ceperuelo-Mallafre et al., 2016 , Serena et al., 2016 , Titos et al., 2011 ). The AT-cell number ratio was defined as the ratio of the number of cells proliferating at P0 per gram of AT digested.…”

Glycogen metabolism regulates macrophage-mediated acute inflammatory responses

“…Glycogen is an important carbohydrate fuel reserve and glycogen metabolism has been previously reported in myeloid cells of the immune system including dendritic cells and macrophages [14][15][16] . Our recent studies additionally found that CD8 + memory T cells actively mobilize glycogen metabolism to generate glucose-6-phosphate (G6P) via glycogenolysis and channel the G6P to the PPP 17 .…”