RT Journal Article
T1 Adipose tissue glycogen accumulation is associated with obesity-linked inflammation in humans.
A1 Ceperuelo-Mallafré, Victòria
A1 Ejarque, Miriam
A1 Serena, Carolina
A1 Duran, Xavier
A1 Montori-Grau, Marta
A1 Rodríguez, Miguel Angel
A1 Yanes, Oscar
A1 Núñez-Roa, Catalina
A1 Roche, Kelly
A1 Puthanveetil, Prasanth
A1 Garrido-Sánchez, Lourdes
A1 Saez, Enrique
A1 Tinahones, Francisco J
A1 Garcia-Roves, Pablo M
A1 Gómez-Foix, Anna Ma
A1 Saltiel, Alan R
A1 Vendrell, Joan
A1 Fernández-Veledo, Sonia
K1 Adipocyte
K1 Autophagy
K1 Glycogen
K1 Insulin resistance
K1 Macrophage
K1 Obesity
AB Glycogen 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. We 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. We 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. Our data establish glycogen mishandling in adipose tissue as a potential key feature of inflammatory-related metabolic stress in human obesity.
SN 2212-8778
YR 2015
FD 2015-10-16
LK https://hdl.handle.net/10668/26322
UL https://hdl.handle.net/10668/26322
LA en
DS RISalud
RD Apr 12, 2025