Adipose tissue expansion in response to positive energy balance can lead to a myriad of local effects including hypoxia. Ceperuelo-Mallafré, Ejarque, and colleagues show that hypoxia, which has been linked to obesity-related adipose tissue dysfunction, increases glucose uptake and stimulates glycogen synthesis in adipocytes. Glycogen loaded adipocytes exhibit increased autophagic flux, which directly impacts their endocrine secretory function. Furthermore, enforced glycogen deposition by overexpression of PTG (protein targeting to glycogen) in macrophages promotes polarization towards the M1 pro-inflammatory phenotype. Studies with human clinical samples confirm the interplay between autophagy and glycogen storage and show that human obesity is associated with glycogen deposition in adipocytes. Overall, the data demonstrate that glycogen accumulation in adipocytes and macrophages contributes to adipose tissue inflammation, and might underlie the metabolic alterations in obesity.