Insulin resistance (IR) and related disorders, such as T2DM, increase the risk of major depressive disorder (MDD) and vice versa. Current evidence indicates that psychological stress and overeating can induce chronic low-grade inflammation that can interfere with glutamate metabolism in MDD as well as insulin signaling, particularly in the atypical subtype. Here we first review the interactive role of inflammatory processes in the development of MDD, IR and related metabolic disorders. Next, we describe the role of the anterior cingulate cortex in the pathophysiology of MDD and IR-related disorders. Furthermore, we outline how specific clinical features of atypical depression, such as hyperphagia, are more associated with inflammation and IR-related disorders. Finally, we examine the regional specificity of the effects of inflammation on the brain that show an overlap with the functional and morphometric brain patterns activated in MDD and IR-related disorders.