Nowadays, the prevalence of neuropsychiatric symptoms is continuously rising, in particular in metabolic disorders such as obesity and metabolic syndrome. Obesity and mood disorders facilitate their co-occurrence and increase the risk of additional metabolic and cardiovascular complications. It is therefore crucial to better understand the pathophysiological mechanisms underlying their comorbid association and their combined deleterious impact on well-being and health. In the last decades, clinical and experimental studies have suggested a key role for inflammatory processes and their neurobiological targets, in particular the enzymes indoleamine 2,3-dioxygenase and GTP-cyclohydrolase-1, in the etiology of neuropsychiatric symptoms. In this chapter, we review evidence showing that they may similarly contribute to obesity-related neuropsychiatric comorbidities. Moreover, we discuss the potential therapeutic implications of reducing inflammation in obesity, including by using nonpharmacological interventions, in particular nutritional strategies.