Depression represents a major public health concern. Its prevalence is continuously rising, notably in patients exposed to chronic stress or suffering from medical conditions associated with low-grade chronic inflammation, such as obesity. These patients also often display increased resistance to conventional antidepressants (AD). There is growing evidence that inflammation plays a role in depressive disorders. Interestingly, recent clinical findings suggest that it may also contribute to therapeutic resistance, although the underlying mechanisms are still poorly understood. A relevant preclinical model of depression allowing to assess the specific features of inflammation is therefore urgently needed. The present study aims to model inflammatory vs. non-inflammatory depression in mice. To address this issue, we compared depressive-like behaviors and peripheral and brain inflammation in mice exposed to diet-induced obesity (DIO) (60% Kcal from fat, 6 months from weaning), a procedure known to induce inflammation, or to unpredictable chronic mild stress (UCMS, 7 weeks), known to induce depressive-like behaviors responding to classical antidepressants. Peripheral inflammation was assessed by measuring plasma concentrations of inflammatory factors by bioplex. Both DIO and UCMS induce depressive-like behaviors, as indicated by increased coat state score, latency to feed in the novelty suppressed feeding test, and immobility in the forced swim test. In contrast, systemic inflammation is only detected in DIO mice, as revealed by higher plasma concentrations of cytokines and chemokines, such as interleukins 6 and 10 (IL-6, IL-10), interferon gamma induced protein 10 (IP-10) and interferon gamma induced monokine (MIG). Detailed analysis of associated activation of brain inflammatory processes is still in progress, but the present data suggest that the preclinical approach reported here can be useful to deeply study the mechanisms underlying inflammation-driven depression and therapeutic resistance, comparatively to non-inflammatory depression.