Ghrelin plays a key role in appetite, energy homeostasis and glucose regulation. Recent evidence suggests ghrelin suppresses inflammation in obesity, however whether this is modulated by the acylated and/or des-acylated peptide is unclear. We used mice deficient in acylated ghrelin (GOAT KO), wildtype littermates (WT) and C57BL/6 mice to examine the endogenous and exogenous effects of acyl and des-acyl ghrelin on inflammatory profiles under non-obese and obese conditions. We demonstrate that in the spleen, both ghrelin and Ghrelin O-Acyl Transferase (GOAT) are localized primarily in the red pulp. Importantly, in the thymus, ghrelin was predominantly localized to the medulla, while GOAT was found in the cortex, implying significant but differing roles in T cell development. Acute exogenous treatment with acyl/des-acyl ghrelin suppressed macrophage numbers in spleen and thymus in obese mice, whereas only acyl ghrelin increased CD3+ T cells in the thymus in both chow and HF fed mice. Consistent with this result, macrophages were increased in the spleen of KO mice on a HFD. While there was no difference in CD3+ T cells in the plasma, spleen or thymus of WT vs KO mice, KO chow and HF fed mice displayed decreased leukocytes. Our results suggest that the acylation status affects the anti-inflammatory properties of ghrelin under chow and HFD conditions.