Growing evidence supports the role of gut microbiota in the development of obesity, type 2 diabetes, and low-grade inflammation. The endocrine activity of adipose tissue has been found to contribute to the regulation of glucose homeostasis and low-grade inflammation. Among the key hormones produced by this tissue, apelin has been shown to regulate glucose homeostasis. Recently, it has been proposed that gut microbiota participate in adipose tissue metabolism via the endocannabinoid system (eCB) and gut microbiota-derived compounds, namely lipopolysaccharide (LPS). We have investigated gut microbiota composition in obese and diabetic leptin-resistant mice (db/db) by combining pyrosequencing and phylogenetic microarray analysis of 16S ribosomal RNA gene sequences. We observed a significant higher abundance of Firmicutes, Proteobacteria, and Fibrobacteres phyla in db/db mice compared to lean mice. The abundance of 10 genera was significantly affected by the genotype. We identified the roles of the eCB and LPS in the regulation of apelinergic system tone (apelin and APJ mRNA expression) in genetic obese and diabetic mice. By using in vivo and in vitro models, we have demonstrated that both the eCB and low-grade inflammation differentially regulate apelin and APJ mRNA expression in adipose tissue. Finally, deep-gut microbiota profiling revealed that the gut microbial community of type 2 diabetic mice is significantly different from that of their lean counterparts. This indicates specific relationships between the gut microbiota and the regulation of the apelinergic system. However, the exact roles of specific bacteria in shaping the phenotype of db/db mice remain to be determined.