Background: Renin-Angiotensin System (RAS) is essential for blood pressure control and electrolytic homeostasis. Besides its classical mechanisms, RAS also represents a link between obesity and its consequences. Angiotensin II/AT1 overactivity reinforces obesity implications, and Angiotensin-(1-7)/Mas activity improves metabolic parameters. Alamandine is a newly described peptide part of the RAS. Alamandine shares functional and structural similarities with Angiotensin-(1-7) and its effects are mediated by a different receptor, MrgD (Lautner et al., 2013). Therefore, we believe that alamandine, closely participates in the RAS-metabolism interaction by mediating different signaling pathways. Aim: Our goal was to evaluate the consequences of the genetic deletion of alamandine receptor, MrgD, on the metabolism of C57BL6/J mice and the mechanisms underlying the possible alterations. Methods and Results: All experimental protocols were approved by UFMG ethics committee. Obesity was induced by high glucose diet (HG) for 8 weeks; control groups were feed with standard diet (ST). Our initial results indicate MrgD as an important influence for brown adipose tissue (BAT). We showed that MrgD/KO mice have diminished BAT regardless of age compared with wild type mice (WT); (i) 5-day-old mice, P value= 0.0246, N=5; (ii) 8-week-old mice, P value<0.0001, N=27 and (iii) 16-week-old mice, P value=0.0007, N=18. Moreover, WT obese mice, decreased not only MrgD expression in BAT (P value<0.0001, N=7) as also decreased alamandine circulating levels (P value=0.0017, N=8). Therefore, to identify potential target of MrgD signaling in BAT, RNA sequencing with RNA isolated from BAT of obese and lean MrgD/KO mice was performed (n=4). HG diet led to a transcriptional regulation in BAT of 1148 genes between WT-HG vs WT-ST groups. In contrast, intriguingly, only 45 genes were regulated between MrgD/KO-HG vs MrgD/KO-ST. Therefore, MrgD/KO-HG group failed in regulating more than 1100 genes in response to the HG diet. MrgD/KO-ST showed a deeply down regulation of transcripts pattern in BAT compared with WT-ST; of 476 regulated genes 445 were down regulated. The comparison of BAT transcriptomes between MrgD/KO vs WT mice was mainly marked by the regulation of genes encoding AMPK, extracellular matrix (ECM) components and ion channels. Conclusion: MrgD receptor absence led to a significant change in gene expression pattern in BAT. It deviated the tissue towards a profound transcripts’ depletion and to a response absence to the caloric challenge. In the view of regulated genes and enrichment analysis, we conclude that alamandine/MrgD activation contributes to RAS-metabolism interaction. MrgD expression is important to BAT protection via maintenance of cell structure, ribosomal structure, mitochondrial structure and proper signaling via ATP, calcium, and AMPK.