In regard with obesity/T2D, the emerging data support that CX3CL1/CX3CR1 axis promotes inflammation and, therefore, therapeutic targeting of this axis represents a promising translational approach which can be achieved, in principle, by: (1) controlling ligand (CX3CL1) shedding by using antagonists of ADAM-10/17 or cathepsin S; and/or (2) blocking cognate receptor (CX3CR1) by using specific antibodies or clinical grade CX3CR1 antagonists. Here, CTSS is linked to obesity due to melanocortin 4 receptor deficiency.