Novel metabolite-derived anorexigens in infection

About This Grant

Abstract: The cytokine IFN-g controls both protective and pathogenic host responses during infection and inflammation. By activating cell autonomous antimicrobial mechanisms, this cytokine mediates host resistance mechanisms that control pathogen replication. Much less is known about how the same cytokine regulates sickness associated behaviors such as anorexia and whole-body weight loss. We have recently published data indicating that IFN-g regulates the systemic levels of the stress hormone GDF-15 which is important for appetite suppression and weight loss during infection. In turn, GDF15 is required for hepatic production of FGF21 and the consequent generation of ketone bodies, including beta-hydroxybutyric acid. Recently, a previously unrecognized biochemical pathway of “reverse proteolysis”, mediated by the enzyme CNDP2 (carnosine dipeptidase 2) has been shown to generate a novel class of anorexigens through chemical conjugation of either beta-hydroxybutyric (BHB) acid or lactic acid to amino acids bearing hydrophobic side chains. While a role for this new pathway has recently been demonstrated in the context of appetite suppression following metformin therapy or physical exercise, its relevance to sickness associated anorexia during infection and inflammation has not been examined. Here, we present preliminary data showing that BHB-amino acid but not lactoyl-amino acid conjugates are elevated in the serum of T. gondii-infected mice. Furthermore, the in vivo expression of CNDP2 transcripts is upregulated during infection and this induction is dependent on IFN-g receptor signaling. Thus, we hypothesize that IFN-g mediates suppression of food intake and sickness associated weight loss, in part, by inducing CNDP2 in immune cells, thus, elevating circulating levels of this novel class of metabolite-derived anorexigens during infection. Specific Aim 1 will test the hypothesis that IFN-g signaling induces CNDP2-mediated generation of BHB-amino acids by immune cells during T. gondii infection. Specific Aim 2 will critically interrogate the role and function of CNDP2 in regulating the sickness associated anorexia and weight loss during T. gondii infection. Completion of this project will provide novel and fundamental insights into how inflammation and immune cytokines control sickness associated anorexia and weight loss during infection and inflammation. These insights may provide avenues to promote health by decreasing disease sequelae that result from hyperactivation of immune response and the ensuing disruption of metabolic homeostasis in the host.