Abstract Body: Background: Metabolic syndrome, a growing health concern linked to cardiovascular disease, remains understudied in terms of cardiokines and sex-specific responses. We examined cardiomyocyte-specific expression of a peptide of the n-terminus of G protein-coupled receptor kinase 2 (βARKnt) versus non-transgenic littermate controls (NLCs) on a high-fat diet (HFD). We found that males exhibited enhanced cardiometabolic signaling, cardioprotection, and improved white adipose tissue (WAT) health, while females showed reduced signaling, maladaptive remodeling, cardiac dysfunction, and decreased brown adipose tissue (BAT) activation.

Hypothesis: A subset of identified serum metabolites likely involved in sex-specific cardiac-adipose crosstalk during metabolic stress is expected to show concentration changes over time on HFD.

Methods: Serum metabolomics was analyzed at baseline, 4, and 16 weeks post-HFD using HPLC-MS, with multi- and univariate statistics and standard curve quantification.

Results: Untargeted analysis showed distinct metabolic profiles between βARKnts and NLCs at baseline and 16 weeks post-HFD. By 16 weeks, male βARKnts had more downregulated metabolites, while females had more upregulated compounds (p<0.05). Several metabolites correlated with HFD duration, either genotype-dependent or independent, and were overrepresented in systemic metabolic pathways.
Key signaling molecules were selected for targeted HPLC-MS, including amino acids, metabolites, polyamine derivatives, and an α-amino acid stereoisomer. These molecules are linked to mitochondrial beta-oxidation, fatty acid synthesis, and arachidonic acid metabolism. Except for one compound, all showed sex-specific differences over time on HFD. The α-amino acid stereoisomer exhibited the most pronounced genotype-dependent changes, with 16-week mean concentrations (ng/mL, n=3-6) of 3,701 (male) and 6,042 (female) in NLCs, compared to 2,667 (male) and 4,621 (female) in βARKnts.

Conclusion: Cardiac health changes significantly impact the systemic metabolome and may affect BAT and WAT function. Branched-chain amino acids influence BAT activation, suggesting structurally similar amino acids, like ones identified, may also regulate thermogenic signaling. Further research is needed to determine their role in lipolysis and tissue structure. Identifying which compounds mediate organ crosstalk may uncover novel sex-specific therapeutic targets for obesity and metabolic dysfunction.