Reciprocal Adipose‐Heart Regulation of NRAC

Metabolic diseases such as obesity and related cardiometabolic disorders are characterized by profound disturbances in lipid metabolism and fatty acid (FA) handling 1-3. White adipose tissue (WAT) and the heart play central yet opposing roles in regulating systemic FA flux. During feeding, FAs are preferentially channeled into WAT for storage through re-esterification into triglycerides (TG); during fasting, circulating FAs are preferentially directed to the heart, where they are oxidized to sustain continuous energy demand 4. Although these tissue-specific functions are well recognized, how FA trafficking is dynamically coordinated between WAT and heart across nutritional states remains incompletely understood. We previously identified NRAC (nutritionally regulated adipose- and cardiac-enriched protein) in mice 5. This dual enrichment is notable given the opposing metabolic roles of WAT and heart and suggests that NRAC may participate in coordinating FA flux between them. Consistently, recent studies have implicated NRAC in FA transport, and human genetic variation at this locus has been associated with obesity-related traits 6, 7. Despite these advances, it remains unclear how NRAC expression is regulated across nutritional states in WAT and heart and how NRAC relates to circulating FA levels in vivo. In the present study, we examined NRAC regulation by fasting and feeding and assessed its relationship to systemic FA homeostasis using complementary human expression analyses and mouse models of NRAC deficiency. In 2012, we reported that NRAC is highly enriched in adipose tissue and heart in mice, predating the availability of large-scale human transcriptomic resources. The Genotype-Tissue Expression (GTEx) project now enables direct evaluation of NRAC expression across human tissues and cell types 8. Analysis of GTEx bulk RNA-seq data showed that NRAC is highly enriched in human adipose and cardiac tissues, with minimal expression elsewhere (Figure 1A). Single-cell RNA-seq analysis further showed that NRAC expression is largely restricted to adipocytes and cardiomyocytes, confirming cell-type specificity within these tissues. This conserved tissue and cell-type specificity across species supports a fundamental role for NRAC in adipocyte and cardiomyocyte biology. To determine whether NRAC is reciprocally regulated between WAT and heart, we examined its expression during fasting and refeeding. In WAT, a 24-h fast suppressed NRAC expression, whereas refeeding restored it (Figure 1B). In contrast, cardiac NRAC was reciprocally regulated: fasting increased its expression, while refeeding induced a time-dependent decline (Figure 1C). Across individual mice, NRAC expression in WAT and heart was inversely correlated (r = −0.69, p < 0.001), supporting reciprocal regulation and a coordinated role in adipose-heart FA handling. We next examined whether NRAC expression in WAT and heart is differentially associated with circulating non-esterified fatty acids (NEFA). In WAT, NRAC expression was inversely correlated with circulating NEFA levels (r = −0.49, p < 0.05), whereas in heart it was positively correlated (r = 0.52, p < 0.05) (Figure 1D,E). These opposing associations are consistent with reciprocal NRAC regulation across the two tissues. To establish a causal role for NRAC in systemic FA regulation, we examined circulating NEFA levels in NRAC knockout (KO) mice. The KO mice were generated by the International Mouse Phenotyping Consortium (IMPC) 9 using the Nrac knockout-first allele, which results in global deletion of NRAC and enables assessment of whole-body lipid homeostasis. Serum NEFA concentrations were measured in overnight-fasted KO mice and WT littermate controls. NRAC deficiency significantly increased circulating NEFA levels in both male and female KO mice (Figure 1F,G). These results suggest that NRAC is needed to maintain normal circulating FA levels in vivo and support a causal role for NRAC in systemic FA handling. To assess the relevance of NRAC to human cardiometabolic phenotypes, we examined reported associations in the TwinsUK cohort 10. Higher adipose NRAC expression was consistently associated with lower visceral and central adiposity and a reduced visceral-to-gynoid fat ratio, while positively associated with gynoid and lower-body depots, a distribution pattern considered metabolically protective. These effects were accompanied by a favorable lipid profile, including lower TG and higher HDL levels. NRAC expression was also associated with a cardiac electrical phenotype (P-axis, an electrocardiographic measure of atrial depolarization), further linking adipose NRAC to systemic cardiometabolic regulation in humans. These findings position NRAC as a molecular link between lipid storage and oxidation across nutritional states. The reciprocal regulation between WAT and heart suggests coordinated control of FA partitioning. Opposing associations with circulating NEFA and elevated NEFA in NRAC-deficient mice further support a role in systemic lipid regulation. Together with conserved adipocyte and cardiomyocyte specificity in humans, these results suggest that NRAC functions as a regulatory node governing adipose-heart FA crosstalk. Recent studies showing physical and functional interactions between NRAC and CD36 provide mechanistic context for these findings 6. Rather than serving as a FA transporter, NRAC modulates CD36-dependent FA uptake, likely in a cell type- and context-dependent manner. The divergent associations of adipose NRAC expression with visceral versus gynoid depots in humans are consistent with a role in FA partitioning. Several limitations should be noted. Our analyses focused on NRAC mRNA expression, without direct assessment of protein abundance or subcellular regulation. In addition, global NRAC deletion does not resolve tissue-specific contributions. Future studies using adipose- and heart-specific KO models and direct measurements of FA flux will be required to define tissue-specific mechanisms and inter-tissue coordination. In summary, we establish NRAC as an evolutionarily conserved, nutritionally regulated adipocyte- and cardiomyocyte-enriched factor that functions as a molecular nexus for adipose-heart crosstalk. Reciprocal regulation of NRAC between these two tissues coordinates systemic FA homeostasis, and its disruption may contribute to lipid dysregulation in cardiometabolic disease, positioning NRAC as a potential therapeutic target. The authors declare no conflicts of interest. The authors have nothing to report.