Reciprocal adipose-heart regulation of NRAC

Abstract

Fatty acids (FAs) are a major energy substrate, and their storage and utilization must be balanced across tissues to maintain metabolic homeostasis. White adipose tissue (WAT) and the heart play opposing roles in FA metabolism, with WAT serving as the primary site of FA storage and the heart relying heavily on FAs as an energy source. However, the molecular factors regulating FA handling between the two tissues remain incompletely understood. We previously identified NRAC as a nutritionally regulated adipose- and cardiac-enriched protein; however, how its expression is regulated between these tissues across nutritional states, and how this relates to systemic FA homeostasis, remains unclear. Here, we integrate analyses of human transcriptomic datasets with nutritional and genetic perturbations in mice to examine the association between NRAC and FA metabolism. Human single-cell transcriptomic data from GTEx show enrichment of NRAC expression in adipocytes and cardiomyocytes, and analysis of subcutaneous adipose tissue from the UK Twins cohort reveals strong associations between NRAC expression and the abundance of multiple adipose lipid species. In mice, NRAC expression in WAT and heart was reciprocally regulated by fasting and refeeding and showed opposing associations with circulating free fatty acid (FFA) levels; moreover, whole-body deletion of NRAC elevated circulating FFA. Together, these findings support a role for NRAC in nutritionally responsive inter-organ regulation of FA between WAT and the heart, with implications for systemic lipid homeostasis.