Connexin43 Links Bone Marrow Mesenchymal Stem Cells to Peripheral Adiposity in Female Mice Under HFD

ABSTRACT Objective Bone marrow mesenchymal stem cells (BMSCs) are a major source of bone marrow adipose tissue and also contribute to the total adipocyte pool under high‐fat diet (HFD) challenge, yet the underlying molecular links are uncertain. Given that connexin 43 (Cx43), a key gap junction protein, regulates BMSC differentiation and energy metabolism, we aimed to determine its effects on BMSCs in controlling peripheral adipose tissue under HFD. Methods BMSC‐specific Cx43 knockout ( Prrx1‐Cre ; Cx43 flox/flox , cKO) and control littermates (Cx43 flox/flox , flox) were fed either a control diet or a HFD for 8 weeks. Single‐cell RNA sequencing (scRNA‐seq) was used to profile BMSC subclusters and identify HFD‐responsive clusters and their secreted factors. Results We observed that cKO mice displayed resistance to HFD‐induced body adiposity and enhanced energy expenditure, an effect that was particularly pronounced in females. Two new clusters ( Prrx1 + Ly6a + and Adipoq + Clec11a + ) were identified, which contribute to Cx43 ablation against HFD. Cx43 inhibition links reduced adipogenesis to lower TXNIP secretion in serum. Lastly, TXNIP inhibition recapitulates the lean phenotype of cKO mice under HFD. Conclusions Our data appear to support a link between BMSC Cx43 and TXNIP secretion within a bone–adipose axis, which might be relevant to addressing challenges in obesity management.