Adipose Tissue Responses to High-Salt Diet are Strain-Specific in Female Mice

High-salt intake has been linked to metabolic dysfunction, yet its direct effects on adipose tissue biology remain poorly defined, especially in females, who have a higher salt appetite than males. We hypothesized that a high-salt diet (HSD) alters visceral adipose tissue (VAT) biology in a strain-specific manner, contributing to fat accumulation in female mice. C57Bl/6 and BALB/cJ female mice, which are respectively prone and resistant to metabolic dysfunction, were fed either a normal salt diet (NSD, NaCl 0.2%) or HSD (NaCl 4%) for one or eight weeks. Body composition assessed by Nuclear Magnetic Resonance (NMR) revealed no changes in fat mass at one week across any group. After eight weeks, however, BALB/c mice on HSD showed a significant increase in fat mass compared to their NSD controls, whereas C57BL/6 mice showed a reduction in fat mass relative to strain-matched NSD mice. Histological assessment further supported significant increase in adipocyte density in HSD-fed BALB/c mice at one week, with no comparable changes observed in C57BL/6 mice (p < 0.05). VAT was analyzed for leptin, leptin receptor (ObRb), SREBP1c, and adipogenic markers (PPARγ, C/EBPα, FABP4) using qPCR. At one week, HSD did not alter leptin or leptin receptor (ObRb) transcript levels in either strain. However, HSD significantly reduced VAT expression of SREBP1c in BALB/c compared to strain-matched NSD mice, suggesting an acute suppression of de novo lipogenesis (2-way ANOVA, p< 0.05). Adipogenic markers (PPARγ, C/EBPα, and FABP4) were unchanged across all groups at this early timepoint. By eight weeks, HSD BALB/c mice exhibited increased fat mass accompanied by markedly increased VAT leptin expression relative to strain-matched NSD mice, while ObRb expression remained unchanged (2-way ANOVA, p< 0.05). SREBP1c expression normalized with chronic HSD exposure, and PPARγ and C/EBPα remained unchanged, indicating preserved adipocyte differentiation. However, FABP4 expression showed a downward trend in HSD BALB/c mice (p = 0.053), suggesting possible impaired intracellular fatty-acid trafficking and reduced lipid mobilization. Collectively, our data suggest that acute high-salt exposure in BALB/c mice results in early suppression of lipogenic signaling, followed by chronic adipocyte hypertrophy characterized by elevated leptin and a trend towards reduced FABP4 with chronic high-salt diet exposure. Core adipogenic regulators, including SREBP1c, PPARγ, and C/EBPα, showed no major changes in response to chronic high-salt exposure. Together, these findings suggest that altered lipid mobilization, rather than increased lipid differentiation, may drive VAT expansion under chronic high-salt exposure in BALB/c mice. Importantly, the differences in metabolic responses between strains reveal an unexpected metabolic phenotype in BALB/c mice, a strain typically considered protected from diet-induced metabolic derangements, along with strain-specific vulnerability to high-salt dietary stress. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.