MON-726 Influence of Diet, Sex, and Strain on Adipose Tissue Distribution and Metabolic Risk in BXD Mouse Models

Abstract Disclosure: J. Hernandez Nava: None. S. Brown Mayfield: None. T. An Pham: None. S.K. Koliwad: None. D.L. Alba: None. Metabolic syndrome susceptibility is influenced by genetics, environment, and gene-by-environment interactions, making mechanistic studies challenging. Obesity promotes expansion of subcutaneous and visceral white adipose tissue (WAT), with visceral fat linked to cardiometabolic risk, whereas subcutaneous WAT can be protective. However, the mechanisms driving these regional differences remain unclear. The BXD recombinant inbred (RI) mouse population models the genetic and metabolic heterogeneity observed in human obesity and allows for mapping causal genetic variants that regulate health outcomes in mice. We hypothesize that BXD strains exhibit distinct WAT distribution and dysfunction under a high-fat diet (HFD), with some strains developing greater visceral adiposity and fibrosis-driven insulin resistance, while others maintain higher subcutaneous fat with preserved metabolic health.For this study, male and female BXD61 and BXD81 mice were maintained on chow diet (CD) or HFD from 8 weeks of age, with weekly body weight measurements (n=62). Glucose tolerance test (GTT), insulin tolerance test (ITT), and EchoMRI were performed after 6 and 12 weeks. At 20 weeks, animals were sacrificed, and blood, liver, and adipose depots (inguinal, retroperitoneal, epididymal, and brown fat) were collected. Adipose fibrosis was assessed via hydroxyproline assay.HFD led to significant adipose tissue expansion, with BXD61 mice showing a greater percentage increase in body weight than BXD81. BXD81 mice had a similar percentage increase in both inguinal and epididymal fat pads, whereas BXD61 exhibited a disproportionately greater increase in epididymal fat. Male BXD81 and BXD61 mice developed glucose intolerance and insulin resistance, while female BXD81 mice on HFD exhibited elevated glucose levels compared to mice on CD. In contrast, female BXD61 mice on HFD maintained lower fasting glucose and did not develop hyperinsulinemia or glucose intolerance despite increased adiposity, highlighting strain- and sex-specific metabolic responses. Notably, female BXD61 mice exhibited significantly higher hydroxyproline content in inguinal fat, marking an increase in adipose tissue fibrosis.The genetic diversity of BXD mice effectively models varying metabolic disease severity, paralleling human heterogeneity. BXD61 males developed early metabolic dysfunction, while female BXD61 mice, despite increased adiposity, remained metabolically resilient, suggesting a protective mechanism. Notably, increased adiposity in BXD61 females was not associated with impaired glucose homeostasis, underscoring the need to explore mechanisms conferring metabolic resilience in obesity. Additionally, the strain-dependent variability in the HFD response suggests that segregating genetic variants in the BXD population may either protect against or exacerbate metabolic dysfunction. Presentation: Monday, July 14, 2025