Cullin3 Deficiency In T Lymphocytes Causes A Lean Phenotype With Increased Carbohydrate Catabolism But Promotes Hypertension And Renal Inflammation

Low body mass is associated with increased risk of death and stroke, but the mechanism is unclear. Cullin3 (Cul3) ubiquitin ligase regulates T lymphocyte polarization, insulin signaling, and blood pressure (BP) and may provide a mechanistic link for the cardiometabolic phenotypes. Deletion of Cul3 in T cells ( Cul3 fl/fl x CD4-Cre , termed CD4-Cul3 -/- ) resulted in 17% lower body weight (BW: CD4-Cul3 -/- vs CD4-Cul3 +/+ littermates, 23.9 ± 0.9 vs 28.7 ± 0.7 g, 12-16 wks old, n = 6, 12, p<0.01) and blunted growth curve (ΔBW over 7 wks: 3.2 ± 0.9 vs 5.0 ± 0.6 g) in male mice. No difference in BW or growth curve was observed in females. Nuclear magnetic resonance analysis found decreased fat mass (6.4 ± 0.4 vs 9.2 ± 0.8 g, n = 10, 13, p < 0.01) in male null mice with no change in lean mass or fluid content. This was confirmed by post-mortem quantitation of inguinal fat and interscapular brown adipose tissue. There was no difference in postprandial blood glucose, but the male null mice exhibited lower area under curve (AUC mg/dL x hr, 543 ± 104 vs 765 ± 40, p < 0.05) in glucose tolerance test (2 g/kg, 5 hr fasting) and developed hypoglycemia and seizure during fasting insulin tolerance test (0.5 U/kg). CD4-Cul3 -/- mice had elevated respiratory exchange ratio (ratio between CO 2 produced by the body and O 2 consumed) (0.83 ± 0.01 vs 0.78 ± 0.01, n= 4, p < 0.05), suggesting a larger reliance on carbohydrates rather than lipids as fuel. Baseline BP was comparable in null and control mice. In response to chronic pressor dose of angiotensin (Ang) II (490 ng/kg/min, s.c. 14 days), CD4-Cul3 -/- mice displayed exaggerated hypertension (systolic BP in mmHg: 164 ± 8.4 vs 150.3 ± 4.9; ΔSBP: 35.3 ± 7.5 vs 15.8 ± 5.3, p < 0.05). Mean and diastolic BP were also greater in the null mice, but there was no difference in heart rate or activity. Ang II-infused CD4-Cul3 -/- mice showed a trend towards increased renal CD3 + T cells and significantly increased CD4 + T helper cells (p < 0.05). Thus, T cell Cul3 deficiency caused a lean phenotype characterized by decreased adiposity, increased carbohydrate catabolism, and augmented Ang II-induced hypertension and renal inflammation. The CD4-Cul3 -/- mice may be a useful model to study the association between low body mass and increased cardiovascular risk in humans.