We rescued the embryonic lethality of global PPARγ knockout by breeding Mox2-Cre (MORE) mice with floxed PPARγ mice to inactivate PPARγ in the embryo but not in trophoblasts and created a generalized PPARγ knockout mouse model, MORE-PPARγ knockout (MORE-PGKO) mice. PPARγ inactivation caused severe lipodystrophy and insulin resistance; surprisingly, it also caused hypotension. Paradoxically, PPARγ agonists had the same effect. We showed that another mouse model of lipodystrophy was hypertensive, ruling out the lipodystrophy as a cause. Further, high salt loading did not correct the hypotension in MORE-PGKO mice. In vitro studies showed that the vasculature from MORE-PGKO mice was more sensitive to endothelial-dependent relaxation caused by muscarinic stimulation, but was not associated with changes in eNOS expression or phosphorylation. In addition, vascular smooth muscle had impaired contraction in response to α-adrenergic agents. The renin-angiotensin-aldosterone system was mildly activated, consistent with increased vascular capacitance or decreased volume. These effects are likely mechanisms contributing to the hypotension. Our results demonstrated that PPARγ is required to maintain normal adiposity and insulin sensitivity in adult mice. Surprisingly, genetic loss of PPARγ function, like activation by agonists, lowered blood pressure, likely through a mechanism involving increased vascular relaxation.
The purpose of this study was to perform a comprehensive geometric, densitometric, biomechanical, and statistical analysis of paired femurs for an adult population over a wide age range using three imaging modalities to quantify the departure from symmetry in size, bone mineral density, and cross-sectional structural rigidities.
Femur measurements were obtained from 20 pairs of cadaveric femurs. Dimensions of these anatomic sites were measured using calipers directly on the bone and plain radiographs. Dual energy X-ray absorptiometry was used to measure bone mineral density. Bone mineral content and axial and bending rigidities were determined from the CT imaging.
No differences were observed between the geometric measurements, DXA based bone mineral density and axial and bending rigidities of left and right femurs (P > 0.05 for all cases). Left and right proximal femurs are not significantly different based on geometric, densitometric, and structural rigidity measurements. However, absolute left–right differences for individual patients can be substantial. When using the contralateral femur as a control, the number of femur pairs required to assess significant changes in anatomic dimensions and structural properties induced by a tumor, infection, fracture, or implanted device can range from 3 to 165 pairs depending on the desired effect size or sensitivity (5% or 10% difference).
This information is important both for femoral arthroplasty implant design and the use of the contralateral femur as an intra-subject control for clinical assessment and research studies. In addition, our statistical analysis provides sample size estimates for planning future orthopedic research studies.
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