Hypotension, lipodystrophy, and insulin resistance in generalized PPARγ-deficient mice rescued from embryonic lethality

We rescued the embryonic lethality of global PPAR gamma knockout by breeding Mox2-Cre (MORE) mice with floxed PPAR gamma mice to inactivate PPAR gamma in the embryo but not in trophoblasts and created a generalized PPAR gamma knockout mouse model, MORE-PPAR gamma knockout (MORE-PGKO) mice. PPAR gamma inactivation caused severe lipodystrophy and insulin resistance; surprisingly, it also caused hypotension. Paradoxically, PPAR gamma 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 MOR.E-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 alpha-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 PPAR gamma is required to maintain normal adiposity and insulin sensitivity in adult mice. Surprisingly, genetic loss of PPAR gamma function, like activation by agonists, lowered blood pressure, likely through a mechanism involving increased vascular relaxation.