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

Abstract

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.

Genetic variations in peroxisome proliferator-activated receptor γ expression affect blood pressure

“…The increased blood pressure in our mice with decreased Pparg expression differs from the hypotensive phenotype described in mice with a generalized lack of PPAR␥ (23). A complete absence of PPAR␥ causes embryonic death, but the investigators in that previous study were able to rescue them from lethality by using a Cre-loxP system that deletes the Pparg gene in the epiblast (and so also in the embryos), but not in extraembryonic tissues.…”

Fat poetry: a kingdom for PPARγ

“…In a model of generalized PPARg ablation where embryonic lethality is prevented by preserving PPARg expression in trophoblasts, severe lipodystrophy, insulin resistance and hypotension, probably due to increased vascular relaxation, were observed [177]. On the contrary, the PPARg+/-heterozygous animals are viable and do not present any major defects except mild growth retardation in males, possibly due to a deregulation of growth hormone signaling in the WAT [178].…”

PPARs and adipocyte function

“…These results were corroborated by Barak et al [21] which utilised a tetraploid-rescue approach that bypasses placental defects to generate a single PPAR -null pup that completely lacked WAT (and BAT). More recently, using Cre-Lox technology to inactivate PPAR in the embryo but not the trophoblasts, Duan et al [22] also generated generalised PPAR deficient mice which similarly displayed severe lipodystrophy in addition to insulin resistance and surprisingly hypotension. Conditional knockout strategies have also allowed several groups to examine the consequences of adipose-selective ablation of PPAR thereby establishing its critical role in post-differentiation survival of mature white (and brown) adipocytes [23][24][25].…”