Hypotension, lipodystrophy, and insulin resistance in generalized PPARgamma-deficient mice rescued from embryonic lethality.
We rescued the embryonic lethality of global PPARgamma knockout by breeding Mox2-Cre (MORE) mice with floxed PPARgamma mice to inactivate PPARgamma in the embryo but not in trophoblasts and created a generalized PPARgamma knockout mouse model, MORE-PPARgamma knockout (MORE-PGKO) mice. PPARgamma inactivation caused severe lipodystrophy and insulin resistance; surprisingly, it also caused hypotension. Paradoxically, PPARgamma 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 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 PPARgamma is required to maintain normal adiposity and insulin sensitivity in adult mice. Surprisingly, genetic loss of PPARgamma function, like activation by agonists, lowered blood pressure, likely through a mechanism involving increased vascular relaxation.
Duan
Sheng Zhong
SZ
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Ivashchenko
Christine Y
CY
Whitesall
Steven E
SE
D'Alecy
Louis G
LG
Duquaine
Damon C
DC
Brosius
Frank C
FC
Gonzalez
Frank J
FJ
Vinson
Charles
C
Pierre
Melissa A
MA
Milstone
David S
DS
Mortensen
Richard M
RM
D000818:Animals; D005260:Female; D005313:Fetal Death / Q000235:genetics*; D007022:Hypotension / Q000235:genetics*; D007333:Insulin Resistance / Q000235:genetics*; D008060:Lipodystrophy / Q000235:genetics* / Q000473:pathology; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D047495:PPAR gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation
D047495:PPAR gamma; D052250:Nitric Oxide Synthase Type III