Visceral adiposity and
insulin resistance are common pathophysiological denominators in patients with primary
aldosteronism. Although we recently reported the
antidiabetic effects of
heme oxygenase (HO), no study has examined the effects of upregulating HO on visceral adiposity in uninephrectomized (UnX)
deoxycorticosterone acetate (
DOCA-
salt) hypertensive rats, a model of human primary
aldosteronism characterized by elevated
endothelin (ET-1) and oxidative/inflammatory events. Here, we report the effects of the HO inducer
heme arginate and the HO blocker
chromium mesoporphyrin (CrMP) on visceral adipose tissue obtained from retroperitoneal fat pads of UnX
DOCA-
salt rats. UnX
DOCA-
salt rats were hypertensive but normoglycemic.
Heme arginate reduced visceral adiposity and enhanced HO activity and cGMP in the adipose tissue, but suppressed ET-1, nuclear-factor κB (NF-κB), activating-
protein (AP-1), c-Jun-NH2-terminal
kinase (JNK), macrophage
chemoattractant protein-1 (MCP-1),
intercellular adhesion molecule-1 (ICAM-1), and
8-isoprostane. These were associated with reduced glycemia, increased
insulin, and the
insulin-sensitizing
protein adiponectin, with corresponding reduction in
insulin resistance. In contrast, the HO inhibitor, CrMP, abolished the effects of
heme arginate, aggravating
insulin resistance, suggesting a role for the HO system in
insulin signaling. Importantly, the effects of the HO system on ET-1, NF-κB,
AP-1, JNK, MCP-1, and
ICAM-1 in visceral or retroperitoneal adiposity in UnX-
DOCA-
salt rats have not been reported. Because
8-isoprostane stimulates ET-1 to enhance oxidative insults, and increased oxidative events deplete
adiponectin and
insulin levels, the suppression of oxidative/inflammatory mediators such as
8-isoprostane, NF-κB,
AP-1, MCP-1,
ICAM-1, and JNK, an inhibitor of
insulin biosynthesis, may account for the potentiation of
insulin signaling/
glucose metabolism by
heme arginate. These data indicate that although UnX
DOCA-
salt rats were normoglycemic,
insulin signaling was impaired, suggesting that dysfunctional
insulin signaling may be a forerunner to overt diabetes in primary
aldosteronism.