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Activation of central PPAR‐γ reduces hypothalamic paraventricular nucleus inflammation and sympathetic excitation in heart failure rats

Activation of peroxisome proliferator‐activated receptor (PPAR)‐γ was recently shown to inhibit the production of proinflammatory cytokines in the brain. We hypothesized that activation of central PPAR‐γ would modulate the expression of inflammatory mediators in paraventricular nucleus of hypothalamus (PVN) and reduce sympathetic excitation in heart failure (HF). Rats underwent coronary ligation to induce HF or sham surgery (SHAM). Two weeks later, an intracerebroventricular (ICV) infusion of the PPAR‐γ agonist pioglitazone or VEH was started in HF rats. After two weeks of treatment, rats were euthanized for molecular studies. VEH‐treated HF and SHAM rats had similar PPAR‐γ mRNA and protein levels, but HF rats had less (*p<0.05) PPAR‐γ DNA binding activity in PVN, augmented TNF‐α, IL‐1β, COX‐2 mRNA and NF‐kB DNA binding activity in PVN, and higher plasma norepinephrine levels. Pioglitazone‐treated HF rats had increased PPAR‐γ mRNA and DNA binding activity in PVN. TNF‐α mRNA in PVN was normalized and IL‐1β, COX‐2 mRNA, NF‐kB DNA binding activity in PVN and plasma norepinephrine levels were reduced. These data demonstrate that PPAR‐γ activity is reduced in the PVN of HF rats, and that stimulation of PPAR‐γ can modulate central inflammation in HF, probably in part by suppressing NF‐kB activity, thereby reducing sympathetic nerve activity. Supported by a VA Merit Review Grant and NIH RO1 HL073986.