Hepatic peroxisome proliferator-activated receptor-γfat-specific protein 27 pathway contributes to obesity-related hypertension via afferent vagal signals

Kenji Uno, Tetsuya Yamada, Yasushi Ishigaki, Junta Imai, Yutaka Hasegawa, Junhong Gao, Keizo Kaneko, Kimihiko Matsusue, Tomomi Yamazaki, Yoshitomo Oka, Hideki Katagiri

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

Aims Obesity is commonly associated with hypertension. Increased sympathetic tonus in obese subjects contributes to the underlying mechanism. However, the precise mechanisms whereby obesity induces this sympathetic activation remain unclear. Hepatic peroxisome proliferator-activated receptor (PPAR)-γ2 expression, which is reportedly upregulated during obesity development, affects sympathetic activation via hepatic vagal afferents. Herein, we report involvement of this neuronal relay in obesity-related hypertension. Methods and results Peroxisome proliferator-activated receptor-γ and a direct PPARγ target, fat-specific protein 27 (Fsp27), were adenovirally overexpressed or knocked down in the liver, in combination with surgical dissection or pharmacological deafferentation of the hepatic vagus. Adenoviral PPARγ2 expression in the liver raised blood pressure (BP) in wild-type but not in β1/β2/β3 adrenergic receptor-deficient mice. In addition, knockdown of endogenous PPARγ in the liver lowered BP in murine obesity models. Either surgical dissection or pharmacological deafferentation of the hepatic vagus markedly blunted BP elevation in mice with diet-induced and genetically-induced obesity. In contrast, BP was not elevated in other models of hepatic steatosis, DGAT1 and DGAT2 overexpressions, in which PPARγ is not upregulated in the liver. Thus, hepatic PPARγ upregulation associated with obesity is involved in BP elevation during obesity development. Furthermore, hepatic expression of Fsp27 raised BP and the effect was blocked by hepatic vagotomy. Hepatic Fsp27 is actually upregulated in murine obesity models and its knockdown reversed BP elevation. Conclusion The hepatic PPARγFsp27 pathway plays important roles in the development of obesity-related hypertension via afferent vagal signals from the liver.

Original languageEnglish
Pages (from-to)1279-1289
Number of pages11
JournalEuropean Heart Journal
Volume33
Issue number10
DOIs
Publication statusPublished - 2012 May
Externally publishedYes

Keywords

  • Fsp27
  • Hypertension
  • Neuronal signals
  • Obesity
  • PPARγ

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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