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

• Published in: European heart journal Vol. 33; no. 10; pp. 1279 - 1289
• Main Authors: Uno, Kenji, Yamada, Tetsuya, Ishigaki, Yasushi, Imai, Junta, Hasegawa, Yutaka, Gao, Junhong, Kaneko, Keizo, Matsusue, Kimihiko, Yamazaki, Tomomi, Oka, Yoshitomo, Katagiri, Hideki
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.05.2012
• Subjects: Animal subjects; Animals; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blood pressure; Capsaicin - pharmacology; Cardiology. Vascular system; Gene Knockdown Techniques; Heart; Hypertension; Hypertension - etiology; Liver; Liver - metabolism; Medical sciences; Metabolic diseases; Mice; Mice, Inbred C57BL; Nerve Block - methods; Obesity; Obesity - etiology; Objectives; PPAR gamma - metabolism; Proteins; Proteins - metabolism; Relays; Sensory System Agents - pharmacology; Signal Transduction - physiology; Synaptic Transmission - physiology; Up-Regulation; Vagus Nerve - physiology; Vagus Nerve - surgery; Hypertension; Obesity; Adipose tissue; Liver; Nutrition disorder; Cardiovascular disease; Peroxisome proliferator; PPARγ; Signal; Fsp27; Receptor protein; Circulatory system; Vagus nerve; Cardiology; Neuronal signals; Nutritional status
• ISSN: 0195-668X; 1522-9645; 1522-9645
• DOI: 10.1093/eurheartj/ehr265

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. 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. The hepatic PPARγ-Fsp27 pathway plays important roles in the development of obesity-related hypertension via afferent vagal signals from the liver.