title: Leptin Mediates High-Fat Diet Sensitization of Angiotensin II-Elicited Hypertension by Upregulating the Brain Renin-Angiotensin System and Inflammation.
abstract: Obesity is characterized by increased circulating levels of the adipocyte-derived hormone leptin, which can increase sympathetic nerve activity and raise blood pressure. A previous study revealed that rats fed a high-fat diet (HFD) have an enhanced hypertensive response to subsequent angiotensin II administration that is mediated at least, in part, by increased activity of brain renin-angiotensin system and proinflammatory cytokines. This study tested whether leptin mediates this HFD-induced sensitization of angiotensin II-elicited hypertension by interacting with brain renin-angiotensin system and proinflammatory cytokine mechanisms. Rats fed an HFD for 3 weeks had significant increases in white adipose tissue mass, plasma leptin levels, and mRNA expression of leptin and its receptors in the lamina terminalis and hypothalamic paraventricular nucleus. Central infusion of a leptin receptor antagonist during HFD feeding abolished HFD sensitization of angiotensin II-elicited hypertension. Furthermore, central infusion of leptin mimicked the sensitizing action of HFD. Concomitant central infusions of the angiotensin II type 1 receptor antagonist irbesartan, the tumor necrosis factor-α synthesis inhibitor pentoxifylline, or the inhibitor of microglial activation minocycline prevented the sensitization produced by central infusion of leptin. RT-PCR analysis indicated that either HFD or leptin administration upregulated mRNA expression of several components of the renin-angiotensin system and proinflammatory cytokines in the lamina terminalis and paraventricular nucleus. The leptin antagonist and the inhibitors of angiotensin II type 1 receptor, tumor necrosis factor-α synthesis, and microglial activation all reversed the expression of these genes. The results suggest that HFD-induced sensitization of angiotensin II-elicited hypertension is mediated by leptin through upregulation of central renin-angiotensin system and proinflammatory cytokines.
authors.affiliation: From the Departments of Psychological and Brain Sciences (B.X., F.G., T.G.B., R.L.T., A.K.J.), Pharmacology (A.K.J.), and Internal Medicine (Y.Y., R.B.F.), and the François M. Abboud Cardiovascular Research Center (B.X., R.B.F., A.K.J.), University of Iowa, Iowa City; and Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Henan, China (Z.Z.). baojian-xue@uiowa.edu alan-johnson@uiowa.edu.
authors.forename: Baojian
authors.initials: B
authors.lastname: Xue
authors.affiliation: From the Departments of Psychological and Brain Sciences (B.X., F.G., T.G.B., R.L.T., A.K.J.), Pharmacology (A.K.J.), and Internal Medicine (Y.Y., R.B.F.), and the François M. Abboud Cardiovascular Research Center (B.X., R.B.F., A.K.J.), University of Iowa, Iowa City; and Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Henan, China (Z.Z.).
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: From the Departments of Psychological and Brain Sciences (B.X., F.G., T.G.B., R.L.T., A.K.J.), Pharmacology (A.K.J.), and Internal Medicine (Y.Y., R.B.F.), and the François M. Abboud Cardiovascular Research Center (B.X., R.B.F., A.K.J.), University of Iowa, Iowa City; and Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Henan, China (Z.Z.).
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: From the Departments of Psychological and Brain Sciences (B.X., F.G., T.G.B., R.L.T., A.K.J.), Pharmacology (A.K.J.), and Internal Medicine (Y.Y., R.B.F.), and the François M. Abboud Cardiovascular Research Center (B.X., R.B.F., A.K.J.), University of Iowa, Iowa City; and Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Henan, China (Z.Z.).
authors.forename: Fang
authors.initials: F
authors.lastname: Guo
authors.affiliation: From the Departments of Psychological and Brain Sciences (B.X., F.G., T.G.B., R.L.T., A.K.J.), Pharmacology (A.K.J.), and Internal Medicine (Y.Y., R.B.F.), and the François M. Abboud Cardiovascular Research Center (B.X., R.B.F., A.K.J.), University of Iowa, Iowa City; and Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Henan, China (Z.Z.).
authors.forename: Terry G
authors.initials: TG
authors.lastname: Beltz
authors.affiliation: From the Departments of Psychological and Brain Sciences (B.X., F.G., T.G.B., R.L.T., A.K.J.), Pharmacology (A.K.J.), and Internal Medicine (Y.Y., R.B.F.), and the François M. Abboud Cardiovascular Research Center (B.X., R.B.F., A.K.J.), University of Iowa, Iowa City; and Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Henan, China (Z.Z.).
authors.forename: Robert L
authors.initials: RL
authors.lastname: Thunhorst
authors.affiliation: From the Departments of Psychological and Brain Sciences (B.X., F.G., T.G.B., R.L.T., A.K.J.), Pharmacology (A.K.J.), and Internal Medicine (Y.Y., R.B.F.), and the François M. Abboud Cardiovascular Research Center (B.X., R.B.F., A.K.J.), University of Iowa, Iowa City; and Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Henan, China (Z.Z.).
authors.forename: Robert B
authors.initials: RB
authors.lastname: Felder
authors.affiliation: From the Departments of Psychological and Brain Sciences (B.X., F.G., T.G.B., R.L.T., A.K.J.), Pharmacology (A.K.J.), and Internal Medicine (Y.Y., R.B.F.), and the François M. Abboud Cardiovascular Research Center (B.X., R.B.F., A.K.J.), University of Iowa, Iowa City; and Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Henan, China (Z.Z.). baojian-xue@uiowa.edu alan-johnson@uiowa.edu.
authors.forename: Alan Kim
authors.initials: AK
authors.lastname: Johnson
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001795:Blood Pressure Determination; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016207:Cytokines; D020738:Leptin; D012333:RNA, Messenger; D000804:Angiotensin II
keywords: blood pressure; high-fat diet; leptin; obesity; renin–angiotensin system