title: Caffeine intake improves fructose-induced hypertension and insulin resistance by enhancing central insulin signaling.
abstract: Recent clinical studies found that fructose intake leads to insulin resistance and hypertension. Fructose consumption promotes protein fructosylation and formation of superoxide. In a previous study, we revealed that inhibition of superoxide production in the nucleus tractus solitarii (NTS) reduces blood pressure. Caffeine displays significant antioxidant ability in protecting membranes against oxidative damage and can lower the risk of insulin resistance. However, the mechanism through which caffeine improves fructose-induced insulin resistance is unclear. The aim of this study was to investigate whether caffeine consumption can abolish superoxide generation to enhance insulin signaling in the NTS, thereby reducing blood pressure in rats with fructose-induced hypertension. Treatment with caffeine for 4 weeks decreased blood pressure, serum fasting glucose, insulin, homeostatic model assessment-insulin resistance, and triglyceride levels and increased the serum direct high-density lipoprotein level in fructose-fed rats but not in control rats. Caffeine treatment resulted in the recovery of fructose-induced decrease in nitric oxide production in the NTS. Immunoblotting and immunofluorescence analyses further showed that caffeine reduced the fructose-induced phosphorylation of insulin receptor substrate 1 (IRS1(S307)) and reversed Akt(S473) and neuronal nitric oxide synthase phosphorylation. Similarly, caffeine was able to improve insulin sensitivity and decrease insulin levels in the NTS evoked by fructose. Caffeine intake also reduced the production of superoxide and expression of receptor of advanced glycation end product in the NTS. These results suggest that caffeine may enhance insulin receptor substrate 1-phosphatidylinositol 3-kinase-Akt-neuronal nitric oxide synthase signaling to decrease blood pressure by abolishing superoxide production in the NTS.
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, 386, Ta-Chung 1st Rd, Kaohsiung, Taiwan 813, Taiwan, Republic of China. cjtseng@vghks.gov.tw; or Jau-Cheng Liou, Department of Biological Sciences, National Sun Yat-sen University, 70, Lien-Hai Rd, Kaohsiung, Taiwan, Republic of China. E-mail netliou@mail.nsysu.edu.tw.
authors.forename: Tung-Chen
authors.initials: TC
authors.lastname: Yeh
authors.forename: Chun-Peng
authors.initials: CP
authors.lastname: Liu
authors.forename: Wen-Han
authors.initials: WH
authors.lastname: Cheng
authors.forename: Bo-Rong
authors.initials: BR
authors.lastname: Chen
authors.forename: Pei-Jung
authors.initials: PJ
authors.lastname: Lu
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Cheng
authors.forename: Wen-Yu
authors.initials: WY
authors.lastname: Ho
authors.forename: Gwo-Ching
authors.initials: GC
authors.lastname: Sun
authors.forename: Jau-Cheng
authors.initials: JC
authors.lastname: Liou
authors.forename: Ching-Jiunn
authors.initials: CJ
authors.lastname: Tseng
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002110:Caffeine / Q000627:therapeutic use*; D000697:Central Nervous System Stimulants / Q000627:therapeutic use; D004195:Disease Models, Animal; D005632:Fructose / Q000633:toxicity; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D051381:Rats; D011921:Rats, Inbred WKY; D015398:Signal Transduction / Q000187:drug effects; D017552:Solitary Nucleus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D000697:Central Nervous System Stimulants; D007328:Insulin; D005632:Fructose; D002110:Caffeine
keywords: caffeine; fructose; hypertension; nitric oxide; solitary nucleus