title: Rhesus macaques develop metabolic syndrome with reversible vascular dysfunction responsive to pioglitazone.
abstract: BACKGROUND
  The metabolic syndrome (MetS) is a constellation of clinical features that include central obesity, hypertension, atherogenic dyslipidemia, and insulin resistance. However, the concept remains controversial; it has been debated whether MetS represents nothing more than simultaneous co-occurrence of individual risk factors or whether there are common shared pathophysiological mechanisms that link the individual components.
  
  
  RESULTS
  To investigate the emergence of metabolic and cardiovascular components during the development of MetS, we identified MetS-predisposed animals (n=35) in a large population of rhesus macaques (Macaca mulatta, 12.7±2.9 years old, n=408), acclimated them to standardized conditions, and monitored the progression of individual component features over 18 months. In 18 MetS animals with recently developed fasting hyperinsulinemia, central obesity, hypertension, and atherogenic dyslipidemia, we found that individual metabolic and cardiovascular components track together during the transition from pre-MetS to onset of MetS; MetS was associated with a 60% impairment of flow-mediated dilation, establishing the mechanistic link with vascular dysfunction. Pioglitazone treatment (3 mg/kg body weight/d for 6 weeks), a peroxisome proliferator-activated receptor γ agonist, reversibly improved atherogenic dyslipidemia and insulin resistance and fully restored flow-mediated dilation with persistent benefits.
  
  
  CONCLUSIONS
  Coemergence of metabolic and cardiovascular components during MetS progression and complete normalization of vascular dysfunction with peroxisome proliferator-activated receptor γ agonists suggest shared underlying mechanisms rather than separate processes, arguing for the benefit of early intervention of MetS components. Predictive nonhuman primate (NHP) models of MetS should be highly valuable in mechanistic and translational studies on the pathogenesis of MetS in relation to cardiovascular disease and diabetes mellitus.
authors.affiliation: Institute of Molecular Medicine, Peking University, No.5 Yiheyuan Rd, Haidian District, Beijing 100871, China.
authors.forename: Xiuqin
authors.initials: X
authors.lastname: Zhang
authors.forename: Rongli
authors.initials: R
authors.lastname: Zhang
authors.forename: Susanne
authors.initials: S
authors.lastname: Raab
authors.forename: Wen
authors.initials: W
authors.lastname: Zheng
authors.forename: Jue
authors.initials: J
authors.lastname: Wang
authors.forename: Na
authors.initials: N
authors.lastname: Liu
authors.forename: Tiangang
authors.initials: T
authors.lastname: Zhu
authors.forename: Lifang
authors.initials: L
authors.lastname: Xue
authors.forename: Zhentao
authors.initials: Z
authors.lastname: Song
authors.forename: Jiaming
authors.initials: J
authors.lastname: Mao
authors.forename: Kaitao
authors.initials: K
authors.lastname: Li
authors.forename: Huiliang
authors.initials: H
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Chao
authors.initials: C
authors.lastname: Han
authors.forename: Yi
authors.initials: Y
authors.lastname: Ding
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Ning
authors.initials: N
authors.lastname: Hou
authors.forename: Yuli
authors.initials: Y
authors.lastname: Liu
authors.forename: Shujiang
authors.initials: S
authors.lastname: Shang
authors.forename: Chuanyun
authors.initials: C
authors.lastname: Li
authors.forename: Elena
authors.initials: E
authors.lastname: Sebokova
authors.forename: Heping
authors.initials: H
authors.lastname: Cheng
authors.forename: Paul L
authors.initials: PL
authors.lastname: Huang
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000187:drug effects* / Q000503:physiopathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D050171:Dyslipidemias / Q000503:physiopathology; D006946:Hyperinsulinism / Q000503:physiopathology; D006973:Hypertension / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology; D008253:Macaca mulatta; D024821:Metabolic Syndrome / Q000503:physiopathology*; D056128:Obesity, Abdominal / Q000503:physiopathology; D000077205:Pioglitazone; D012039:Regional Blood Flow / Q000187:drug effects* / Q000502:physiology; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077205:Pioglitazone