title: Elevated resistin levels induce central leptin resistance and increased atherosclerotic progression in mice.
abstract: OBJECTIVE
  Resistin was originally identified as an adipocyte-derived factor upregulated during obesity and as a contributor to obesity-associated insulin resistance. Clinically, resistin has also been implicated in cardiovascular disease in a number of different patient populations. Our aim was to simultaneously address these phenomena.
  
  
  METHODS
  We generated mice with modest adipocyte-specific resistin overexpression. These mice were crossed with mice deficient in the LDL receptor (Ldlr (-/-)) to probe the physiological role of resistin. Both metabolic and atherosclerotic assessments were performed.
  
  
  RESULTS
  Resistin overexpression led to increased atherosclerotic progression in Ldlr (-/-) mice. This was in part related to elevated serum triacylglycerol levels and a reduced ability to clear triacylglycerol upon a challenge. Additional phenotypic changes, such as increased body weight and reduced glucose clearance, independent of the Ldlr (-/-) background, confirmed increased adiposity associated with a more pronounced insulin resistance. A hallmark of elevated resistin was the disproportionate increase in circulating leptin levels. These mice thus recapitulated both the proposed negative cardiovascular correlation and the insulin resistance. A unifying mechanism for this complex phenotype was a resistin-mediated central leptin resistance, which we demonstrate directly both in vivo and in organotypic brain slices. In line with reduced sympathetic nervous system outflow, we found decreased brown adipose tissue (BAT) activity. The resulting elevated triacylglycerol levels provide a likely explanation for accelerated atherosclerosis.
  
  
  CONCLUSIONS
  Resistin overexpression leads to a complex metabolic phenotype driven by resistin-mediated central leptin resistance and reduced BAT activity. Hypothalamic leptin resistance thus provides a unifying mechanism for both resistin-mediated insulin resistance and enhanced atherosclerosis.
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-8549, USA.
authors.forename: Ingrid W
authors.initials: IW
authors.lastname: Asterholm
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Rutkowski
authors.forename: Teppei
authors.initials: T
authors.lastname: Fujikawa
authors.forename: You-Ree
authors.initials: YR
authors.lastname: Cho
authors.forename: Makoto
authors.initials: M
authors.lastname: Fukuda
authors.forename: Caroline
authors.initials: C
authors.lastname: Tao
authors.forename: Zhao V
authors.initials: ZV
authors.lastname: Wang
authors.forename: Rana K
authors.initials: RK
authors.lastname: Gupta
authors.forename: Joel K
authors.initials: JK
authors.lastname: Elmquist
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005260:Female; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000097:blood; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D052243:Resistin / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood
chemical_list: D020738:Leptin; D011973:Receptors, LDL; D052243:Resistin; C499623:Retn protein, mouse; D014280:Triglycerides