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01.06.2014 | Article | Ausgabe 6/2014

Diabetologia 6/2014

Elevated resistin levels induce central leptin resistance and increased atherosclerotic progression in mice

Zeitschrift:
Diabetologia > Ausgabe 6/2014
Autoren:
Ingrid W. Asterholm, Joseph M. Rutkowski, Teppei Fujikawa, You-Ree Cho, Makoto Fukuda, Caroline Tao, Zhao V. Wang, Rana K. Gupta, Joel K. Elmquist, Philipp E. Scherer
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s00125-014-3210-3) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Ingrid W. Asterholm and Joseph M. Rutkowski contributed equally to this study.

Abstract

Aims/hypothesis

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/interpretation

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.

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