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

Author
item ASTERHOLM, INGRID - University Of Texas Southwestern Medical Center
item RUTKOWSKI, JOSEPH - University Of Texas Southwestern Medical Center
item FUJIKAWA, TEPPEI - University Of Texas Southwestern Medical Center
item CHO, YOU - University Of Texas Southwestern Medical Center
item FUKUDA, MAKOTO - Children'S Nutrition Research Center (CNRC)
item TAO, CAROLINE - University Of Texas Southwestern Medical Center
item WANG, ZHAO - University Of Texas Southwestern Medical Center
item GUPTA, RANA - University Of Texas Southwestern Medical Center
item ELMQUIST, JOEL - University Of Texas Southwestern Medical Center
item SCHERER, PHILLIP - University Of Texas Southwestern Medical Center

Submitted to: Diabetologia
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/14/2014
Publication Date: 6/1/2014
Citation: Asterholm, I.W., Rutkowski, J.M., Fujikawa, T., Cho, Y.R., Fukuda, M., Tao, C., Wang, Z.V., Gupta, R.K., Elmquist, J.K., Scherer, P.E. 2014. Elevated resistin levels induce central leptin resistance and increased atherosclerotic progression in mice. Diabetologia. 57(6):1209-1218.

Interpretive Summary: Resitin is a fat derived hormone that links obesity and insulin resistance. Experimental studies suggest that resistin plays a direct role in the origination and development of atherosclerosis (a disease in which plaque builds up inside arteries). To examine the changes associated with resistin in metabolic regulation, we generated a mouse model that produces high levels of resistin. Using this mouse model, we found that increased resistin led to insulin resistance, atherosclerotic progression and increased body weight. Thus, these mice recapitulated both the proposed negative cardiovascular correlation and the insulin resistance. More importantly, we found that resistin directly causes leptin resistance, which is a hallmark of obesity and metabolic syndrome. Since leptin resistance reduces sympathetic outflow from the brain and thus impairs fat metabolism, leptin resistance is responsible for impaired insulin sensitivity and more rapid atherosclerotic plaque formation. Altogether, a resistin-mediated leptin resistance may provide a unifying mechanism for this complex phenotype. Our findings collectively provide a new insight into the role of resistin in the development of obesity and its associated complications.

Technical Abstract: 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. 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. 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 amore 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. 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.