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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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Zusatzmaterial
ESM Methods (PDF 84 kb)
125_2014_3210_MOESM1_ESM.pdf
ESM Fig. 1 Male Retn-tg mice display some metabolic dysregulation comparable to their female counterparts. Retn-tg mice (black bars) exhibit (a) increased body weight (p = 0.144), (b) normal glucose (p = 0.898), (c) increased total % fat mass by NMR (p = 0.133), (d) significantly increased leptin levels (p = 0.026) on chow diet (WD increased both over baseline, (e) and elevated FA levels (p = 0.213) as compared to wild type littermates (white bars). (f) Serum triacylglycerol levels and (g) liver weight are unchanged (p = 0.678 and p = 0.845, respectively), while (h) hepatic lipid levels were significantly reduced in male chow-fed Retn-tg mice as female mice on Western diet (p = 0.020). (i) Triacylglycerol clearance was reduced in male Retn-tg mice (black squares) on chow diet compared to wild type (white squares; p = 0.035), but after themale mice were on Western diet for 5 weeks (j) the effect was lost (p = 0.543). *p < 0.05 compared to wild type. †p < 0.05 with diet. (PDF 97 kb)
125_2014_3210_MOESM2_ESM.pdf
ESM Fig. 2 Arterial plaques and lipid alterations in female Ldlr −/− Retn-tg mice. (a) No difference in atherosclerotic plaque quality and quantity between wildtype Ldlr −/− (white bars) and Retn-tg (black bars) female mice on Ldlr −/− background after 15 weeks on Western diet. (b) Slightly increased body weight Ldlr −/− Retn-tg females after 8 weeks on Western diet (p = 0.018). (c) No difference in baseline serum triacylglycerol levels (p = 0.172), but slightly impaired triacylglycerol clearance (d) in chow-fed Ldlr −/− Retn-tg female mice (black squares) compared to Ldlr −/− litter mates (white squares; AUC p = 0.071). *p < 0.05 compared to wild type Ldlr −/−. (PDF 467 kb)
125_2014_3210_MOESM3_ESM.pdf
ESM Fig. 3 Retn overexpression reduced liver lipid content. (a) Reduced Western diet-induced gain of hepatic lipids in relation to weight gain in female Ldlr −/− Retn-tg mice (R2 = 0.853; black squares) compared to Ldlr −/− wild type female mice (R2 = 0.390; white squares). Reduced hepatic cholesterol (b) and triacylglycerol (c) levels in female Ldlr −/− Retn-tg mice (black bars) after 15 weeks on Western diet compared to Ldlr −/− litter mates (white bars; p = 0.038 and 0.022, respectively). (d) No difference in hepatic VLDLtriacylglycerol production rate between female Ldlr −/− Retn-tg and littermate Ldlr −/− controls (p = 0.080). *p < 0.05 compared to wild type Ldlr −/−. (PDF 77 kb)
125_2014_3210_MOESM4_ESM.pdf
ESM Fig. 4 Brown adipose tissue and adipocyte phenotyping in Retn-tg mice. (a) Reduced UCP-1 immunofluorescence (green) in Retn-tg brown adipose tissue (BAT) and increased lipid droplet size is not weight dependent (tissue from 35 g and 55 g matched mice shown). (b) Reduced UCP-1 protein levels in BAT of female Western diet-fed Ldlr −/− Retn-tg mice compared to littermate Ldlr −/− controls. Normal capacity for brown ex vivo adipogenesis isolated stromal-vascular fraction from Retn-tg BAT as judged by Oil-Red O stain (c) and normal mRNA levels of (d) Fabp4, Cfd and Slc2a4, while the expression of Cidea, Ppargc1a, Pparg2, and Ucp1 are reduced (p = 0.031, 0.050, 0.003, and 0.038) and Cebpa is increased (p = 0.027) in differentiated primary Retn-tg brown adipocytes (black bars) compared to wild type (white bars). (e) Isoproterenol treatment (hashes on white: WT; on black: Retn-tg) induced marked BAT gene expression in wildtype cells and significant increases in Dio2 and Ucp1 in Retn-tg cells (p = 0.011 and p < 0.001), but overall levels of response were less than wild type levels (each p < 0.001). *p < 0.05 compared to wild type. †p < 0.05, †††p < 0.001 with treatment. (PDF 1394 kb)
125_2014_3210_MOESM5_ESM.pdf
ESM Fig. 5 (a) Hypothalamic leptin-signaling gene expression in Retn-tg mice is reduced with Cntf, Lepr, and Ptp1b being the most different (p = 0.075, p = 0.097, and p = 0.080, respectively). (b) Organotopic hypothalamic slices treated demonstrate reduced STAT3 phosphorylation (red) in the arcuate nucleus following leptin treatment if pre-treated with recombinant resistin protein. Slice size and thickness after 10 days of culture likely increase displayed variability. Blue = DAPI, third ventricle is centered in each image. (PDF 667 kb)
125_2014_3210_MOESM6_ESM.pdf
ESM Table 1 (PDF 8 kb)
125_2014_3210_MOESM7_ESM.pdf
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