Leptin dose-dependently decreases atherosclerosis by attenuation of hypercholesterolemia and induction of adiponectin

Hoffmann, Annett; Ebert, Thomas; Klöting, Nora; Dokas, Janine; Jeromin, F.; Jeßnitzer, Beate; Burkhardt, Ralph; Faßhauer, Mathias; Kralisch, Susan

doi:10.1016/j.bbadis.2015.10.022

Cited by 39 publications

(29 citation statements)

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“…MCP‐1 plays a fundamental role in monocyte recruitment and increased MCP‐1 expression is detected in atherosclerotic lesions of both humans and animals but not in normal arteries . In agreement with proatherogenic effects of IL‐6 and MCP‐1, leptin within the subphysiological to physiological range dose‐dependently decreases atherosclerotic lesion area in female leptin‐deficient LDLR −/− ; ob/ob mice in this study similar to recent findings from our group in male animals . These published findings and our present data are in agreement with the hypothesis that the anti‐atherogenic effects of subphysiological to physiological leptin doses are mediated in part by reduction of both pro‐inflammatory IL‐6 and MCP‐1.…”

Section: Discussionsupporting

confidence: 93%

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Leptin decreases circulating inflammatory IL‐6 and MCP‐1 in mice

et al. 2018

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Leptin influences inflammation and immune response. Dose‐dependent effects of leptin on biomarkers of inflammation have not been studied in vivo, so far. Leptin‐deficient low‐density lipoprotein receptor (LDLR) knockout (LDLR−/−;ob/ob) female mice were treated with three different leptin doses or saline for 12 weeks. The effect of leptin on plasma interleukin (IL)‐6 and monocyte chemoattractant protein (MCP)‐1 concentrations and Il‐6 and Mcp‐1 mRNA expression in vivo were assessed. Macrophage infiltration in epididymal adipose tissue (epiAT) after leptin treatment was determined by quantitative immunohistochemical analysis. Aortic root atherosclerotic lesions were analyzed by oil red O staining. Mean plasma IL‐6 and MCP‐1 decreased significantly in the 3.0 mg/kg BW/day group as compared to control mice (both P < 0.01). Messenger RNA expression of Il‐6 and Mcp‐1 was significantly down‐regulated by leptin treatment in different adipose tissues in vivo. Characteristic crown‐like structures formed by adipose tissue macrophages were significantly reduced by leptin treatment in epiAT. Recombinant leptin dose‐dependently diminished plaque area in the aortic root. Leptin administration within the subphysiological to physiological range diminishes circulating pro‐inflammatory IL‐6 and MCP‐1. Reduction of Il‐6 and Mcp‐1 gene expression in adipose tissue, as well as decreased adipose tissue macrophage infiltration might contribute. © 2018 BioFactors, 45(1):43–48, 2019

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Section: Discussionsupporting

confidence: 93%

“…Similar to published data from our group in male animals [20], leptin dose-dependently decreased lesion size in the aortic root (Fig. 4A) in female LDLR −/− ;ob/ob mice as compared to saline with most pronounced effects observed at 3.0 mg/kg BW/day leptin.…”

Section: Leptin Dose-dependently Reduces Atherosclerotic Lesion Size supporting

confidence: 90%

Leptin decreases circulating inflammatory IL‐6 and MCP‐1 in mice

et al. 2018

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“…Previous studies have shown lower adiponectin mRNA expression in leptin-deficient ob/ob and leptin receptor-deficient db/db mice 29–31 , as well as in obese Zucker fa/fa rats lacking functional leptin receptors 32 , and that leptin significantly increases Adipoq expression in WAT 18, 23, 33, 34 and in the heart 35 . Interestingly, we found lower amounts of adiponectin protein in WAT of ob/ob mice consistent with other studies 30, 36, 37 , but leptin replacement failed to normalize its levels.…”

Section: Discussionmentioning

confidence: 95%

Normalization of adiponectin concentrations by leptin replacement in ob/ob mice is accompanied by reductions in systemic oxidative stress and inflammation

Frühbeck

Catalán

Rodríguez

et al. 2017

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The circulating concentrations of adiponectin, an antidiabetic adipokine, have been shown to be reduced in obesity, in relation to an increase in inflammation. The aim of the present work was to assess the effect of leptin replacement on adiponectin levels and expression as well as on markers of oxidative stress and inflammation in leptin-deficient ob/ob mice. Twelve-week-old male mice (n = 7–10 per group) were treated with either saline (wild type and ob/ob mice) or leptin (ob/ob mice) for 18 days. A third group of ob/ob mice was treated with saline and pair-fed to the amount of food consumed by the leptin-treated group. Leptin replacement restored values of adiponectin (P < 0.001), reduced circulating 8-isoprostane and serum amyloid A (SAA) levels (P < 0.05 for both), and significantly downregulated the increased gene expression of osteopontin (Spp1, P < 0.05), Saa3 (P < 0.05), Cd68 (P < 0.01), Il6 (P < 0.01) and NADPH oxidase (Nox1 and Nox2, P < 0.01) in the perirenal WAT and Spp1 (P < 0.05) in the liver of ob/ob mice. In cultured adipocytes from ob/ob mice, leptin increased (P < 0.05) the mRNA expression and secretion of adiponectin. We concluded that circulating concentrations of adiponectin are positively regulated by leptin and ameliorate obesity-associated oxidative stress and inflammation in mice.

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“…This reduction was associated to an increased circulating leptin level in HF-fed mice. While Ad and leptin were described as two independent factors which are dysregulated in MetS [48], recent studies found that leptin could induce Ad expression in differentiated human white preadipocytes [49], in ob/ob [50, 51] and in LDLR -/- mice [51]. Singh et al also suggested that leptin resistance may contribute to the reduced Ad expression in obese patients [49].…”

Section: Discussionmentioning

confidence: 99%

Interactions of exercise training and high-fat diet on adiponectin forms and muscle receptors in mice

et al. 2016

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BackgroundMetabolic syndrome (MetS) is characterized by systemic disturbances that increase cardiovascular risk. Adiponectin (Ad) exhibits a cardioprotective function because of its anti-inflammatory and anti-atherosclerotic properties. In the bloodstream, this adipocytokine circulates on multimers (Admer), among which high molecular weight (HMW) are the most active forms. Because alterations of Ad plasmatic levels, Admer distribution and receptor (AdipoR) expression have been described in murine models and obese patients, strategies that aim to enhance Ad production or its effect on target tissues are the subject of intense investigations. While exercise training is well known to be beneficial for reducing cardiovascular risk, the contribution of Ad is still controversial. Our aim was to evaluate the effect of exercise training on Ad production, Admer distribution and AdipoR muscle expression in a murine model of MetS.MethodsAt 6 weeks of age, mice were submitted to a standard (SF) or high-fat high-sugar (HF) diet for 10 weeks. After 2 weeks, the SF- and HF-fed animals were randomly assigned to a training program (SFT, HFT) or not (SFC, HFC). The trained groups were submitted to sessions of running on a treadmill 5 days a week.Results and conclusionsThe HF mice presented the key problems associated with MetS (increased caloric intake, body weight, glycemia and fat mass), a change in Admer distribution in favor of the less-active forms and increased AdipoR2 expression in muscle. In contrast, exercise training reversed some of the adverse effects of a HF diet (increased glucose tolerance, better caloric intake control) without any modifications in Ad production and Admer distribution. However, increased AdipoR1 muscle expression was observed in trained mice, but this effect was hampered by HF diet. These data corroborate a recent hypothesis suggesting a functional divergence between AdipoR1 and AdipoR2, with AdipoR1 having the predominant protective action on metabolic function.Electronic supplementary materialThe online version of this article (doi:10.1186/s12986-016-0138-2) contains supplementary material, which is available to authorized users.

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Leptin dose-dependently decreases atherosclerosis by attenuation of hypercholesterolemia and induction of adiponectin

Cited by 39 publications

References 40 publications

Leptin decreases circulating inflammatory IL‐6 and MCP‐1 in mice

Leptin decreases circulating inflammatory IL‐6 and MCP‐1 in mice

Normalization of adiponectin concentrations by leptin replacement in ob/ob mice is accompanied by reductions in systemic oxidative stress and inflammation

Interactions of exercise training and high-fat diet on adiponectin forms and muscle receptors in mice

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