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Dietary polyphenols suppress elevated levels of proinflammatory mediators and aromatase in the mammary gland of obese mice.

ABSTRACT: In postmenopausal women, obesity is a risk factor for the development of hormone receptor-positive breast cancer driven by estrogen. After menopause, aromatization of androgen precursors in adipose tissue is a major synthetic source of estrogen. Recently, in mouse models and women, we identified an obesity-inflammation-aromatase axis. This obesity-induced inflammation is characterized by crown-like structures (CLS) consisting of dead adipocytes encircled by macrophages in breast white adipose tissue. CLS occur in association with NF-κB activation, elevated levels of proinflammatory mediators, and increased aromatase expression. Saturated fatty acids released from adipocytes have been linked to obesity-related white adipose tissue inflammation. Here we found that stearic acid, a prototypic saturated fatty acid, stimulated Akt-dependent activation of NF-κB resulting in increased levels of proinflammatory mediators [TNF-α, interleukin (IL)-1β, COX-2] in macrophages leading, in turn, to the induction of aromatase. Several polyphenols (resveratrol, curcumin, epigallocatechin gallate) blocked these inductive effects of stearic acid. Zyflamend, a widely used polyherbal preparation that contains numerous polyphenols, possessed similar suppressive effects. In a mouse model of obesity, treatment with Zyflamend suppressed levels of phospho-Akt, NF-κB binding activity, proinflammatory mediators, and aromatase in the mammary gland. Collectively, these results suggest that targeting the activation of NF-κB is a promising approach for reducing levels of proinflammatory mediators and aromatase in inflamed mouse mammary tissue. Further investigation in obese women is warranted.

SUBMITTER: Subbaramaiah K

PROVIDER: S-EPMC3767430 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundInflammatory processes have been suggested as a culprit of vascular damage in pediatric hypertension. We aimed to investigate transcriptional changes of immune modulators and determine their association with office blood pressure in adolescents who were not diagnosed with hypertension at the time of the study visit.MethodsOffice blood pressure measurements and blood samples were taken from adolescents of 2 German birth cohorts, GINIplus (The German Infant Study on the Influence of Nutrition Intervention Plus Air Pollution and Genetics on Allergy Development; discovery cohort, n=1219) and LISA (Influences of Lifestyle-related factors on the Immune System and the Development of Allergies in Childhood; validation cohort, n=809), during the 15-year follow-up visit and categorized based on the European Society of Hypertension Guideline. Hs-CRP (high-sensitivity C-reactive protein) and expression of 51 genes encoding cytokines/receptors and transcription factors were analyzed.ResultsThe prevalence of elevated systolic blood pressure (overweight/obese) was 14.0% (5.1%) and 16.4% (5.2%) in the discovery and validation cohorts, respectively. An enhanced cytotoxic (GZMB, PRF1, IL2RB) and proinflammatory (FOS, IL1B, hs-CRP) immune profile was observed in association with the hypertension class in both cohorts. Expression of hs-CRP and IL1B was driven by overweight with IL1B being identified as a mediator between body mass index and elevated systolic blood pressure (adj.β/95% CI, 0.01/0.0002-0.02). The association of GZMB (adjusted odds ratio/95% CI, 1.67/1.26-2.21; P=0.0004) and PRF1 (adjusted odds ratio/95% CI, 1.70/1.26-2.29; P=0.0005) in the hypertension class remained significant in normal-weight individuals without parental predisposition. These effects were confirmed in LISA.ConclusionsAdolescent hypertension is not limited to known risk groups. As adolescents in the hypertension class show an inflammatory profile similar to that of established hypertension in adults, blood pressure monitoring at a young age is critical to ensure early intervention and prevention of adverse sequelae.

Project description:BackgroundObesity is a risk factor for breast cancer, and women with obesity that develop breast cancer have a worsened prognosis. Within the mammary gland, obesity causes chronic, macrophage-driven inflammation and adipose tissue fibrosis. Weight loss is a recommended intervention to resolve obesity, but the impact of weight loss on the mammary gland microenvironment and in tumors has not been well identified.MethodsTo examine the effects of weight loss following obesity, mice were fed a high-fat diet for 16 weeks to induce obesity, then switched to a low-fat diet for 6 weeks. We examined changes in immune cells, including fibrocytes, which are myeloid lineage cells that have attributes of both macrophages and myofibroblasts, and collagen deposition within the mammary glands of non-tumor-bearing mice and within the tumors of mice that were transplanted with estrogen receptor alpha positive TC2 tumor cells.ResultsIn formerly obese mice, we observed reduced numbers of crown-like structures and fibrocytes in mammary glands, while collagen deposition was not resolved with weight loss. Following transplant of TC2 tumor cells into the mammary glands of lean, obese, and formerly obese mice, diminished collagen deposition and cancer-associated fibroblasts were observed in tumors from formerly obese mice compared to obese mice. Within tumors of obese mice, increased myeloid-derived suppressor cells and diminished CD8+ T cells were identified, while the microenvironment of tumors of formerly obese mice were more similar to tumors from lean mice. When TC2 tumor cells were mixed with CD11b+CD34+ myeloid progenitor cells, which are the cells of origin for fibrocytes, and transplanted into mammary glands of lean and obese mice, collagen deposition within the tumors of both lean and obese was significantly greater than when tumor cells were mixed with CD11b+CD34- monocytes or total CD45+ immune cells.ConclusionsOverall, these studies demonstrate that weight loss resolved some of the microenvironmental conditions within the mammary gland that may contribute to tumor progression. Additionally, fibrocytes may contribute to early collagen deposition in mammary tumors of obese mice leading to the growth of desmoplastic tumors.

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Dietary polyphenols suppress elevated levels of proinflammatory mediators and aromatase in the mammary gland of obese mice.

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