Human epicardial adipose tissue is a source of inflammatory mediators.

BACKGROUND: Inflammatory mediators that originate in vascular and extravascular tissues promote coronary lesion formation. Adipose tissue may function as an endocrine organ that contributes to an inflammatory burden in patients at risk of cardiovascular complications. In this study, we sought to compare expression of inflammatory mediators in epicardial and subcutaneous adipose stores in patients with critical CAD. METHODS AND RESULTS: Paired samples of epicardial and subcutaneous adipose tissues were harvested at the outset of elective CABG surgery (n=42; age 65+/-10 years). Local expression of chemokine (monocyte chemotactic protein [MCP]-1) and inflammatory cytokines (interleukin [IL]-1beta, IL-6, and tumor necrosis factor [TNF]-alpha) was analyzed by TaqMan real-time reverse transcription-polymerase chain reaction (mRNA) and by ELISA (protein release over 3 hours). Significantly higher levels of IL-1beta, IL-6, MCP-1, and TNF-alpha mRNA and protein were observed in epicardial adipose stores. Proinflammatory properties of epicardial adipose tissue were noted irrespective of clinical variables (diabetes, body mass index, and chronic use of statins or ACE inhibitors/angiotensin II receptor blockers) or plasma concentrations of circulating biomarkers. In a subset of samples (n=11), global gene expression was explored by DNA microarray hybridization and confirmed the presence of a broad inflammatory reaction in epicardial adipose tissue in patients with coronary artery disease. The above findings were paralleled by the presence of inflammatory cell infiltrates in epicardial adipose stores. CONCLUSIONS: Epicardial adipose tissue is a source of several inflammatory mediators in high-risk cardiac patients. Plasma inflammatory biomarkers may not adequately reflect local tissue inflammation. Current therapies do not appear to eliminate local inflammatory signals in epicardial adipose tissue.

Functional microarray analysis of mammary organogenesis reveals a developmental role in adaptive thermogenesis.

The use of DNA microarrays to study vertebrate organogenesis presents unique analytical challenges compared with expression profiling of homogeneous cell populations. We have used a general approach that permits the automated, unbiased identification of biologically relevant patterns of gene expression to study murine mammary gland development. Our studies confirm the utility of this approach by demonstrating the ready identification of cellular processes and pathways of known functional importance in mammary development. Additionally, this approach permitted the identification of genetic pathways with unpredicted patterns of developmental regulation, including those involved in angiogenesis, extracellular matrix synthesis, and the beta-oxidation of fatty acids. Surprisingly, our findings demonstrate that the coordinate regulation of genes involved in the beta-oxidation of fatty acids reflects the presence of an abundant, yet previously unrecognized stromal compartment within the mammary gland that is composed of brown adipose tissue. Our data demonstrate that the amount of brown adipose tissue present in the mammary gland is developmentally regulated; that PPARalpha, Ucp1, and genes involved in fatty acid oxidation are spatially and temporally coregulated during development; that the mammary gland plays a functional role in adaptive thermogenesis; and that the transcriptional control of this adaptive response to cold is itself developmentally regulated.

Persistent parity-induced changes in growth factors, TGF-beta3, and differentiation in the rodent mammary gland.

Epidemiological studies have repeatedly demonstrated that women who undergo an early first full-term pregnancy have a significantly reduced lifetime risk of breast cancer. Similarly, rodents that have previously undergone a full-term pregnancy are highly resistant to carcinogen-induced breast cancer compared with age-matched nulliparous controls. Little progress has been made, however, toward understanding the biological basis of this phenomenon. We have used DNA microarrays to identify a panel of 38 differentially expressed genes that reproducibly distinguishes, in a blinded manner, between the nulliparous and parous states of the mammary gland in multiple strains of mice and rats. We find that parity results in the persistent down-regulation of multiple genes encoding growth factors, such as amphiregulin, pleiotrophin, and IGF-1, as well as the persistent up-regulation of the growth-inhibitory molecule, TGF-beta3, and several of its transcriptional targets. Our studies further indicate that parity results in a persistent increase in the differentiated state of the mammary gland as well as lifelong changes in the hematopoietic cell types resident within the gland. These findings define a developmental state of the mammary gland that is refractory to carcinogenesis and suggest novel hypotheses for the mechanisms by which parity may modulate breast cancer risk.