Apoptosis, mastocytosis, and diminished adipocytokine gene expression accompany reduced epididymal fat mass in long-standing diet-induced obese mice

Abstract

BackgroundObesity is characterized by increased cell death and inflammatory reactions in the adipose tissue. Here, we explored pathophysiological alterations taking place in the adipose tissue in long-standing obesity. In the epididymal fat of C57BL/6 mice fed a high-fat diet for 20 weeks, the prevalence and distribution of dead adipocytes (crown-like structures), mast cells (toluidine blue, mMCP6), macrophages (F4/80), and apoptotic cells (cleaved caspase-3) were measured. Moreover, gene and/or protein expression of several adipocytokines (leptin, adiponectin, TNF-α, IL-10, IL-6, MCP-1), F4/80, mMCP6, cleaved caspase-3 were determined.ResultsWe observed that the epididymal fat mass was lower in obese than in lean mice. In obese mice, the epididymal fat mass correlated inversely with body weight and liver mass. Dead adipocytes, mast cells, macrophages, and apoptotic cells were abundant in the epididymal fat of obese mice, especially in the rostral vs. caudal zone. Accordingly, mMCP6, F4/80, and cleaved caspase-3 gene and/or protein expression was increased. Conversely, adiponectin, leptin, IL-6, and MCP-1 gene expression levels were lower in the epididymal fat of obese than lean mice. Although TNF-α and IL-10 gene expression was higher in the epididymal fat of obese mice, their expression relative to F4/80 and mMCP6 expression were lower in the heavily infiltrated rostral than caudal zone.ConclusionsThis study demonstrates that in mice with long-standing obesity diminished gene expression of several adipocytokines accompany apoptosis and reduced mass of the epididymal fat. Our findings suggest that this is due to both increased prevalence of dead adipocytes and altered immune cell activity. Differential distribution of metabolically challenged adipocytes is indicative of the presence of biologically diverse zones within the epididymal fat.

Oxytocin administration attenuates atherosclerosis and inflammation in Watanabe Heritable Hyperlipidemic rabbits

“…Another consideration is that in the current study, epididymal fat samples were taken from random regions of this visceral fat depot. A study published subsequently revealed that epididymal adipose tissue may not have uniform metabolic activity across its proximal and distal (relative to the testes) segments (Altintas et al, 2011), which may explain the variability of gene expression in our samples. Given these concerns, it is likely that the present study was not sufficiently powered to detect significant differences in adipokine gene expression.…”

No Role for Mast Cells in Obesity-Related Metabolic Dysregulation

“…It was previously described that the AT of lean and obese mice differ substantially with regards to mast cell numbers (14, 29, 30). In addition, the obesity-related increase of mast cell numbers is more prominent in gAT (29), thereby suggesting that mast cells might participate in obesity-related AT inflammation and metabolic dysregulation (12).…”

Mast cells in human and experimental cardiometabolic diseases

“…This white adipose tissue deposit contained an abundance of mast cells and macro phages, and the protein levels of both mMCP-6 and the macrophage marker F4/80 were increased, as were the gene-expression levels of TNF and IL-10. 132 Inasmuch as mast cells in the white adipose tissue of mice release TNF, neutralization of TNF ameliorates insulin resistance in various rodent models, 133 and obese mice lacking TNF have improved insulin sensitivity. 134 Adipogenic factors increased the expression of adipocyte biomarkers from a stromal vascular fraction prepared from Kit W-sh/W-sh mice, whereas mast-cell reconstitution in Kit W-sh/W-sh mice reduced the expression of preadipocyte biomarkers in white adipose tissue from these recipient mice, indicating that mastcell-deficiency led to the accumulation of pre-adipocytes in white adipose tissue (Figure 7).…”