Abstract
We have developed an in vitro hepatocyte-adipose tissue explant (ATE) co-culture model enabling examination of the effect of visceral and subcutaneous adipose tissues on primary rat hepatocytes. Initial analyses of inflammatory marker genes were performed in fractionated epididymal or inguinal adipose tissues. Expressions of inflammation related genes (IL-6, TNF-α, COX-2) were higher in the inguinal than the epididymal ATE. Similarly, expressions of marker genes of macrophage and monocyte (MPEG-1, CD68, F4/80, CD64) were higher in the stromal vascular fraction (SVF) isolated from inguinal ATE than that from epididymal ATE. However, expressions of lipolysis related genes (ATGL, HSL, perilipin-1) were higher in the epididymal adipocytes than inguinal adipocytes. Moreover, secretion of IL-6 and PGE2 was higher from inguinal ATEs than from epididymal ATEs. There was a trend that the total levels of IL-6, TNF-α and PGE2 in the media from inguinal ATEs co-cultured with primary rat hepatocytes were higher than that in the media from epididymal ATEs co-cultured with hepatocytes, although the significant difference was only seen in PGE2. Lipolysis, measured as glycerol release, was similar in the ATEs isolated from inguinal and epididymal adipose tissues when cultured alone, but the glycerol release was higher in the ATEs isolated from epididymal than from inguinal adipose tissue when co-cultured with hepatocytes. Compared to epididymal ATEs, the ATEs from inguinal adipose tissue elicited a stronger cytotoxic response and higher level of insulin resistance in the co-cultured hepatocytes. In conclusion, our results reveal depot-dependent effects of ATEs on co-cultured primary hepatocytes, which in part may be related to a more pronounced infiltration of stromal vascular cells (SVCs), particularly macrophages, in inguinal adipose tissue resulting in stronger responses in terms of hepatotoxicity and insulin-resistance.
Highlights
Obesity is the major factor predisposing individuals to a complex of dyslipidemic/metabolic disorders collectively named the metabolic syndrome
Except for Tumor necrosis factor-a (TNF-a) and COX-2, almost all inflammatory marker genes were expressed at higher levels in stromal vascular cells (SVCs) isolated from iWAT than eWAT (Fig 2C), the genes selectively expressed in macrophages (MPEG-1, Cluster of differentiation 68 (CD68), F4/ 80) and monocyte/neutrophil (CD64)
The increased levels of circulating cytokines produced by both adipocytes and infiltrating macrophages are causally linked to development of insulin resistance and diabetes [1,2,21]
Summary
Obesity is the major factor predisposing individuals to a complex of dyslipidemic/metabolic disorders collectively named the metabolic syndrome. Elevated levels of circulating free fatty acids (FFA), mainly liberated from adipocytes in obese individuals, are recognized as a significant contributor to insulin resistance pathophysiology [4]. The elevated level of FFA in circulation leads to accumulation of lipid in non-adipose tissues resulting in cellular dysregulation and functional impairment in liver [5] and muscle [6]. This kind of FFA-induced insulin resistance and cellular toxicity has been referred to as ‘‘lipotoxicity’’ [7]
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