Increased TNFα and CCAAT/enhancer-binding protein homologous protein with aging predispose preadipocytes to resist adipogenesis

Abstract

Fat depot sizes peak in middle age but decrease by advanced old age. This phenomenon is associated with ectopic fat deposition, decreased adipocyte size, impaired differentiation of preadipocytes into fat cells, decreased adipogenic transcription factor expression, and increased fat tissue inflammatory cytokine generation. To define the mechanisms contributing to impaired adipogenesis with aging, we examined the release of TNF␣, which inhibits adipogenesis, and the expression of CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), which blocks activity of adipogenic C/EBP family members, in preadipocytes cultured from young, middle-aged, and old rats. Medium conditioned by fat tissue, as well as preadipocytes, from old rats impeded lipid accumulation by preadipocytes from young animals. More TNF␣ was released by preadipocytes from old than young rats. Differences in TNF␣-converting enzyme, TNF␣ degradation, or the presence of macrophages in cultures were not responsible. TNF␣ induced rat preadipocyte CHOP expression. CHOP was higher in undifferentiated preadipocytes from old than younger animals. Overexpression of CHOP in young rat preadipocytes inhibited lipid accumulation. TNF␣ short interference RNA reduced CHOP and partially restored lipid accumulation in old rat preadipocytes. CHOP normally increases during late differentiation, potentially modulating the process. This late increase in CHOP was not affected substantially by aging: CHOP was similar in differentiating preadipocytes and fat tissue from old and young animals. Hypoglycemia, which normally causes an adaptive increase in CHOP, was less effective in inducing CHOP in preadipocytes from old than younger animals. Thus increased TNF␣ release by undifferentiated preadipocytes with elevated basal CHOP contributes to impaired adipogenesis with aging.

Shox2 is a molecular determinant of depot-specific adipocyte function

“…In fact, in some studies, s.c. obesity is even protective against the effects of visceral obesity (3). Several factors have been suggested to contribute to these differences: first, anatomical differences between visceral and s.c. fat, and especially the fact that visceral fat drains directly into the portal vein, exposing the liver to higher levels of free fatty acids, adipokines, and cytokines, which can lead to insulin resistance (22); second, obesity is associated with inflammation and the infiltration of activated macrophages into fat, and these occur to a greater extent in visceral fat compared with s.c. fat (23); and finally, a number of studies indicate intrinsic differences in gene expression between adipocytes from different fat depots, which might lead to different biological and physiological function (6)(7)(8).…”

“…These clear differences between s.c. and visceral fat suggest that, in addition to their anatomical location, these fat depots have intrinsic differences at the cellular level. These studies have demonstrated major functional and gene expression differences between s.c. and visceral fat (6,7). Both isolated adipocytes and the stromovascular fraction containing preadipocytes show cell autonomous differences in the expression of developmental patterning genes between s.c. and visceral depots, suggesting different developmental origins for these fat depots (8).…”

RNase L controls terminal adipocyte differentiation, lipids storage and insulin sensitivity via CHOP10 mRNA regulation

“…5 Actually, RNase L À/À mice possess a higher number of smaller adipocytes than WT mice ( Figure 8A), that is characteristic of hyperplasia. 31 This number of adipocytes increases with aging, as we observed an adipose tissue expansion in aged RNase L À/À mice.…”

“…At present, it is known that CHOP10 is more expressed in old individuals preadipocytes than from young ones. 5 Change in adipogenesis process is due to the incapacity of preadipocytes to express appropriate levels of key adipogenic regulators: CHOP10, C/EBPa and PPARg. 4,32 We assume that overexpression of CHOP10 in RNase L À/À mice added to the physiological overexpression of CHOP10 in old age would lead to even higher levels of CHOP10.…”

“…Particularly, the expansion phase of preadipocytes precedes their differentiation to adipocytes. 4,5 Like other differentiation pathways, adipogenesis involves sequential and orderly expression of many factors triggering a whole activation/inactivation cascade of genes expression. Among the several transcription factors known to have a significant role in promoting adipogenesis, two of them have a central role by regulating several downstream target genes: the CCAAT/enhancer-binding protein a (C/EBPa) and the nuclear receptor peroxisome proliferator-activated receptor g2 (PPARg2).…”