Altered expression of C/EBP family members results in decreased adipogenesis with aging

Abstract

Fat mass, adipocyte size and metabolic responsiveness, and preadipocyte differentiation decrease between middle and old age. We show that expression of CCAAT/enhancer binding protein (C/EBP)-alpha, a key regulator of adipogenesis and fat cell function, declined substantially with aging in differentiating preadipocytes cultured under identical conditions from rats of various ages. Overexpression of C/EBP alpha in preadipocytes cultured from old rats restored capacity to differentiate into fat cells, indicating that downstream differentiation-dependent genes maintain responsiveness to regulators of adipogenesis. C/EBP alpha-expression also decreased with age in fat tissue from three different depots and in isolated fat cells. The overall level of C/EBP beta, which modulates C/EBP alpha-expression, did not change with age, but the truncated, dominant-negative C/EBP beta-liver inhibitory protein (LIP) isoform increased in cultured preadipocytes and isolated fat cells. Overexpression of C/EBP beta-LIP in preadipocytes from young rats impaired adipogenesis. C/EBP delta, which acts with full-length C/EBP beta to enhance adipogenesis, decreased with age. Thus processes intrinsic to adipose cells involving changes in C/EBP family members contribute to impaired adipogenesis and altered fat tissue function with aging. These effects are potentially reversible.

Aging Up-Regulates Expression of Inflammatory Mediators in Mouse Adipose Tissue

“…This is compatible with the lack of difference in MCP-1 production by young and old adipocytes in this study. Our observation that old mice had higher yield of SVC from the same amount of fat tissue compared with young mice is in accordance with the previous finding that aging impairs adipocyte maturation, resulting in the presence of more preadipocytes in the fat tissue of old rats compared with that of young (6). Furthermore, the observation that adipose tissue from old mice have lower mRNA levels of PPAR-␥, a nuclear receptor shown to promote adipocyte differentiation, is also in agreement with the results reported by Karagiannides et al (6).…”

“…However, the sharp increase in T2D prevalence with advancing age cannot be fully explained by the prevalence of obesity, because the obesity rate in the elderly with T2D or in general population is not higher than that in their younger counterparts (Centers for Disease Control and Prevention, Risk Factors for Complications: http://www.cdc.gov/diabetes/statistics/comp/ table7_3a.htm). Fat mass peaks at middle age or early old age and then declines substantially in advanced old age (6). In contrast, decline in insulin sensitivity begins in the middle age and progressively increases in the later years of life (7).…”

Obesity and related consequences to ageing

“…Interestingly, the adipocyte number in AT depots in obese individuals declined between 45 and 65 years of age (Virtue and Vidal-Puig 2010;Spalding et al 2008). Metabolic responsiveness decrease at the end of life (Slawik and Vidal-Puig 2006;Visser et al 2003), and there is an age-related decline in expression of pro-adipogenic transcription factors such as PPARγ or C/EBPα (Karagiannides et al 2001). As ATE may fail with advancing age, the need for increased storage of fat may lead to ectopic fat deposition, i.e., in muscle or bone marrow (Slawik and Vidal-Puig 2006;Rudman et al 1991).…”

Changes in lipid distribution during aging and its modulation by calorie restriction

“…The notion of lipid storage over-capacity is supported by several studies in which cultured preadipocytes from old animals consistently showed reduced lipid accumulation, reduced lipogenic enzyme activities, and changes in differentiation-dependent gene expression (Djian et al 1985;Hauner et al 1989;Gregerman 1994;Karagiannides et al 2001;Cartwright et al 2007). Since adipogenesis is a result of transcriptional activities, a better way to understand the above-mentioned shift is to examine the molecular events involved in adipogenesis that are modulated by the activation of a large number of adipose-related genes (Fève 2005).…”

“…Two key regulatory mediators of the adipogenesis process are the peroxisome proliferators-activated receptor (PPAR)γ and sterol regulatory element-binding protein-1 (SREBP-1) (MacDougald and Lane 1995;Fève 2005). Studies of differentiating preadipocytes isolated from old rats have shown that when the capacity of preadipocytes becomes fully lipidloaded, adipocytes decreases with age (Karagiannides et al 2001;Cartwright et al 2007). In addition, the expression of PPARγ is substantially lowered (Karagiannides et al 2006) and lower levels of SREBP-1 mRNA were observed in the WAT of old rats compared to that of young rats (Swierczynski 2006).…”