| Aging is associated with a substantial decline in body weight, fat mass and percent body fat. Loss of fat tissue predisposes the elderly to chronic skin ulcers, disturbances of body temperature, and decreased energy reserves in the face of chronic illness. It can also result in glucose intolerance, potentially contributing to the development of type II diabetes in elderly, lean patients. Since adipocyte responsiveness to lipolytic agents declines and adipocyte numbers increase with aging, these changes in fat mass and percent body fat in old individuals may be due to the reduced capacity of preadipocytes to accumulate lipid. We have investigated the effects of aging on transcription factors involved in adipogenesis. C/EBPα and PPARγ adipogenic transcription factors are essential for maintenance of the differentiated fat cell phenotype. We observed that the expression of both C/EBPα and PPARγ, as well as their downstream target aP2, decreased with increasing age. Furthermore, the levels of C/EBPβ and C/EBδ, which trans-activate the promoters of both C/EBPα and PPARγ, also decreased with aging. Augmentation of adipogenic transcription factor expression in rat preadipocytes from old animals restored their adipogenic potential. RXRα expression was unaffected by aging. In contrast, the expression of upstream, anti-adipogenic factors, such as C/EBPβ-LIP, CHOP, and CUGBP, increased with aging. Overexpression of C/EBPβ-LIP in preadipocytes from young animals abolished their ability to differentiate. The anti-adipogenic potential of CUGBP, which causes C/EBPβ-LIP production from C/EBPβ mRNA, was demonstrated for the first time. Thus, reduced differentiation with aging is due to specific effects of aging on the expression of preadipocyte transcription factors. Aging is associated with decreased expression of adipogenic transcription factors and increased expression of anti-adipogenic factors. The ability of predipocytes from old animals to regain their adipogenic potential after the induction of either C/EBPα or PPARγ expression suggests that effects upstream of adipogenic regulator expression are responsible for reduced adipogenesis with aging. The association of the anti-adipogenic factors studied here with stress responses, as well as the induction of CUGBP by TNFα, suggest that activation of cellular stress responses may be the means through which aging decreases adipogenesis. |
