Adipocytes (fat cells) are the site of much metabolic and endocrine activity; their physiology affects our energy balance, insulin sensitivity and a host of other processes throughout the body. And of course, as some of us know all too well, their behavior is dynamic not only from hour to hour but from year to year, over the course of aging. It’s natural to ask questions about the impact of life-extending regimens like calorie restriction (CR) on the biology of adipocytes.

A study of rat adipocytes reveals that CR influences the expression of a wide range of signaling molecules, and reverses or mitigates some of the age-related changes in gene expression observed in previous research. From Zhu et al.:

Adipogenic signaling in rat white adipose tissue: Modulation by aging and calorie restriction

Alterations in adipogenesis could have significant impact on several aging processes. We previously reported that calorie restriction (CR) in rats significantly increases the level of circulating adiponectin, a distinctive marker of differentiated adipocytes, leading to a concerted modulation in the expression of key transcription target genes and, as a result, to increased fatty acid oxidation and reduced deleterious lipid accumulation in other tissues. These findings led us to investigate further the effects of aging on adipocytes and to determine how CR modulates adipogenic signaling in vivo. CR for 2 and 25 months, significantly increased the expression of PPARγ, C/EBPβ and Cdk-4, and partially attenuated age-related decline in C/EBPα expression relative to rats fed ad libitum (AL). As a result, adiponectin was upregulated at both mRNA and protein levels, resulting in activation of target genes involved in fatty acid oxidation and fatty acid synthesis, and greater responsiveness of adipose tissue to insulin. Moreover, CR significantly decreased the ratio of C/EBPβ isoforms LAP/LIP, suggesting the suppression of gene transcription associated with terminal differentiation while facilitating preadipocytes proliferation. Morphometric analysis revealed a greater number of small adipocytes in CR relative to AL feeding. Immunostaining confirmed that small adipocytes were more strongly positive for adiponectin than the large ones. Overall these results suggest that CR increased the expression of adipogenic factors, and maintained the differentiated state of adipocytes, which is critically important for adiponectin biosynthesis and insulin sensitivity.

The findings regarding C/EBPβ and LAP/LIP are especially interesting in light of observations we discussed last year (see Mechanisms of translational control in aging liver). LAP/LIP, a dominant negative isoform of the transcription factor C/EBPβ, is upregulated at the translational level in aging liver (also a hotbed of fat metabolism); high levels of LAP/LIP diminish transcriptional activation by C/EBPβ family transcription factors. At the time we last discussed the issue, it was unclear whether this gene regulation represented a deleterious outcome of aging or a protective response against its ravages.

Here, we see that CR decreases LAP/LIP while increasing overall levels of C/EBPβ, suggesting that the treatment boosts transcriptional activation by this pathway. CR extends lifespan, and it has a variety of other positive effects on physical health (though not necessarily mental health; see So hungry, so sad: Calorie restriction and depression). Taken together, the results of Zhu et al. and the earlier liver paper strongly imply that C/EBPβ transcription serves a life-extending function, and that the age-related increase in LAP/LIP expression is likely to be deleterious.

About these ads