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Impaired beta-adrenergic receptor-mediated regulation of gene expression in adipocytes from older rats
L Shilo1, J H Chin, B B Hoffman
1Department of Medicine, Stanford University School of Medicine, California.
Abstract:
With aging, in many cells there is a blunted capacity of beta-adrenergic agonists to increase adenosine 3',5'-cyclic monophosphate (cAMP) accumulation. We wondered if blunted cAMP responses led to impaired regulation of genes in which expression is modified by cAMP. To test this hypothesis, adipocytes were isolated from 2- and 12- to 16-mo-old Sprague-Dawley rats that were stimulated with isoproterenol, and the inhibitory effect on expression of genes for lipoprotein lipase (LPL) and fatty acid synthase (FAS) were examined. Isoproterenol-stimulated cAMP accumulation and glycerol release were impaired in adipocytes from the older rats. Isoproterenol inhibited expression of LPL and FAS mRNAs in cells from the younger but not older rats. Removal of endogenous adenosine partially restored isoproterenol-mediated inhibition of expression of these genes in the cells. These results demonstrate that blunted cAMP responses associated with aging in obese Sprague-Dawley rats led to altered regulation of LPL and FAS genes. These findings extend the possible physiological implications of impaired hormone-induced cAMP responses with aging.
Insights
Aging impairs the body's ability to produce cyclic adenosine monophosphate (cAMP) in response to beta-adrenergic agonists. This leads to altered gene regulation, specifically impacting lipoprotein lipase (LPL) and fatty acid synthase (FAS) gene expression in older rats.
Area of Science:
- Cellular biology
- Molecular biology
- Aging research
Background:
- With aging, cells often show a reduced capacity to increase cyclic adenosine monophosphate (cAMP) when stimulated by beta-adrenergic agonists.
- It remains unclear if these blunted cAMP responses contribute to impaired gene regulation influenced by cAMP.
Purpose of the Study:
- To investigate whether diminished cAMP signaling with aging affects the regulation of genes, specifically lipoprotein lipase (LPL) and fatty acid synthase (FAS).
- To examine the impact of aging on isoproterenol-induced cAMP accumulation and gene expression in rat adipocytes.
Main Methods:
- Adipocytes were isolated from young (2-month-old) and aged (12- to 16-month-old) Sprague-Dawley rats.
- Cells were stimulated with isoproterenol to assess cAMP accumulation, glycerol release, and the expression of LPL and FAS mRNAs.
- The effect of removing endogenous adenosine on gene expression was also evaluated.
Main Results:
- Adipocytes from older rats exhibited impaired isoproterenol-stimulated cAMP accumulation and glycerol release compared to younger rats.
- Isoproterenol inhibited LPL and FAS gene expression in adipocytes from younger rats but not in those from older rats.
- Partial restoration of isoproterenol-mediated gene expression inhibition was observed upon removal of endogenous adenosine in aged rat adipocytes.
Conclusions:
- Blunted cAMP responses associated with aging in Sprague-Dawley rats lead to altered regulation of LPL and FAS genes.
- These findings highlight the physiological consequences of impaired hormone-induced cAMP signaling during the aging process.