Attenuation of Age-Related Metabolic Dysfunction in Mice With a Targeted Disruption of the C  Subunit of Protein Kinase A

Enns, Linda C.; Morton, John; Mangalindan, Ruby; McKnight, G. Stanley; Schwartz, Michael W.; Kaeberlein, Matt; Kennedy, Brian K.; Rabinovitch, Peter S.; Ladiges, Warren

doi:10.1093/gerona/glp133

Cited by 35 publications

(37 citation statements)

References 56 publications

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“…It is also reported that PPAR-␣-null mice show increased fatty acid accumulation and decreased cholesterol synthesis, glucose storage and gluconeogenesis in the liver with aging (36). In addition, with a diabetogenic diet, it is reported that plasma insulin level is increased with aging (37). Thus, it must be true that lipid metabolism is changed by aging.…”

Section: Discussionmentioning

confidence: 99%

Increased Lipid Accumulation in Liver and White Adipose Tissue in Aging in the SAMP10 Mouse

Honma

Yanaka

Tsuduki

et al. 2011

J Nutr Sci Vitaminol

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SummaryThe population of elderly persons has increased worldwide. However, few studies have examined age-dependent changes in lipid and carbohydrate metabolism related to age-related diseases. The number of cases of metabolic syndrome is increasing worldwide and prevention of lifestyle diseases may lead to prolongation of lifespan. In this study, we examined age-dependent changes in lipid and carbohydrate metabolism in the senescenceaccelerated (SAM) P10 mouse. Tissue weights and biochemical parameters in plasma and liver were examined in SAMP10 mice aged 3, 6, 9 and 12 mo. White adipose tissue weight and the levels of liver triacylglycerol, plasma free fatty acids, and plasma insulin all showed increases with aging of the mice. To examine this mechanism in detail, aging-related changes in mRNA expression of genes related to lipid and carbohydrate metabolism were examined by DNA microarray analysis. The mRNA level for Hsd11b1 (hydroxysteroid 11-beta dehydrogenase 1), which increases insulin secretion and resistance, was elevated with aging in the liver of SAMP10 mice. These results show that lipid accumulation in liver and white adipose tissue is promoted by aging in SAMP10 mice through an increase in plasma insulin levels. Key Words aging, DNA microarray, Hsd11b1, hyperinsulinemia, SAMP10The population of elderly persons has increased worldwide ( 1 , 2 ) and this trend is expected to continue, with a concurrent increase in age-related diseases ( 2 ). Studies of aging are important for prevention of these diseases, maintenance of personal quality of life (QOL), and societal health. Many studies on age-related diseases have been performed, with a particular focus on encephalopathy ( 3-5 ). However, few studies have examined age-dependent changes in lipid and carbohydrate metabolism related to lifestyle diseases. The number of cases of metabolic syndrome is increasing worldwide ( 6 ) and prevention of lifestyle diseases may lead to prolongation of lifespan. Therefore, an understanding of the dependence of lifestyle diseases on aging is particularly important.In this study, we investigated age-dependent changes of lipid and carbohydrate metabolism in the senescenceaccelerated (SAM) P10 mouse. This mouse was developed in 1981 by a research team at Kyoto University ( 7 ). At present, there are nine senescence-prone inbred strains, which are referred to as SAMP1,2,3,6,7,8,9, 10 and 11 ( 8 ). The SAMP10 mouse exhibits encephalatrophy along with aging, which reflects learning and memory disorder ( 9 ). In this study, tissue weights and biochemical parameters for lipid and carbohydrate metabolism in plasma and liver were examined in SAMP10 mice aged 3, 6, 9, and 12 mo. To examine the mechanisms underlying age-dependent changes in lipid and carbohydrate metabolism, changes with age of mRNA levels for genes related to lipid and carbohydrate metabolism were examined by DNA microarray analysis. MATERIALS AND METHODS Animals and diets.All procedures were performed in accordance with the Animal Experiment Guidelines of Tohoku...

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Section: Discussionmentioning

confidence: 99%

Increased Lipid Accumulation in Liver and White Adipose Tissue in Aging in the SAMP10 Mouse

Honma

Yanaka

Tsuduki

et al. 2011

J Nutr Sci Vitaminol

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“…RII thus represents a potential pharmacological target for the treatment of diet and age-induced obesity and fatty liver. Our studies have indicated that the C catalytic subunit of PKA also plays a role in maintaining a set point of adiposity (Enns et al, 2009b). Young C null mice appear overtly normal when maintained on a regular chow diet, but when challenged with a HF/HC diet, show resistance to the obesity and fatty liver disease suffered by their WT littermates.…”

Section: Pka and Obesity Resistancementioning

confidence: 70%

“…Plasma both total cholesterol as well as very low density and low density lipoproteins (VLDL and LDL) were significantly lower in RII null mice compared to WT (Schreyer, 2001). C null mutants, at least for males, when challenged with the HF/HC diet were resistant to the increases in LDL and VLDL and partially resistant to the increases in high density lipoprotein (HDL) observed in the serum of WT mice (Enns et al, 2009b). Because insulin inhibits the assembly and release of VLDLs from the liver (Koo & Montminy, 2006), it is possible that the reduced serum VLDL levels seen in both types of mutants is an indirect effect of their insulin sensitivity.…”

Section: Pka and Dyslipidemiamentioning

confidence: 95%

“…Reduced function of TPK1, 2 and 3, functionally redundant yeast PKA catalytic www.intechopen.com subunits which are homologous to those in both mouse and human, also promotes longevity (Lin et al, 2000). PKA activity also mediates age-related decline in flies (Yamazaki et al, 2007;Laviada et al, 1997), and recent studies in mice have described delayed cardiac aging and extended lifespan by deletion of the adenylyl cyclase, AC5 (Yan et al, 2007) and obesity resistance, increased lifespan and healthy aging by disruption of specific PKA subunit genes (Cummings et al, 1996;Enns et al, 2009aEnns et al, , 2009b. This chapter will focus on recent studies describing the health benefits of disruption of two different PKA subunits, the regulatory isoform RII , and the catalytic subunit C .…”

Section: Introductionmentioning

confidence: 99%

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Targeting PKA Signaling to Prevent Metabolic Syndrome and Delay Aging

Enns¹,

Ladiges²

2011

Medical Complications of Type 2 Diabetes

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“…Transgenic mice that carry the middle T oncogene under the transcriptional control of the mouse mammary tumor virus promoter/ enhancer (MMTV-PyMT) develop widespread transformation of the mammary epithelium and the production of multi-focal mammary adenocarcinomas, with secondary metastasis to the lungs [7]. We developed a population of transgenic (MMTV-PyMT) 634Mul mice on a C57BL6/J background, a strain known to be obesity and diabetes sensitive when challenged with a high caloric diet [8]. Because we were interested in the role that obesity plays in tumor progression, rather than its contribution to increased cancer risk, we waited until tumors were palpable before switching mice to an HC diet.…”

Section: Introductionmentioning

confidence: 99%

The Anti-Tumor Effect of a High Caloric Diet in the PyMT Mouse Breast Cancer Model Is Initiated by an Increase in Metabolic Rate

Enns¹,

Ladiges²

2012

JCT

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Obesity is associated with an increased risk of mortality from certain types of cancer, including cancer of the breast. Because obesity is associated with multiple risk factors, however, the exact reasons remain unclear. The objective of this study was to determine which of the risk factors associated with obesity are related to enhanced tumor development. The MMTV-PyMT mouse model develops mammary tumors which share numerous characteristics with those of humans. We challenged these mice with a high fat/high carbohydrate, high caloric (HC) diet, and looked for relationships between enhanced primary tumor development and adiposity, various aspects of glucose homeostasis, and metabolic factors. The HC diet enhanced tumor progression in PyMT mice. While mice on the HC diet also developed increased adiposity, hyperglycemia and hyperinsulinemia, none of these risk factors was found to be associated with the observed increases in tumor growth. Rather, we found that while overall, tumor growth was enhanced in HC diet-fed mice compared to those maintained on a regular diet, it was attenuated in individuals by an HC diet-induced increase in metabolic rate and decrease in respiratory exchange ratio. Tumor size in HC diet-fed mice was directly related to p38 phosphorylation and Bcl-2 inhibition, and the degree of vascularization of these tumors was closely and indirectly related to the rate of mouse oxygen consumption. The data suggest that an increase in metabolic rate and oxygen consumption, induced by the introduction of a high caloric diet, has a protective effect against tumor growth by increasing the activity levels of the tumor suppressor p38 and decreasing the activity of the antiapoptotic protein Bcl-2, as well as by reducing hypoxia-induced tumor vascularization.

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Attenuation of Age-Related Metabolic Dysfunction in Mice With a Targeted Disruption of the C Subunit of Protein Kinase A

Cited by 35 publications

References 56 publications

Increased Lipid Accumulation in Liver and White Adipose Tissue in Aging in the SAMP10 Mouse

Increased Lipid Accumulation in Liver and White Adipose Tissue in Aging in the SAMP10 Mouse

Targeting PKA Signaling to Prevent Metabolic Syndrome and Delay Aging

The Anti-Tumor Effect of a High Caloric Diet in the PyMT Mouse Breast Cancer Model Is Initiated by an Increase in Metabolic Rate

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