Attenuation of age-related metabolic dysfunction in mice with a targeted disruption of the Cbeta subunit of protein kinase A.
The cyclic adenosine monophosphate-dependent protein kinase A (PKA) pathway helps regulate both cell growth and division, and triglyceride storage and metabolism in response to nutrient status. Studies in yeast show that disruption of this pathway promotes longevity in a manner similar to caloric restriction. Because PKA is highly conserved, it can be studied in mammalian systems. This report describes the metabolic phenotype of mice lacking the PKA catalytic subunit Cbeta. We confirmed that Cbeta has high levels of expression in the brain but also showed moderate levels in liver. Cbeta-null animals had reduced basal PKA activity while appearing overtly normal when fed standard rodent chow. However, the absence of Cbeta protected mice from diet-induced obesity, steatosis, dyslipoproteinemia, and insulin resistance, without any differences in caloric intake or locomotor activity. These findings have relevant pharmacological implications because aging in mammals is characterized by metabolic decline associated with obesity, altered body fat distribution, and insulin resistance.
Department of Comparative Medicine, University of Washington, Seattle, WA, 98915, USA.
Linda C
LC
Enns
John F
JF
Morton
Ruby Sue
RS
Mangalindan
G Stanley
GS
McKnight
Michael W
MW
Schwartz
Matt R
MR
Kaeberlein
Brian K
BK
Kennedy
Peter S
PS
Rabinovitch
Warren C
WC
Ladiges
D000375:Aging / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001823:Body Composition / Q000235:genetics; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000172:deficiency / Q000378:metabolism*; D004040:Dietary Carbohydrates / Q000009:adverse effects; D004041:Dietary Fats / Q000009:adverse effects; D004195:Disease Models, Animal; D015151:Immunoblotting; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000502:physiology*; D008136:Longevity; D024821:Metabolic Syndrome / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D011336:Probability; D011897:Random Allocation; D015398:Signal Transduction
D001786:Blood Glucose; D004040:Dietary Carbohydrates; D004041:Dietary Fats; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; C463959:protein kinase A Calpha