Low utilization of circulating glucose after food withdrawal in Snell dwarf mice.
Glucose metabolism is altered in long-lived people and mice. Although it is clear that there is an association between altered glucose metabolism and longevity, it is not known whether this link is causal or not. Our current hypothesis is that decreased fasting glucose utilization may increase longevity by reducing oxygen radical production, a potential cause of aging. We observed that whole body fasting glucose utilization was lower in the Snell dwarf, a long-lived mutant mouse. Whole body fasting glucose utilization may be reduced by a decrease in the production of circulating glucose. Our isotope labeling analysis indicated both gluconeogenesis and glycogenolysis were suppressed in Snell dwarfs. Elevated circulating adiponectin may contribute to the reduction of glucose production in Snell dwarfs. Adiponectin lowered the appearance of glucose in the media over hepatoma cells by suppressing gluconeogenesis and glycogenolysis. The suppression of glucose production by adiponectin in vitro depended on AMP-activated protein kinase, a cell mediator of fatty acid oxidation. Elevated fatty acid oxidation was indicated in Snell dwarfs by increased utilization of circulating oleic acid, reduced intracellular triglyceride content, and increased phosphorylation of acetyl-CoA carboxylase. Finally, protein carbonyl content, a marker of oxygen radical damage, was decreased in Snell dwarfs. The correlation between high glucose utilization and elevated oxygen radical production was also observed in vitro by altering the concentrations of glucose and fatty acids in the media or pharmacologic inhibition of glucose and fatty acid oxidation with 4-hydroxycyanocinnamic acid and etomoxir, respectively.
Brooks
Natasha L
NL
Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Trent
Chad M
CM
Raetzsch
Carl F
CF
Flurkey
Kevin
K
Boysen
Gunnar
G
Perfetti
Michael T
MT
Jeong
Yo-Chan
YC
Klebanov
Simon
S
Patel
Kajal B
KB
Khodush
Valerie R
VR
Kupper
Lawrence L
LL
Carling
David
D
Swenberg
James A
JA
Harrison
David E
DE
Combs
Terry P
TP
D000818:Animals; D001011:Aorta / Q000378:metabolism; D001823:Body Composition; D002417:Cattle; D003373:Coumaric Acids / Q000737:chemistry; D004852:Epoxy Compounds / Q000737:chemistry; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005508:Food Deprivation; D005947:Glucose / Q000378:metabolism*; D050261:Glycogenolysis; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D019301:Oleic Acid / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D017382:Reactive Oxygen Species; D014280:Triglycerides / Q000378:metabolism
D003373:Coumaric Acids; D004852:Epoxy Compounds; D005227:Fatty Acids; D017382:Reactive Oxygen Species; D014280:Triglycerides; C007175:alpha-cyano-4-hydroxycinnamate; D019301:Oleic Acid; D005947:Glucose; C054207:etomoxir; D010100:Oxygen