Journal
AGING-US
Volume 7, Issue 12, Pages 1086-1093Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/aging.100854
Keywords
Indy; aging; hepatic insulin resistance; type 2 diabetes; Slc13a5
Categories
Funding
- Austrian Science Fund (FWF) [J 3267]
- German Research Foundation [BI1292/4-2]
- German Center for Diabetes Research (DZD)
- National Institutes of Health [R01 DK-40936, P30 DK-45735]
- Austrian Science Fund (FWF) [J 3267] Funding Source: researchfish
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Reducing the expression of the Indy (I'm Not Dead Yet) gene in lower organisms extends life span by mechanisms resembling caloric restriction. Similarly, deletion of the mammalian homolog, mIndy (Slc13a5), encoding for a plasma membrane tricarboxylate transporter, protects from aging- and diet-induced adiposity and insulin resistance in mice. The organ specific contribution to this phenotype is unknown. We examined the impact of selective inducible hepatic knockdown of mIndy on whole body lipid and glucose metabolism using 2'-O-methoxyethyl chimeric anti-sense oligonucleotides (ASOs) in high-fat fed rats. 4-week treatment with 2'-O-methoxyethyl chimeric ASO reduced mIndy mRNA expression by 91% (P<0.001) compared to control ASO. Besides similar body weights between both groups, mIndy-ASO treatment lead to a 74% reduction in fasting plasma insulin concentrations as well as a 35% reduction in plasma triglycerides. Moreover, hepatic triglyceride content was significantly reduced by the knockdown of mIndy, likely mediating a trend to decreased basal rates of endogenous glucose production as well as an increased suppression of hepatic glucose production by 25% during a hyperinsulinemic-euglycemic clamp. Together, these data suggest that inducible liver-selective reduction of mIndy in rats is able to ameliorate hepatic steatosis and insulin resistance, conditions occurring with high calorie diets and during aging.
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