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Pesta 2012 Abstract Bioblast

From Bioblast
Pesta D, Jamison PR, Zhang D, Jurczak M, Manchem VP, Bhanot S, Samuel V, Shulman GI (2012) Prevention of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotides targeted to mIndy. Mitochondr Physiol Network 17.12.

Link: MiPNet17.12 Bioblast 2012 - Open Access

Pesta D, Jamison PR, Zhang D, Jurczak M, Manchem VP, Bhanot S, Samuel V, Shulman GI (2012)

Event: Bioblast 2012

Dominik Pesta

INDY as part of the SLC13 protein family is a high-affinity di- and tricarboxylate plasma membrane transporter involved in citrate import. In Drosophila, genetic deletion of INDY alters energy metabolism and extends lifespan. Mice lacking INDY are protected from both diet induced and age associated insulin resistance 1. In the present work, we use anti-sense oligonucleotides (ASOs) to study the effects of a constitutional knock down in the liver of the mitochondrial Indy protein (mINDY) of rats on energy and glucose metabolism assessed by a hyperinsulinemic-euglycemic clamp (HEC). Rats were fed a high fat diet (safflower diet) for 4 weeks. The treatment group (n=15) was injected 2 times per week with Indy ASO, the control group (n=15) with the same volume of saline. After 4 weeks of treatment, mINDY mRNA was reduced by 91% (p<0.001) in the treatment group. No changes in body weight between control and INDY ASO group were observed after treatment [388 ± 7.8 vs. 377 ± 5.1 g]. Hepatic triglycerides were reduced by 55% in mINDY ASO treated rats [57.7 ± 8.1 vs. 31.2 ± 4.1 mg/g liver, p<0.001]. Basal glucose turnover [5.9 ± 0.6 vs. 8.4 ± 0.8 mg/(kg-min), p<0.05] as well as insulin stimulated glucose turnover [30.7 ± 1.8 vs. 34.7 ± 1.2 mg/(kg-min), p<0.1] and suppression of hepatic glucose production during HEC [19.7 vs. 61.6%, p<0.05] were higher in the mINDY ASO treated group. Peripheral glucose uptake was not different in muscle and white adipose tissue. Conclusion: Taken together these data suggest that knockdown of hepatic mINDY by ASO may be a novel therapeutic approach for the treatment of non-alcoholic fatty liver disease and hepatic insulin resistance.

  1. Birkenfeld AL, Lee HY, Guebre-Egziabher F, Alves TC, Jurczak MJ, Jornayvaz FR, Zhang D, Hsiao JJ, Martin-Montalvo A, Fischer-Rosinsky A, Spranger J, Pfeiffer AF, Jordan J, Fromm MF, Konig J, Lieske S, Carmean CM, Frederick DW, Weismann D, Knauf F, Irusta PM, De Cabo R, Helfand SL, Samuel VT, Shulman GI (2011) Deletion of the mammalian INDY homolog mimics aspects of dietary restriction and protects against adiposity and insulin resistance in mice. Cell metabolism 14: 184-195. Open Access

Keywords: Indy, ASO, citrate, mitochondria


Affiliations and author contributions

Pesta D (1,2), Jamison PR (1,2,3), Zhang D (1), Jurczak M (2), Manchem VP (5), Bhanot S (5), Samuel V (2,4), Shulman GI (1,2,3)

(1) Howard Hughes Medical Institute

(2) Department of Internal Medicine

(3) Department of Cellular & Molecular Physiology; Yale University School of Medicine, New Haven, CT, USA; Email: [email protected]

(4) Veteran’s Affairs Medical Center, West Haven, CT, USA

(5) Isis Pharmaceuticals, Carlsbad, CA, USA