Insulin Resistance due to Nutrient Excess involves AMPK Downregulation by multiple mechanisms

The principal objective of my research has been two fold: (1) to determine how AMP-activated protein kinase (AMPK) is regulated in mammalian tissues and cultured cells and (2) to define conditions under which AMPK activity is downregulated. We have established that exercise activates AMPK and enzymes of lipid metabolism in various tissues in rodents. In addition, we have shown that AMPK activity is diminished in numerous rodents with insulin resistance and that AMPK activation prevents or reverses this.  Excesses of glucose and branched chain amino acids, most notably leucine lead to insulin resistance in skeletal muscle by activating mTOR/p70S6 kinase (p70S6K). We recently demonstrated that glucose and leucine most likely produce these effects by downregulating AMP-activated protein kinase (AMPK) which, when activated, diminishes mTOR/p70S6 K signaling. How they decrease AMPK activity was not known. There are many factors that have been shown to regulate AMPK activity. They include SIRT1, a histone protein deacetylase that can activate AMPK and vice versa; an unidentified kinase that phosphorylated at Ser485/491 of the catalytic a-subunit of AMPK leading to its inhibition; and activation of a protein phosphatase (PP2A) that has been associated with decreased AMPK activity.


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3. Saha AK, Xu XJ, Lawson E, Deoliveira R, Brandon AE, Kraegen EW, Ruderman NB. Downregulation of AMPK accompanies leucine- and glucose-induced increases in protein synthesis and insulin resistance in rat skeletal muscle. Diabetes. 59:2426-34,2010. PMCID:PMC3279521

4. Saha AK, Xu XJ, Balon TW, Brandon A, Kraegen EW, Ruderman NB. Insulin resistance due to nutrient excess: is it a consequence of AMPK downregulation? Cell Cycle. 10:3447-51, 2011. PMCID:PMC3356833

5. Brandon AE, Hoy AJ, Wright LE, Turner N, Hegarty BD, Iseli TJ, Julia Xu X, Cooney GJ, Saha AK, Ruderman NB, Kraegen EW. The evolution of insulin resistance in muscle of the glucose infused rat. Arch Biochem Biophys. 509:133-41, 2011. PMCID: PMC3087290

6. Laurent G, German NJ, Saha AK, De Boer VCJ, Davies M, Koves, TR, Dephoure N, Fischer F, Boanca, G, Valthee B, Lovitch SB, Sharpe AH, Kurland, IJ, Steegborn C, Gygi SP, Muoio DM, Ruderman NB, Haigis MC. SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase Mol Cell 50:1-13, 2013. PMCID:PMC3721068[Available on 2014/6/6]

7. Ho L, Titus AS, Banerjee KK, George S, Lin W, Deota S, Saha AK, Nakamura K, Gut P, Verdin E, Kolthur-Seetharam U. SIRT4 regulates ATP homeostasis and mediates a retrograde signaling via AMPK. Aging (Albany NY). Aging (Albany NY). 5:835-49, 2013. PMCID: PMC3868726