Sirtuin 4 controls leucine metabolism and insulin secretion by reversing effects of reactive metabolites

Abstract

Sirtuins are a family of conserved NAD+‐dependent enzymes that remove a variety of post‐translational acyl lysine modifications. By performing this deacylation function, sirtuins can regulate several aspects of metabolism and aging. Recently, we discovered new post‐translational modifications (PTMs) that can be removed by sirtuin 4 (SIRT4). Interestingly, these PTMs can be generated by reactive metabolites produced during leucine oxidation and in the absence of SIRT4, these PTMs accumulate on and inhibit enzymes in the leucine oxidation pathway. These observations suggest that SIRT4 is a key regulator of leucine metabolism through a novel mechanism that responds to levels of reactive metabolites. Accordingly, we found that SIRT4KO mice have dysregulated leucine metabolism. As a consequence of this, SIRT4KO mice have elevated leucine‐stimulated insulin secretion. Long‐term stimulation of insulin secretion by leucine over time in SIRT4KO mice led to elevated plasma insulin levels even in the basal state. This chronic elevation of insulin was associated with an acceleration of aging‐induced insulin resistance in SIRT4KO mice. Interestingly, when leucine was administered as a bolus with glucose, insulin secretion was synergistically increased more than 3‐fold over glucose or leucine alone in aged SIRT4KO mice. Importantly, this elevated insulin secretion resulted in total normalization of glucose tolerance to resemble that of a young mouse and despite extremely high insulin levels, there was no sign of dangerous hypoglycemia. Thus, our data reveal that short‐term inhibition of SIRT4 potentially has therapeutically relevant effects on leucine metabolism and insulin secretion, but a long‐term loss of SIRT4 can drive inappropriate hyperinsulinemia and lead to insulin resistance. Taken together, our data reveal a novel mechanism of metabolic control involving reactive metabolites and position SIRT4 as a key regulator of leucine metabolism and insulin secretion.Support or Funding InformationWe would like to acknowledge funding support from the American Heart Association grants 12SDG8840004 and 12IRG9010008, The Ellison Medical Foundation, the National Institutes of Health and the NIA grant R01AG045351, and the Duke Pepper Older Americans Independence Center (OAIC) Program in Aging Research supported by the National Institute of Aging (P30AG028716‐01). FKH was supported by an American Diabetes Association/Canadian Diabetes Association Post‐doctoral Fellowship (PF‐3‐13‐4342‐FH).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.