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Is acetylation a metabolic rheostat that regulates skeletal muscle insulin action?

LaBarge S, Migdal C, Schenk S - Mol. Cells (2015)

Bottom Line: Skeletal muscle insulin resistance, which increases the risk for developing various metabolic diseases, including type 2 diabetes, is a common metabolic disorder in obesity and aging.While recent large-scale "omics" studies have revealed the acetylome to be comparable in size to the phosphorylome, the acetylation of insulin signaling proteins and its functional relevance to insulin-stimulated glucose transport and glucose metabolism is not fully understood.In this Mini Review we discuss the acetylation status of proteins involved in the insulin signaling pathway and review their potential effect on, and relevance to, insulin action in skeletal muscle.

View Article: PubMed Central - PubMed

Affiliation: Department of Orthopaedic Surgery, University of California, San Diego, CA, 92093, USA.

ABSTRACT
Skeletal muscle insulin resistance, which increases the risk for developing various metabolic diseases, including type 2 diabetes, is a common metabolic disorder in obesity and aging. If potential treatments are to be developed to treat insulin resistance, then it is important to fully understand insulin signaling and glucose metabolism. While recent large-scale "omics" studies have revealed the acetylome to be comparable in size to the phosphorylome, the acetylation of insulin signaling proteins and its functional relevance to insulin-stimulated glucose transport and glucose metabolism is not fully understood. In this Mini Review we discuss the acetylation status of proteins involved in the insulin signaling pathway and review their potential effect on, and relevance to, insulin action in skeletal muscle.

No MeSH data available.


Related in: MedlinePlus

Theoretical overview of acetylation in insulin signaling and glucose metabolism. (A) KATs and DACs have been shown to regulate the acetylation patterns of various proteins within the insulin signaling pathway. However, the exact pattern of acetylation and the effect acetylation plays in response to insulin stimulation is not known. (B) Acetylation within glucose metabolism has been shown to regulate glycolytic enzymes and promote glycogen synthesis. However, the dynamics of acetylation patterns within these pathways, and the KATs and DACs that regulate them, following insulin stimulation, are not known. (C) Insulin stimulation may activate ACLY within the cytosol that produces acetyl CoA, from Citrate, required for subsequent acetylation of target proteins.
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f1-molce-38-4-297: Theoretical overview of acetylation in insulin signaling and glucose metabolism. (A) KATs and DACs have been shown to regulate the acetylation patterns of various proteins within the insulin signaling pathway. However, the exact pattern of acetylation and the effect acetylation plays in response to insulin stimulation is not known. (B) Acetylation within glucose metabolism has been shown to regulate glycolytic enzymes and promote glycogen synthesis. However, the dynamics of acetylation patterns within these pathways, and the KATs and DACs that regulate them, following insulin stimulation, are not known. (C) Insulin stimulation may activate ACLY within the cytosol that produces acetyl CoA, from Citrate, required for subsequent acetylation of target proteins.

Mentions: We present a theoretical overview of this in Fig. 1. The translocation of GLUT4 to the plasma membrane is central to insulin-stimulated glucose transport. Under physiological conditions, the number of GLUT4 vesicles recruited to the membrane is a function of the efficiency of insulin signaling. Moreover, maintenance of the interstitial-to-intracellular glucose gradient is essential to maintain glucose transport through GLUT4 after insulin stimulation. In skeletal muscle, this gradient is maintained by conversion of glucose to glucose-6-phosphate (G6P), by hexokinase II (HKII). Once inside the muscle cell, glucose is disposed of oxidatively or non-oxidatively, via glycolysis or glycogen synthesis, respectively, with approximately two-thirds of glucose being shuttled toward glycogen. Thus, if one ascribes that acetylation of glycolytic enzymes results in a general slowing of reaction rates, then there would be an accumulation of intracellular G6P and reduced glucose transport. If concurrently, however, acetylation of glycogen-related enzymes favors glycogen synthesis, then G6P will be incorporated into glycogen, and a picture of flexible coordination of glucose disposal toward glycogen synthesis is revealed. Parallel changes in the cytosolic availability of acetyl CoA and NAD+, as a function of glucose flux, would allow for rapid temporal control of the flow of glucose, as well as simultaneous modulation of the acetylation status of insulin signaling proteins. The end result being coordinated control of insulin signaling, with glucose uptake and glucose disposal by acetylation. Certainly, the fact that insulin stimulation leads to activation of ACLY adds credence to this line of thinking.


Is acetylation a metabolic rheostat that regulates skeletal muscle insulin action?

LaBarge S, Migdal C, Schenk S - Mol. Cells (2015)

Theoretical overview of acetylation in insulin signaling and glucose metabolism. (A) KATs and DACs have been shown to regulate the acetylation patterns of various proteins within the insulin signaling pathway. However, the exact pattern of acetylation and the effect acetylation plays in response to insulin stimulation is not known. (B) Acetylation within glucose metabolism has been shown to regulate glycolytic enzymes and promote glycogen synthesis. However, the dynamics of acetylation patterns within these pathways, and the KATs and DACs that regulate them, following insulin stimulation, are not known. (C) Insulin stimulation may activate ACLY within the cytosol that produces acetyl CoA, from Citrate, required for subsequent acetylation of target proteins.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4400303&req=5

f1-molce-38-4-297: Theoretical overview of acetylation in insulin signaling and glucose metabolism. (A) KATs and DACs have been shown to regulate the acetylation patterns of various proteins within the insulin signaling pathway. However, the exact pattern of acetylation and the effect acetylation plays in response to insulin stimulation is not known. (B) Acetylation within glucose metabolism has been shown to regulate glycolytic enzymes and promote glycogen synthesis. However, the dynamics of acetylation patterns within these pathways, and the KATs and DACs that regulate them, following insulin stimulation, are not known. (C) Insulin stimulation may activate ACLY within the cytosol that produces acetyl CoA, from Citrate, required for subsequent acetylation of target proteins.
Mentions: We present a theoretical overview of this in Fig. 1. The translocation of GLUT4 to the plasma membrane is central to insulin-stimulated glucose transport. Under physiological conditions, the number of GLUT4 vesicles recruited to the membrane is a function of the efficiency of insulin signaling. Moreover, maintenance of the interstitial-to-intracellular glucose gradient is essential to maintain glucose transport through GLUT4 after insulin stimulation. In skeletal muscle, this gradient is maintained by conversion of glucose to glucose-6-phosphate (G6P), by hexokinase II (HKII). Once inside the muscle cell, glucose is disposed of oxidatively or non-oxidatively, via glycolysis or glycogen synthesis, respectively, with approximately two-thirds of glucose being shuttled toward glycogen. Thus, if one ascribes that acetylation of glycolytic enzymes results in a general slowing of reaction rates, then there would be an accumulation of intracellular G6P and reduced glucose transport. If concurrently, however, acetylation of glycogen-related enzymes favors glycogen synthesis, then G6P will be incorporated into glycogen, and a picture of flexible coordination of glucose disposal toward glycogen synthesis is revealed. Parallel changes in the cytosolic availability of acetyl CoA and NAD+, as a function of glucose flux, would allow for rapid temporal control of the flow of glucose, as well as simultaneous modulation of the acetylation status of insulin signaling proteins. The end result being coordinated control of insulin signaling, with glucose uptake and glucose disposal by acetylation. Certainly, the fact that insulin stimulation leads to activation of ACLY adds credence to this line of thinking.

Bottom Line: Skeletal muscle insulin resistance, which increases the risk for developing various metabolic diseases, including type 2 diabetes, is a common metabolic disorder in obesity and aging.While recent large-scale "omics" studies have revealed the acetylome to be comparable in size to the phosphorylome, the acetylation of insulin signaling proteins and its functional relevance to insulin-stimulated glucose transport and glucose metabolism is not fully understood.In this Mini Review we discuss the acetylation status of proteins involved in the insulin signaling pathway and review their potential effect on, and relevance to, insulin action in skeletal muscle.

View Article: PubMed Central - PubMed

Affiliation: Department of Orthopaedic Surgery, University of California, San Diego, CA, 92093, USA.

ABSTRACT
Skeletal muscle insulin resistance, which increases the risk for developing various metabolic diseases, including type 2 diabetes, is a common metabolic disorder in obesity and aging. If potential treatments are to be developed to treat insulin resistance, then it is important to fully understand insulin signaling and glucose metabolism. While recent large-scale "omics" studies have revealed the acetylome to be comparable in size to the phosphorylome, the acetylation of insulin signaling proteins and its functional relevance to insulin-stimulated glucose transport and glucose metabolism is not fully understood. In this Mini Review we discuss the acetylation status of proteins involved in the insulin signaling pathway and review their potential effect on, and relevance to, insulin action in skeletal muscle.

No MeSH data available.


Related in: MedlinePlus