Role of Dietary Proteins and Amino Acids in the Pathogenesis of Insulin Resistance

Tremblay, François; Lavigne, Charles; Jacques, Hélène; Marette, André

doi:10.1146/annurev.nutr.25.050304.092545

Cited by 275 publications

(224 citation statements)

References 160 publications

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“…Most recently, it has been reported that branched-chain amino acids in diet contribute to insulin resistance in high fat diet-fed rats and that a similar consequence of such a dietary pattern may exist in human (10). Currently, a role of dietary proteins in the pathogenesis of insulin resistance has been well recognized (11), but the underlying molecular mechanisms are not yet fully understood.…”

mentioning

confidence: 99%

Signal Transducer and Activator of Transcription 3 (STAT3) Mediates Amino Acid Inhibition of Insulin Signaling through Serine 727 Phosphorylation

Kim¹,

Yoon²,

Chen

2009

Journal of Biological Chemistry

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Nutrient overload is associated with the development of obesity, insulin resistance, and type II diabetes. High plasma concentrations of amino acids have been found to correlate with insulin resistance. At the cellular level, excess amino acids impair insulin signaling, the mechanisms of which are not fully understood. Here, we report that STAT3 plays a key role in amino acid dampening of insulin signaling in hepatic cells. Excess amino acids inhibited insulin-stimulated Akt phosphorylation and glycogen synthesis in mouse primary hepatocytes as well as in human hepatocarcinoma HepG2 cells. STAT3 knockdown protected insulin sensitivity from inhibition by amino acids. Amino acids stimulated the phosphorylation of STAT3 at Ser 727 , but not Tyr 705 . Replacement of the endogenous STAT3 with wild-type, but not S727A, recombinant STAT3 restored the ability of amino acids to inhibit insulin signaling, suggesting that Ser 727 phosphorylation was critical for STAT3-mediated amino acid effect. Furthermore, overexpression of STAT3-S727D was sufficient to inhibit insulin signaling in the absence of excess amino acids. Our results also indicated that mammalian target of rapamycin was likely responsible for the phosphorylation of STAT3 at Ser 727 in response to excess amino acids. Finally, we found that STAT3 activity and the expression of its target gene socs3, known to be involved in insulin resistance, were both stimulated by excess amino acids and inhibited by rapamycin. In conclusion, our study reveals STAT3 as a novel mediator of nutrient signals and identifies a Ser 727 phosphorylation-dependent and Tyr 705 phosphorylation-independent STAT3 activation mechanism in the modulation of insulin signaling.Insulin resistance is a major risk factor and a principal defect in type II diabetes. Nutrient overload in affluent societies has been associated with increased occurrence of metabolic syndrome (1, 2). High protein diets are associated with altered glucose metabolism and increased occurrence of type II diabetes (3, 4). Elevated plasma concentrations of amino acids have long been found in obesity and insulin-resistant states (5-8). Furthermore, amino acid infusion induces insulin resistance in healthy individuals (9). Most recently, it has been reported that branched-chain amino acids in diet contribute to insulin resistance in high fat diet-fed rats and that a similar consequence of such a dietary pattern may exist in human (10). Currently, a role of dietary proteins in the pathogenesis of insulin resistance has been well recognized (11) (14); among them the mammalian target of rapamycin (mTOR) has been shown to phosphorylate STAT3 in neuronal cells (15, 16) and IL-6-stimulated hepatocytes (17).As a negative feedback control, STATs induce the expression of SOCS proteins, which are characterized by their ability to down-regulate cytokine signaling (18). SOCSs also play an important role in the pathogenesis of insulin resistance by integrating cytokine signaling with insulin signaling (19). Overexpression of SOCS3 inhibited ...

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confidence: 99%

Signal Transducer and Activator of Transcription 3 (STAT3) Mediates Amino Acid Inhibition of Insulin Signaling through Serine 727 Phosphorylation

Kim¹,

Yoon²,

Chen

2009

Journal of Biological Chemistry

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“…Due to the high prevalence of diabetes worldwide, extensive research is still being performed to develop new antidiabetic agents (ADA 2007;Venkateswaran and Pari 2003;Udayakumar et al 2009;Samane et al 2006;Luo and Luo 2006). Modulating dietary proteins and the flux of circulating amino acids generated by their consumption and digestion might underlie powerful new approaches to treat various metabolic diseases such as obesity and diabetes (Tremblay et al 2007;Wu 2009). Previously we have reported the hypoglycemic effect of CKP in alloxan treated rats, but its effect on nitric oxide pathway and RAGE was unknown.…”

Section: Resultsmentioning

confidence: 99%

Dietary coconut kernel protein beneficially modulates NFκB and RAGE expression in streptozotocin induced diabetes in rats

et al. 2012

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Previous studies showed that arginine rich coconut kernel protein (CKP) maintains glucose homeostasis in experimental diabetic rats. But the mechanism of this effect was not clear. This study investigated the effect of CKP on the expression of liver receptor for advance glycated end products (RAGE), inducible nitric oxide synthase (iNOS) and NFkB. Diabetes was induced by injecting a single dose of streptozotocin (75 mg/kg body weight) intraperitoneally. After inducing diabetes, CKP was administered to rats orally for 45 days. After the experimental period, serum glucose, insulin, liver glycogen, glucose metabolizing enzyme activities and the expression of liver RAGE, iNOS and NFkB was evaluated. The results showed that CKP beneficially modulated the levels of glucose and insulin as well as the metabolizing enzyme activities. Expression of RAGE and NFkB was found to be over expressed in diabetic rats but was found to be down regulated in CKP fed diabetic rats. iNOS expression was down regulated in diabetic rats, which was expressed normally in CKP fed diabetic rats.These results clearly demonstrated that anti diabetic activity of CKP is mediated through NFkB pathway.

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“…In vitro and in vivo findings indicate an important role of amino acids in glucose homeostasis through inhibition of insulin action on muscle glucose transport and hepatic glucose production. This negative effect of amino acids on insulin action appears to be associated with mTOR/S6K1-dependent inhibitory phosphorylation of insulin receptor substrate-1 (IRS-1) on serine and/or threonine residues and impaired activation of PI3K, a key effector of the metabolic actions of insulin (Tremblay et al, 2007;Um et al, 2006). Depletion of S6K1 was recently shown to enhance basal glucose utilization in mammalian muscle cells and to protect against the development of impaired insulin action in response to excessive leucine (Deshmukh et al, 2009).…”

Section: Atrogin-1 Murf1mentioning

confidence: 99%

Manipulating tissue metabolism by amino acids

Tesseraud

Everaert

Ezzine

et al. 2011

World's Poultry Science Journal

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Protein metabolism is considered to be regulated by amino acids, with major consequences on tissue development. There is evidence that lysine greatly affects carcass composition and muscle growth. In particular, a drastic effect of dietary provision of lysine has been observed on breast muscle development in chickens. Other essential amino acids, such as threonine and valine, do not have as pronounced an effect as lysine on body composition. Increasing lysine can also improve chicken breast muscle quality by increasing its ultimate pH and water holding capacity, but the underlying mechanisms are still unknown. Studies conducted over the last ten years indicate that, in addition to being substrates for protein synthesis, amino acids act as modulators of signal transduction pathways that control metabolism and cell functions. For instance, certain amino acids can modulate the activity of the intracellular protein kinases involved in the control of mRNA translation. Interestingly, enhanced responses to amino acids have been reported during the neonatal period, suggesting that early protein nutrition impacts on the development of broiler chicks. Methionine and cysteine have a very significant place among amino acids because they have several additional roles: they are precursors of essential molecules, for example cysteine is used for the synthesis of the antioxidant glutathione, and thus participates in the control of oxidative status, methionine is a source of the methyl groups needed for all biological methylation reactions, including methylation of DNA and histones, etc. These findings together indicate the importance of optimizing amino acid nutrition and providing a rationale for nutritional advice.

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Role of Dietary Proteins and Amino Acids in the Pathogenesis of Insulin Resistance

Cited by 275 publications

References 160 publications

Signal Transducer and Activator of Transcription 3 (STAT3) Mediates Amino Acid Inhibition of Insulin Signaling through Serine 727 Phosphorylation

Signal Transducer and Activator of Transcription 3 (STAT3) Mediates Amino Acid Inhibition of Insulin Signaling through Serine 727 Phosphorylation

Dietary coconut kernel protein beneficially modulates NFκB and RAGE expression in streptozotocin induced diabetes in rats

Manipulating tissue metabolism by amino acids

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