Lipid-Induced Mitochondrial Stress and Insulin Action in Muscle

Muoio, Deborah M.; Neufer, P. Darrell

doi:10.1016/j.cmet.2012.04.010

Cited by 297 publications

(298 citation statements)

References 121 publications

(160 reference statements)

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“…Thus, SIRT3 may also play a role in mediating islet compensation of insulin resistance, such that only when SIRT3 levels decrease can impaired islet function and type 2 diabetes occur. Increased islet SIRT3 levels are consistent with other studies in skeletal muscle and liver, which reported increases in mitochondrial proteins, including SIRT3, in earlier stages of high-fat feeding [48,49]. We also demonstrated marked reductions in SIRT3 levels in islets isolated from animals that had been fasted for 24 h. This is at odds with findings in liver, where SIRT3 levels increased following a 24 h fast [50,51].…”

Section: Discussioncontrasting

confidence: 55%

Sirtuin 3 regulates mouse pancreatic beta cell function and is suppressed in pancreatic islets isolated from human type 2 diabetic patients

et al. 2013

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Aims/hypothesis Sirtuin (SIRT)3 is a mitochondrial protein deacetylase that regulates reactive oxygen species (ROS) production and exerts anti-inflammatory effects. As chronic inflammation and mitochondrial dysfunction are key factors mediating pancreatic beta cell impairment in type 2 diabetes, we investigated the role of SIRT3 in the maintenance of beta cell function and mass in type 2 diabetes. Methods We analysed changes in SIRT3 expression in experimental models of type 2 diabetes and in human islets isolated from type 2 diabetic patients. We also determined the effects of SIRT3 knockdown on beta cell function and mass in INS1 cells. Results SIRT3 expression was markedly decreased in islets isolated from type 2 diabetes patients, as well as in mouse islets or INS1 cells incubated with IL1β and TNFα. SIRT3 knockdown in INS1 cells resulted in lowered insulin secretion, increased beta cell apoptosis and reduced expression of key beta cell genes. SIRT3 knockdown also blocked the protective effects of nicotinamide mononucleotide on proinflammatory cytokines in beta cells. The deleterious effects of SIRT3 knockdown were mediated by increased levels of cellular ROS and IL1β. Conclusions/interpretation Decreased beta cell SIRT3 levels could be a key step in the onset of beta cell dysfunction, occurring via abnormal elevation of ROS levels and amplification of beta cell IL1β synthesis. Strategies to increase the activity or levels of SIRT3 could generate attractive therapies for type 2 diabetes.

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Section: Discussioncontrasting

confidence: 55%

Sirtuin 3 regulates mouse pancreatic beta cell function and is suppressed in pancreatic islets isolated from human type 2 diabetic patients

et al. 2013

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“…As many would expect, inhibition of mitochondrial FAO causes the muscle to rely more heavily on carbohydrate for fuel. Enhanced glucose disposal and elevated pyruvate oxidation as a result of restricted FAO are consistent with substrate competition models between glucose and fatty acids and the allosteric regulation of hexokinase and PDH regulating both glucose uptake and oxidation (14,30). However, as with any homeostatic system, perturbations in one component cause compensatory adaptations.…”

Section: Discussionmentioning

confidence: 67%

“…Supporting evidence was obtained using a whole-body genetic approach to elevate levels of the endogenous carnitine palmitoyltransferase-1 (Cpt1) inhibitor, malonyl-CoA (12). These studies have led to the contrasting theory that lipid overload and incomplete FAO within the mitochondria accelerate the progression of insulin resistance (14). Faced with a plethora of studies supporting both hypotheses, a crucial question remains: "Is inhibition of mitochondrial FAO in skeletal muscle sufficient to initiate development of insulin resistance?…”

mentioning

confidence: 99%

Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism

Wicks

Vandanmagsar

Haynie

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

131

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The correlations between intramyocellular lipid (IMCL), decreased fatty acid oxidation (FAO), and insulin resistance have led to the hypothesis that impaired FAO causes accumulation of lipotoxic intermediates that inhibit muscle insulin signaling. Using a skeletal muscle-specific carnitine palmitoyltransferase-1 KO model, we show that prolonged and severe mitochondrial FAO inhibition results in increased carbohydrate utilization, along with reduced physical activity; increased circulating nonesterified fatty acids; and increased IMCLs, diacylglycerols, and ceramides. Perhaps more importantly, inhibition of mitochondrial FAO also initiates a local, adaptive response in muscle that invokes mitochondrial biogenesis, compensatory peroxisomal fat oxidation, and amino acid catabolism. Loss of its major fuel source (lipid) induces an energy deprivation response in muscle coordinated by signaling through AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) to maintain energy supply for locomotion and survival. At the whole-body level, these adaptations result in resistance to obesity.carnitine palmitoyltransferase | muscle | fatty acid | lipid | carbohydrate C onsiderable evidence suggests that when oversupply of dietary fat exceeds the storage capacity of adipose tissue, ectopic lipids accumulate in skeletal muscle, leading to "metabolic stress" that induces insulin resistance. One prevailing theory is that impaired skeletal muscle fatty acid oxidation (FAO) (1-4) leads to cytosolic accumulation of lipotoxic intermediates that are directly linked to defects in insulin signaling (5-11). Recent findings counter this premise because they have shown that models of insulin resistance consistently exhibit enhanced (not reduced) FAO, as demonstrated by elevated incomplete β-oxidation and accumulation of excess lipid-derived acylcarnitines (12, 13). Supporting evidence was obtained using a whole-body genetic approach to elevate levels of the endogenous carnitine palmitoyltransferase-1 (Cpt1) inhibitor, malonyl-CoA (12). These studies have led to the contrasting theory that lipid overload and incomplete FAO within the mitochondria accelerate the progression of insulin resistance (14). Faced with a plethora of studies supporting both hypotheses, a crucial question remains: "Is inhibition of mitochondrial FAO in skeletal muscle sufficient to initiate development of insulin resistance?" Cpt1 is essential for long-chain acyl-CoA transport into the mitochondria, and lies at the nexus of both the lipotoxicity and the mitochondrial overload hypotheses. If decreased FAO is a root cause of lipotoxicity, then muscle-specific ablation of Cpt1b activity should lead to impaired FAO, intramyocellular lipid (IMCL) accumulation, and insulin resistance. In stark contrast, the mitochondrial overload hypothesis suggests that decreased Cpt1b activity would preserve insulin sensitivity by preventing unbalanced overfueling of β-oxidation. Characterization of the rare genetic disorders o...

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“…Another mechanism invokes the metabolic shift toward an increased fat consumption occurring in skeletal muscle when fat acid circulating levels increase during obesity (Muoio & Neufer 2012) and high-fat feeding (Randle et al 1988, Muoio & Neufer 2012. Regardless of the energy intake or energy requirement, mitochondrial ROS generation is higher during fatty acid oxidation than that during glycolytic metabolite pyruvate oxidation (Anderson et al 2007, Seifert et al 2010.…”

Section: Mechanisms Of H 2 O 2 Generationmentioning

confidence: 99%

Skeletal muscle insulin resistance: role of mitochondria and other ROS sources

Meo

Iossa

Venditti

2017

Journal of Endocrinology

206

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At present, obesity is one of the most important public health problems in the world because it causes several diseases and reduces life expectancy. Although it is well known that insulin resistance plays a pivotal role in the development of type 2 diabetes mellitus (the more frequent disease in obese people) the link between obesity and insulin resistance is yet a matter of debate. One of the most deleterious effects of obesity is the deposition of lipids in non-adipose tissues when the capacity of adipose tissue is overwhelmed. During the last decade, reduced mitochondrial function has been considered as an important contributor to 'toxic' lipid metabolite accumulation and consequent insulin resistance. More recent reports suggest that mitochondrial dysfunction is not an early event in the development of insulin resistance, but rather a complication of the hyperlipidemia-induced reactive oxygen species (ROS) production in skeletal muscle, which might promote mitochondrial alterations, lipid accumulation and inhibition of insulin action. Here, we review the literature dealing with the mitochondria-centered mechanisms proposed to explain the onset of obesity-linked IR in skeletal muscle. We conclude that the different pathways leading to insulin resistance may act synergistically because ROS production by mitochondria and other sources can result in mitochondrial dysfunction, which in turn can further increase ROS production leading to the establishment of a harmful positive feedback loop.

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Lipid-Induced Mitochondrial Stress and Insulin Action in Muscle

Cited by 297 publications

References 121 publications

Sirtuin 3 regulates mouse pancreatic beta cell function and is suppressed in pancreatic islets isolated from human type 2 diabetic patients

Sirtuin 3 regulates mouse pancreatic beta cell function and is suppressed in pancreatic islets isolated from human type 2 diabetic patients

Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism

Skeletal muscle insulin resistance: role of mitochondria and other ROS sources

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