Muscle lipogenesis balances insulin sensitivity and strength through calcium signaling

Funai, Katsuhiko; Song, Houyan; Li, Yin; Lodhi, Irfan J.; Wei, Xiaochao; Yoshino, Jun; Coleman, Trey; Semenkovich, Clay F.

doi:10.1172/jci65726

Cited by 121 publications

(161 citation statements)

References 58 publications

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“…Although muscle tissue is not thought to significantly contribute to overall lipid production, ectopic lipid accumulation is associated with IR and NEFA in tissues, including muscle, and is thought to cause lipotoxicity and promote IR. Although increased fatty acid levels may indicate a larger supply from plasma by enhanced adipose tissue lipolysis or decreased fatty acid clearance [20,21], increased activity of muscle-specific fatty acid synthase (FAS) might also contribute to increased levels of fatty acids [22].…”

Section: Discussionmentioning

confidence: 99%

Metabolite profiling in plasma and tissues of ob/ob and db/db mice identifies novel markers of obesity and type 2 diabetes

et al. 2015

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Aims/hypothesis Metabolomics approaches in humans have identified around 40 plasma metabolites associated with insulin resistance (IR) and type 2 diabetes, which often coincide with those for obesity. We aimed to separate diabetesassociated from obesity-associated metabolite alterations in plasma and study the impact of metabolically important tissues on plasma metabolite concentrations. Methods Two obese mouse models were studied; one exclusively with obesity (ob/ob) and another with type 2 diabetes (db/db). Both models have impaired leptin signalling as a cause for obesity, but the different genetic backgrounds determine the susceptibility to diabetes. In these mice, we profiled plasma, liver, skeletal muscle and adipose tissue via semiquantitative GC-MS and quantitative liquid chromatography (LC)-MS/MS for a wide range of metabolites. Results Metabolite profiling identified 24 metabolites specifically associated with diabetes but not with obesity. Among these are known markers such as 1,5-anhydro-D-sorbitol, 3-hydroxybutyrate and the recently reported marker glyoxylate. New metabolites in the diabetic model were lysine, Ophosphotyrosine and branched-chain fatty acids. We also identified 33 metabolites that were similarly altered in both models, represented by branched-chain amino acids (BCAA) as well as glycine, serine, trans-4-hydroxyproline, and various lipid species and derivatives. Correlation analyses showed stronger associations for plasma amino acids with adipose tissue metabolites in db/db mice compared with ob/ob mice, suggesting a prominent contribution of adipose tissue to changes in plasma in a diabetic state. Conclusions/interpretation By studying mice with metabolite signatures that resemble obesity and diabetes in humans, we have found new metabolite entities for validation in appropriate human cohorts and revealed their possible tissue of origin.

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Section: Discussionmentioning

confidence: 99%

Metabolite profiling in plasma and tissues of ob/ob and db/db mice identifies novel markers of obesity and type 2 diabetes

et al. 2015

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“…Thus, DGK haploinsufficiency may decreases SERCA activity by reducing PE levels. Indeed, muscle-specific ablation of fatty acid synthase causes muscle weakness by reducing PE content and SERCA activity in sarcoplasmic reticulum (16). Whether insufficient energy supply or reduced SERCA activity causes functional defects in skeletal muscle from DGK␦ ϩ/Ϫ mice remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Diacylglycerol kinase-δ regulates AMPK signaling, lipid metabolism, and skeletal muscle energetics

Jiang

Barbosa

Massart

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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-Decrease of AMPK-related signal transduction and insufficient lipid oxidation contributes to the pathogenesis of obesity and type 2 diabetes. Previously, we identified that diacylglycerol kinase-␦ (DGK␦), an enzyme involved in triglyceride biosynthesis, is reduced in skeletal muscle from type 2 diabetic patients. Here, we tested the hypothesis that DGK␦ plays a role in maintaining appropriate AMPK action in skeletal muscle and energetic aspects of contraction. Voluntary running activity was reduced in DGK␦ ϩ/Ϫ mice, but glycogen content and mitochondrial markers were unaltered, suggesting that DGK␦ deficiency affects skeletal muscle energetics but not mitochondrial protein abundance. We next determined the role of DGK␦ in AMPK-related signal transduction and lipid metabolism in isolated skeletal muscle. AMPK activation and signaling were reduced in DGK␦ ϩ/Ϫ mice, concomitant with impaired lipid oxidation and elevated incorporation of free fatty acids into triglycerides. Strikingly, DGK␦ deficiency impaired work performance, as evident by altered force production and relaxation dynamics in response to repeated contractions. In conclusion, DGK␦ deficiency impairs AMPK signaling and lipid metabolism, thereby highlighting the deleterious role of excessive lipid metabolites in the development of peripheral insulin resistance and type 2 diabetes pathogenesis. DGK␦ deficiency also influences skeletal muscle energetics, which may lead to low physical activity levels in type 2 diabetes. lipid oxidation; skeletal muscle; diacylglycerol kinase; AMPK; contraction DIACYLGLYCEROL (DAG) KINASES (DGK) are a family of lipid kinases that catalyze the phosphorylation and conversion of DAG into phosphatidic acid (PA). Elevated DAG content is linked with the development of insulin resistance in type 2 diabetes (27, 36). Thus, modulating the level of distinct DGK isoforms may influence the level of DAG and consequently insulin sensitivity.DGKs regulate signal transduction via protein kinase C, Ras and Rho family proteins, and phosphatidylinositol 5-kinases (42). Of the ten different isoforms of mammalian DGKs, each may have a different subcellular localization and function (31). Protein abundance of DGK␦ and total DGK activity are reduced in skeletal muscle from type 2 diabetic patients and diabetic rodents and normalized upon correction of hyperglycemia (11). Given that DAG is a precursor for triglyceride biosynthesis, DGKs are potentially involved in regulating fat deposition. Indeed, DGK␦ haploinsufficient (DGK␦ ϩ/Ϫ ) mice develop obesity later in life (11), and knockdown of DGK␦ markedly suppresses triglyceride (TG) synthesis in 3T3-L1 preadipocytes (28). Yet, the mechanism by which DGK␦ affects lipid synthesis and other aspects of lipid metabolism remains unclear.AMP-activated protein kinase (AMPK) is a central regulator of energy metabolism. AMPK is heterotrimeric complex composed of a catalytic ␣-subunit and regulatory ␤-and ␥-subunits. Phosphorylation on the Thr 172 residue of ␣-subunit by liver kinase B (LKB1) (20) or calmo...

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“…Perturbation in intracellular Ca 2+ homeostasis resulting from decreased expression/ activity of sarco/ER calcium ATPase (SERCA) and compromised mitochondrial Ca 2+ handling in STZ-induced diabetic hearts ( 76 ) can potentially modulate ceramide metabolism. However, variations in activity of SERCA and mitochondrial Ca 2+ controlling mPTP opening/closure do not affect the levels of diacylglycerol or ceramide ( 77,78 ). This suggests that deregulation of Ca 2+ homeostasis and mPTP activity is likely downstream of ceramide metabolism, or they are independent factors.…”

Section: Lactosylceramide Suppresses Mitochondrial Respiration and Dementioning

confidence: 98%

Lactosylceramide contributes to mitochondrial dysfunction in diabetes

Novgorodov

Riley

et al. 2016

Journal of Lipid Research

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This article is available online at http://www.jlr.orgCompelling epidemiological and clinical data indicate that diabetes mellitus increases the risk for cardiac dysfunction and heart failure independently of other risk factors, such as coronary disease and hypertension. Lipotoxicity is an important contributor to cardiac dysfunction in both type 1 ( 1, 2 ) and type 2 ( 3-6 ) diabetes, which are characterized by excessive accumulation of triacylglycerols, long-chain acyl-CoAs, diacylglycerols, and ceramides in myocardium. Correlation of the increased ceramide level with development of diabetic cardiomyopathy has attracted special attention in recent years because of the well-documented ability of this sphingolipid to regulate a number of cell processes, including cell proliferation, growth arrest, differentiation and apoptosis, and the mediation of responses to stress stimuli .Ceramide is a hub of sphingolipid metabolism ( 7,8 ). The balance between ceramide-producing pathways and pathways that consume it dictates ceramide level in the cell. The de novo ceramide biosynthesis pathway, one of the major ceramide producing pathways, localizes in the endoplasmic reticulum (ER) and starts with the condensation of serine and palmitoyl-CoA producing 3-ketosphingonine, which, in turn, is rapidly converted to dihydrosphingosine. Subsequent acylation of dihydrosphingosine by a set of (dihydro)ceramide synthases (CerSs) gives rise to dihydroceramide. Finally, the removal of two hydrogens from the fatty acid chain of dihydroceramide by desaturase leads to the formation of ceramide. Other possible contributors to elevated ceramide level are: hydrolysis of SM catalyzed by SMases, Abstract Sphingolipids have been implicated as key mediators of cell-stress responses and effectors of mitochondrial function. To investigate potential mechanisms underlying mitochondrial dysfunction, an important contributor to diabetic cardiomyopathy, we examined alterations of cardiac sphingolipid metabolism in a mouse with streptozotocininduced type 1 diabetes. Diabetes increased expression of desaturase 1, (dihydro)ceramide synthase (CerS)2, serine palmitoyl transferase 1, and the rate of ceramide formation by mitochondria-resident CerSs, indicating an activation of ceramide biosynthesis. However, the lack of an increase in mitochondrial ceramide suggests concomitant upregulation of ceramide-metabolizing pathways. Elevated levels of lactosylceramide, one of the initial products in the formation of glycosphingolipids were accompanied with decreased respiration and calcium retention capacity (CRC) in mitochondria from diabetic heart tissue. In baseline mitochondria, lactosylceramide potently suppressed state 3 respiration and decreased CRC, suggesting lactosylceramide as the primary sphingolipid responsible for mitochondrial defects in diabetic hearts. Moreover, knocking down the neutral ceramidase (NCDase) resulted in an increase in lactosylceramide level, suggesting a crosstalk between glucosylceramide synthase-and NCDase-mediated ceramide utiliz...

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Muscle lipogenesis balances insulin sensitivity and strength through calcium signaling

Cited by 121 publications

References 58 publications

Metabolite profiling in plasma and tissues of ob/ob and db/db mice identifies novel markers of obesity and type 2 diabetes

Metabolite profiling in plasma and tissues of ob/ob and db/db mice identifies novel markers of obesity and type 2 diabetes

Diacylglycerol kinase-δ regulates AMPK signaling, lipid metabolism, and skeletal muscle energetics

Lactosylceramide contributes to mitochondrial dysfunction in diabetes

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