The Role of Mitochondria in the Pathogenesis of Type 2 Diabetes

In the paper

“PGC-1 activity can also be modulated at the level of translation and by posttranscriptional changes, including inhibitory GCN5-mediated acetylation (147) and stimulatory sirtuin 1 mediated deacetylation (148).”

What the sources say

• Not checked yetcites [147] Lerin, 2006, GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC-1α., Cell Metab source
• Supported

  The citation is attached to stimulatory SIRT1-mediated deacetylation, not to translation or GCN5-mediated acetylation. In the Results, the authors describe SIRT1 as deacetylating and activating PGC-1α and report experiments consistent with that mechanism. (LLM, conf=0.93)

  cites [148] Lagouge, 2006, Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α., Cell source

In the paper

“Short-term experimental induction of acute hyperglycemia in humans does not fully mirror this pattern of gene expression (143), suggesting that the response to insulin deficiency is not completely due to resultant hyperglycemia.”

What the sources say

• Partly supported

  The Discussion reports that a three-hour hyperglycemic clamp in healthy subjects markedly reduced gene expression in skeletal muscle and adipose tissue. The paper does not compare those results with the gene-expression pattern of insulin deficiency, so it does not establish the cited clause that the patterns do not fully mirror each other. (LLM, conf=0.76)

  cites [143] Meugnier, 2007, Acute hyperglycemia induces a global downregulation of gene expression in adipose tissue and skeletal muscle of healthy subjects., Diabetes sourceExperimental — accuracy not yet measured

In the paper

“White adipocyte mitochondrial content is decreased in both rodent and human obesity (177, 188 -191) and correlates with insulin resistance that accompanies obesity.”

What the sources say

• Partly supported

  The mouse adipocyte results (indexed under “Conflict of interest,” page unavailable) report a mitochondrial-staining deficit relative to cell size in obese ob/ob mice, supporting the rodent part. The paper does not establish decreased white-adipocyte mitochondrial content in human obesity or a correlation between that content and insulin resistance; its Discussion instead describes related human oxidative-phosphorylation findings. (LLM, conf=0.86)

  cites [177] Wilson-Fritch, 2004, Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone., J Clin Invest sourceExperimental — accuracy not yet measured
• Partly supported

  The section ‘Mitochondrial biogenesis is reduced in the adipocytes of db/db mice’ reports lower adipocyte mtDNA content in db/db and ob/ob mice, supporting the rodent portion of the claim. The paper does not report a finding in humans or a correlation between mitochondrial content and insulin resistance; its Discussion describes a possible relationship with insulin resistance rather than a measured correlation. Page numbers were not available in our copy. (LLM, conf=0.88)

  cites [188] Choo, 2006, Mitochondria are impaired in the adipocytes of type 2 diabetic mice., Diabetologia sourceExperimental — accuracy not yet measured
• Not checked yetcites [189] Okamoto, 2007, Comparison of mitochondrial and macrophage content between subcutaneous and visceral fat in db/db mice., Exp Mol Pathol source
• Not checked yetcites [190] Rong, 2007, Adipose mitochondrial biogenesis is suppressed in db/db and high-fat diet-fed mice and improved by rosiglitazone., Diabetes source
• Not checked yetcites [191] Sutherland, 2008, Time course of high-fat diet-induced reductions in adipose tissue mitochondrial proteins: potential mechanisms and the relationship to glucose intolerance, Am J Physiol Endocrinol Metab source

In the paper

“Functionally, decreases in ATP levels, state 3 respiration, and metabolic efficiency are seen, and cardiac and skeletal muscle performance is reduced in response to stress.”

What the sources say

• Partly supported

  The Abstract reports reduced state 3 respiration with palmitoyl-l-carnitine, reduced ATP synthesis and metabolic efficiency, and reduced skeletal-muscle performance. The Discussion reports impaired cardiac function and metabolic responses under stress, and cites prior work finding lower cardiac ATP concentrations. However, the Abstract also reports increased state 3 respiration with pyruvate, so an unqualified decrease in state 3 respiration overstates the finding. Page numbers are unavailable in our copy. (LLM, conf=0.87)

  cites [61] Lehman, 2008, The transcriptional coactivator PGC-1α is essential for maximal and efficient cardiac mitochondrial fatty acid oxidation and lipid homeostasis, Am J Physiol Heart Circ Physiol sourceExperimental — accuracy not yet measured
• Partly supported

  The Results sections on muscle mitochondria and muscle function report reduced state 3 respiration and poorer exercise and fatigue performance in PGC-1α-null mice; the cardiac Results report a blunted heart-rate response to stress. The copy does not report decreased ATP levels or metabolic efficiency. It says that coupling of respiration to ATP production was not significantly altered. (LLM, conf=0.86)

  cites [67] Leone, 2005, PGC-1α deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis, PLoS Biol sourceExperimental — accuracy not yet measured
• Partly supported

  The section on energy-deficient hearts reports approximately 20% lower ATP in unstimulated PGC-1α-knockout hearts, and the article reports reduced cardiac work under dobutamine stimulation (page numbers unavailable). Our copy does not establish decreased state 3 respiration or metabolic efficiency, or reduced skeletal-muscle performance under stress; its skeletal-muscle findings concern fiber types rather than performance. (LLM, conf=0.86)

  cites [68] Arany, 2005, Transcriptional coactivator PGC-1 α controls the energy state and contractile function of cardiac muscle., Cell Metab sourceExperimental — accuracy not yet measured
• Partly supported

  The paper reports impaired mitochondrial metabolism in PGC-1α-null mice: isolated hepatocytes have reduced oxygen consumption (p. 4), skeletal muscle shows altered energy-metabolism markers (p. 8), and the mice fail a cold challenge (Discussion, p. 13). It does not establish decreases in ATP levels, state 3 respiration, or metabolic efficiency. The Discussion (p. 13) says functional testing of skeletal muscle and heart was still under study, so reduced performance of those tissues under stress is not supported. (LLM, conf=0.88)

  cites [69] Lin, 2004, Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1α null mice., Cell sourceExperimental — accuracy not yet measured

In the paper

“For example, rates of mitochondrial OXPHOS in offspring of type 2 diabetic subjects, as assessed by 31 P spectroscopy, are reduced by 30% in the fasting state (117), and TCA cycle flux, modeled using rates of 4-13 C-glutamate enrichment during infusion of 13 C-acetate, is reduced by 30% (118).”

What the sources say

• Not checked yetcites [117] Petersen, 2004, Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes., N Engl J Med source
• Not checked yetcites [118] Befroy, 2007, Impaired mitochondrial substrate oxidation in muscle of insulin-resistant offspring of type 2 diabetic patients., Diabetes source

In the paper

“Similarly, insulin-stimulated ATP synthesis is reduced by more than 90% in nonobese first-degree relatives of type 2 diabetics (120), more than would be expected from the 30% decrease in mitochondrial density and oxidative function observed in the same population.”

What the sources say

• Not checked yetcites [120] Petersen, 2005, Decreased insulin-stimulated ATP synthesis and phosphate transport in muscle of insulin-resistant offspring of type 2 diabetic parents, PLoS Med source

In the paper

“Ritov et al. (114) demonstrated that the enzymatic activity of OXPHOS complex I, as assessed by the activity of rotenone-sensitive NADH:O 2 oxidoreductase, was reduced by about 40% in skeletal muscle biopsy samples from individuals with type 2 DM and by 20% in obese individuals.”

What the sources say

• Not checked yetcites [114] Ritov, 2005, Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes., Diabetes source

In the paper

“Mogensen et al. (119) observed decreases in maximal ADP-stimulated respiration (state 3, malate and pyruvate as substrates) in mitochondria isolated from obese subjects with DM as compared with obesity alone; these differences persisted even after normalization to citrate synthase activity.”

What the sources say

• Not checked yetcites [119] Mogensen, 2007, Mitochondrial respiration is decreased in skeletal muscle of patients with type 2 diabetes., Diabetes source

In the paper

“The comparison between successive frames reveals scission events (arrowheads), branching events (V), and fusion events (brackets) occurring at 30-sec intervals.”

In the paper

“Both obesity and related inactivity are likely to contribute to the pathogenesis of diabetes because the incidence of diabetes can be reduced by modest weight loss and exercise (7)(8)(9).”

What the sources say

• Not checked yetcites (7)(8)(9)

In the paper

“However, insulin resistance is not predictive of diabetes in individuals without a family history of diabetes, indicating that additional unidentified factors are necessary for disease progression (30).”

What the sources say

• Not checked yetcites [30] Goldfine, 2003, Insulin resistance is a poor predictor of type 2 diabetes in individuals with no family history of disease., Proc Natl Acad Sci USA source

In the paper

“However, we hypothesize that genetically determined and/or inactivity-mediated alterations in mitochondrial oxidative activity may directly impact adaptive responses to overnutrition, causing an imbalance between oxidative activity and nutrient load.”

In the paper

“We conclude that, whereas the association between impaired mitochondrial function and DM is strong, a causal pathogenic relationship remains uncertain.”

In the paper

“Thus, these data suggest that in addition to decreased mitochondrial density, there is an additional intrinsic defect(s) in TCA, OXPHOS, membrane potential, or adenine nucleotide transporters in mitochondria of individuals with established diabetes.”

In the paper

“In these individuals, expression of OXPHOS and TCA cycle genes, mtDNA content, and ATP production rates were actually higher in both nondiabetic and diabetic individuals compared with Northern European controls, despite lower overall insulin sensitivity.”

What the sources say

• Not checked yetcites [125] Nair, 2008, Asian Indians have enhanced skeletal muscle mitochondrial capacity to produce ATP in association with severe insulin resistance., Diabetes source

In the paper

“Multiple studies suggest that human insulin resistance is indeed accompanied by impaired in vivo mitochondrial oxidative function-in turn linked, at least in part, to reduced mitochondrial density.”

In the paper

“In each of these studies, differences in oxidative capacity did not remain after normalization for mitochondrial mass by citrate synthase activity or mtDNA content, respectively, suggesting that reduced mitochondrial mass might be a major contributor.”

In the paper

“The magnitude of these changes is strikingly similar to the 38% lower muscle mitochondrial density, assessed by electron microscopy, in this same population-again suggesting that decreased mitochondrial density might be an important factor in reduced oxidative capacity in individuals with a family history of diabetes.”

In the paper

“Additional mechanisms potentially linking impaired mitochondrial oxidative function to insulin resistance include: 1) reduced ATP synthesis for energyrequiring functions such as insulin-stimulated glucose uptake; 2) abnormalities in calcium homeostasis (necessary for exercise-induced glucose uptake) (103-105); and 3) reduced ATP production during exercise (106), potentially contributing to reduced”

What the sources say

• Not checked yetcites [103] Lanner, 2008, Ca(2+) and insulin-mediated glucose uptake., Curr Opin Pharmacol source
• Not checked yetcites [104] Lebeche, 2008, Interplay between impaired calcium regulation and insulin signaling abnormalities in diabetic cardiomyopathy., Nat Clin Pract Cardiovasc Med source
• Not checked yetcites [105] Park, 2009, Chronic elevated calcium blocks AMPK-induced GLUT-4 expression in skeletal muscle, Am J Physiol Cell Physiol source
• Not checked yetcites [106] Kacerovsky-Bielesz, 2009, Short-term exercise training does not stimulate skeletal muscle ATP synthesis in relatives of humans with type 2 diabetes., Diabetes source

In the paper

“For example, primary myotubes isolated from obese humans with type 2 DM display reduced basal lipid oxidation and insulinstimulated glucose oxidation with no differences in OXPHOS gene expression (126).”

What the sources say

• Not checked yetcites [126] Frederiksen, 2008, Transcriptional profiling of myotubes from patients with type 2 diabetes: no evidence for a primary defect in oxidative phosphorylation genes., Diabetologia source

In the paper

“These results also raise the question of whether levels of OXPHOS gene expression and function must be considered relative to the oxidative fuel load in an individual.”

In the paper

“Thus, mitochondrial functional capacity is likely to directly affect muscle metabolic function and, because of its large contribution to total body mass, to have a significant impact on whole-body metabolism.”

In the paper

“Impaired flexibility also correlates with intramyocellular accumulation of lipids (107), and 24-h RQ can predict subsequent weight gain (110, 113).”

What the sources say

• Not checked yetcites [107] Simoneau, 1995, Skeletal muscle glycolytic and oxidative enzyme capacities are determinants of insulin sensitivity and muscle composition in obese women., FASEB J source
• Not checked yetcites [110] Bruce, 2003, Muscle oxidative capacity is a better predictor of insulin sensitivity than lipid status., J Clin Endocrinol Metab source
• Not checked yetcites [113] Zurlo, 1990, Low ratio of fat to carbohydrate oxidation as predictor of weight gain: study of 24-h RQ, Am J Physiol

In the paper

“These differences may reflect population-specific differences in obesity, physical fitness, or ethnicity.”

In the paper

“Increased tissue lipid load, as with obesity, and/or sustained inactivity, may lead to the accumulation of fatty acyl coenzyme A (CoA), diacylglycerols, ceramides, products of incomplete oxidation, and ROS, all of which have been linked experimentally to reduced insulin signaling and action (96 -102).”

What the sources say

• Not checked yetcites [96] Dresner, 1999, Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity., J Clin Invest source
• Not checked yetcites [97] Savage, 2007, Disordered lipid metabolism and the pathogenesis of insulin resistance., Physiol Rev source
• Not checked yetcites [98] Koves, 2008, Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance., Cell Metab source
• Not checked yetcites [99] Holland, 2007, Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance., Cell Metab source
• Not checked yetcites [100] Yu, 2002, Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle., J Biol Chem source
• Not checked yetcites [101] Chibalin, 2008, Downregulation of diacylglycerol kinase δ contributes to hyperglycemia-induced insulin resistance., Cell source
• Not checked yetcites [102] Houstis, 2006, Reactive oxygen species have a causal role in multiple forms of insulin resistance., Nature source

In the paper

“Moreover, lipid excess has been linked experimentally to induction of insulin resistance (96) and alterations in insulin signal transduction (97-99).”

What the sources say

• Not checked yetcites [96] Dresner, 1999, Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity., J Clin Invest source
• Not checked yetcites [97] Savage, 2007, Disordered lipid metabolism and the pathogenesis of insulin resistance., Physiol Rev source
• Not checked yetcites [98] Koves, 2008, Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance., Cell Metab source
• Not checked yetcites [99] Holland, 2007, Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance., Cell Metab source

In the paper

“For example, high OXPHOS expression in the population mentioned above may still be inadequate for appropriate and complete oxidation of a chronic high load of circulating lipids, whereas lower OXPHOS levels may be sufficient under conditions of a low circulating lipid load (see Fig. 5).”

In the paper

“Although it remains unclear whether any of these defects play a causal role in insulin resistance, intramyocellular lipid excess strongly correlates with the severity of insulin resistance, even after correction for the degree of obesity (94), and has been observed in muscles of multiple fiber types (95).”

What the sources say

• Not checked yetcites [94] Jacob, 1999, Association of increased intramyocellular lipid content with insulin resistance in lean nondiabetic offspring of type 2 diabetic subjects., Diabetes source
• Not checked yetcites [95] Malenfant, 2001, Fat content in individual muscle fibers of lean and obese subjects., Int J Obes Relat Metab Disord source

In the paper

“Genetic polymorphisms may also influence age-dependent reductions in expression (137).”

What the sources say

• Not checked yetcites [137] Ling, 2004, Multiple environmental and genetic factors influence skeletal muscle PGC-1α and PGC-1β gene expression in twins., J Clin Invest source

In the paper

“PGC-1␣ has been recognized as an important coactivator in skeletal muscle, contributing to fiber type determination, glucose uptake, and oxidative capacity (see Section IV.A).”

What the sources say

• Not checked yetcites Section IV.A

In the paper

“Conversely, OXPHOS expression can be increased with exercise training (133, 135), a potent insulin sensitizer.”

What the sources say

• Not checked yetcites [133] Parikh, 2008, Molecular correlates for maximal oxygen uptake and type 1 fibers, Am J Physiol Endocrinol Metab source
• Not checked yetcites [135] Wright, 2007, Exercise-induced mitochondrial biogenesis begins before the increase in muscle PGC-1α expression., J Biol Chem source

In the paper

“Expression of multiple OXPHOS genes is also markedly reduced in mice made insulin deficient by treatment with the ␤-cell toxin streptozotocin, and can be normalized by insulin (141).”

What the sources say

• Not checked yetcites [141] Yechoor, 2002, Coordinated patterns of gene expression for substrate and energy metabolism in skeletal muscle of diabetic mice., Proc Natl Acad Sci USA source

In the paper

“Additionally, because OXPHOS gene expression is coordinately regulated, patterns of differential OXPHOS expression may be more readily detectable in disease states, yet not necessarily mirror other aspects of mitochondrial oxidative capacity.”

In the paper

“Moreover, alterations in muscle PGC-1␣ and -␤ mRNA expression are observed in humans with insulin resistance-being reduced by nearly 50% in muscle from individuals with diabetes (122, 145) and in some populations of normoglycemic insulin-resistant humans (121, 124, 137).”

What the sources say

• Not checked yetcites [122] Patti, 2003, Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1., Proc Natl Acad Sci USA source
• Not checked yetcites [145] Southgate, 2005, PGC-1α gene expression is down-regulated by Akt-mediated phosphorylation and nuclear exclusion of FoxO1 in insulin-stimulated skeletal muscle., FASEB J source
• Not checked yetcites [121] Mootha, 2003, PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes., Nat Genet source
• Not checked yetcites [124] Morino, 2005, Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents., J Clin Invest source
• Not checked yetcites [137] Ling, 2004, Multiple environmental and genetic factors influence skeletal muscle PGC-1α and PGC-1β gene expression in twins., J Clin Invest source

In the paper

“Moreover, experimental insulin therapy does not modulate mitochondrial respiration (144), so mechanisms linking insulin action with OXPHOS gene expression remain unclear.”

What the sources say

• Not checked yetcites [144] Rabøl, 2009, Effect of hyperglycemia on mitochondrial respiration in type 2 diabetes., J Clin Endocrinol Metab source

In the paper

“These multiple modes of PGC-1␣ regulation are likely to have evolved from the need to adapt mitochondrial energy metabolism in response to increasingly diverse inputs.”

In the paper

“However, these responses are not observed in all studies of high-fat feeding; in fact, some studies demonstrate that high-fat feeding is associated with increased numbers of mitochondrial protein and DNA content, potentially mediated by chronic fatty acid activation of PPAR nuclear receptors (130 -132).”

What the sources say

• Not checked yetcites [130] Garcia-Roves, 2007, Raising plasma fatty acid concentration induces increased biogenesis of mitochondria in skeletal muscle., Proc Natl Acad Sci USA source
• Not checked yetcites [131] Hancock, 2008, High-fat diets cause insulin resistance despite an increase in muscle mitochondria., Proc Natl Acad Sci USA source
• Not checked yetcites [132] Sreekumar, 2002, Effects of caloric restriction on mitochondrial function and gene transcripts in rat muscle, Am J Physiol Endocrinol Metab source

In the paper

“In turn, PGC-1␣ expression may also be reduced as a consequence of promoter methylation (146) or caused by insulin itself (145), obesity (126), and sustained lipid exposure (126).”

What the sources say

• Not checked yetcites [146] Barrès, 2009, Non-CpG methylation of the PGC-1α promoter through DNMT3B controls mitochondrial density., Cell Metab source
• Not checked yetcites [145] Southgate, 2005, PGC-1α gene expression is down-regulated by Akt-mediated phosphorylation and nuclear exclusion of FoxO1 in insulin-stimulated skeletal muscle., FASEB J source
• Not checked yetcites [126] Frederiksen, 2008, Transcriptional profiling of myotubes from patients with type 2 diabetes: no evidence for a primary defect in oxidative phosphorylation genes., Diabetologia source

In the paper

“Together, these seemingly disparate data suggest that genetic background (127), age at dietary intervention, specific dietary lipid composition, and duration of diet may be important variables to consider when analyzing the interaction between OXPHOS gene expression and diet.”

What the sources say

• Not checked yetcites [127] Crunkhorn, 2007, Peroxisome proliferator activator receptor γ coactivator-1 expression is reduced in obesity: potential pathogenic role of saturated fatty acids and p38 mitogen-activated protein kinase activation., J Biol Chem source

In the paper

“UCP1 hinders the establishment of, or dissipates, a proton gradient of sufficient magnitude to sustain the synthetic activity of the mitochondrial ATPase (150, 153-155), thus driving continuous accelerated electron transport.”

What the sources say

• Not checked yetcites [150] Cannon, 1985, The biochemistry of an inefficient tissue: brown adipose tissue., Essays Biochem
• Not checked yetcites [153] Bouillaud, 1985, Molecular approach to thermogenesis in brown adipose tissue: cDNA cloning of the mitochondrial uncoupling protein., Proc Natl Acad Sci USA source
• Not checked yetcites [154] Jacobsson, 1985, Mitochondrial uncoupling protein from mouse brown fat. Molecular cloning, genetic mapping, and mRNA expression., J Biol Chem source
• Not checked yetcites [155] Ricquier, 1997, The mitochondrial uncoupling protein: structural and genetic studies., Prog Nucleic Acid Res Mol Biol source

In the paper

“Among the mitochondrial functions that may be relevant for white adipose tissue function are the anaplerotic generation of metabolic intermediates for fatty acid synthesis and esterification (159), the maintenance of a robust pathway for the folding and secretion of high abundance circulating proteins such as adiponectin (160), and interactions between mitochondrial function and components of the”

What the sources say

• Not checked yetcites [159] Owen, 2002, The key role of anaplerosis and cataplerosis for citric acid cycle function., J Biol Chem source
• Not checked yetcites [160] Koh, 2007, Essential role of mitochondrial function in adiponectin synthesis in adipocytes., Diabetes source
• Not checked yetcites [161] Shi, 2008, Paradoxical effect of mitochondrial respiratory chain impairment on insulin signaling and glucose transport in adipose cells., J Biol Chem source

In the paper

“Rather, alterations in relative utilization of substrates, an imbalance between fuel load and cellular energy requirements, and/or differential thresholds for generation of or resolution of oxidative stress in this setting may contribute to differential susceptibility to insulin resistance in muscle.”

In the paper

“However, recent work has led to reconsideration of this notion, noting that humans possess adipose tissue depots that are cold-sensitive and hypermetabolic, as assessed by their very high uptake of labeled glucose (152,163).”

What the sources say

• Not checked yetcites [152] Weber, 2004, Brown adipose tissue and nuclear medicine imaging., J Nucl Med
• Not checked yetcites [163] Nedergaard, 2007, Unexpected evidence for active brown adipose tissue in adult humans, Am J Physiol Endocrinol Metab source

In the paper

“However, mitochondrial density increases dramatically, and mitochondrial remodeling occurs during white adipocyte differentiation (156 -158), suggesting that mitochondrial functions are required to support the multiple biological roles of mature white adipocytes.”

What the sources say

• Not checked yetcites [156] Luo, 2008, Alteration of mitochondrial oxidative capacity during porcine preadipocyte differentiation and in response to leptin., Mol Cell Biochem source
• Not checked yetcites [157] Kim, 2004, Extracellular ATP is generated by ATP synthase complex in adipocyte lipid rafts., Exp Mol Med source
• Not checked yetcites [158] Wilson-Fritch, 2003, Mitochondrial biogenesis and remodeling during adipogenesis and in response to the insulin sensitizer rosiglitazone., Mol Cell Biol source

In the paper

“The role of adipose tissue mitochondria is most apparent in brown adipose tissue, where flux through the ETC generates heat in the process of thermogenesis, a potentially important mechanism regulating systemic metabolism even in adult humans (149 -152).”

What the sources say

• Not checked yetcites [149] Astrup, 1986, Thermogenesis in human brown adipose tissue and skeletal muscle induced by sympathomimetic stimulation., Acta Endocrinol Suppl (Copenh)
• Not checked yetcites [150] Cannon, 1985, The biochemistry of an inefficient tissue: brown adipose tissue., Essays Biochem
• Not checked yetcites [151] Cypess, 2009, Identification and importance of brown adipose tissue in adult humans., N Engl J Med source
• Not checked yetcites [152] Weber, 2004, Brown adipose tissue and nuclear medicine imaging., J Nucl Med

In the paper

“Higher mitochondrial density and even UCP1 can be induced in response to pharmacological or genetic alterations of white adipocytes (170 -177), suggesting that white adipose tissue could potentially be induced to acquire more oxidative metabolic phenotypes, promoting increased fuel consumption and thus energy expenditure.”

What the sources say

• Not checked yetcites [170] Bogacka, 2005, Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo., Diabetes source
• Not checked yetcites [171] Himms-Hagen, 2000, Multilocular fat cells in WAT of CL-316243-treated rats derive directly from white adipocytes, Am J Physiol Cell Physiol source
• Not checked yetcites [172] Loncar, 1991, Convertible adipose tissue in mice., Cell Tissue Res source
• Not checked yetcites [173] Orci, 2004, Rapid transformation of white adipocytes into fat-oxidizing machines., Proc Natl Acad Sci USA source
• Not checked yetcites [174] Ström, 2008, Attainment of brown adipocyte features in white adipocytes of hormone-sensitive lipase null mice, PLoS ONE source
• Not checked yetcites [175] Tiraby, 2003, Acquirement of brown fat cell features by human white adipocytes., J Biol Chem source
• Not checked yetcites [176] Toh, 2008, Up-regulation of mitochondrial activity and acquirement of brown adipose tissue-like property in the white adipose tissue of fsp27 deficient mice, PLoS ONE source
• Not checked yetcites [177] Wilson-Fritch, 2004, Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone., J Clin Invest source

In the paper

“The large capacity of brown adipose tissue mitochondria to oxidize fatty acids results in a measurable impact on whole-body metabolism; increased brown adipose tissue abundance correlates negatively with fuel storage and weight gain in rodents, and vice versa (162).”

What the sources say

• Not checked yetcites [162] Marette, 1991, Mechanism linking insulin resistance to defective thermogenesis in brown adipose tissue of obese diabetic SHR/N-cp rats., Int J Obes

In the paper

“Thus, impaired mitochondrial capacity in brown adipose tissue might be functionally linked to impaired thermogenesis and energy expenditure, and thus increased susceptibility to obesity-linked insulin resistance.”

In the paper

“White adipocytes display a high degree of plasticity (168), and regional differences in metabolic activity can be linked to varying mitochondria densities (169).”

What the sources say

• Not checked yetcites [168] Cinti, 2002, Adipocyte differentiation and transdifferentiation: plasticity of the adipose organ., J Endocrinol Invest source
• Not checked yetcites [169] Deveaud, 2004, Regional differences in oxidative capacity of rat white adipose tissue are linked to the mitochondrial content of mature adipocytes., Mol Cell Biochem source

In the paper

“In humans, white adipocyte mtDNA copy number is inversely correlated with age and BMI and directly correlated with basal and insulin-induced lipogenesis (192).”

What the sources say

• Not checked yetcites [192] Kaaman, 2007, Strong association between mitochondrial DNA copy number and lipogenesis in human white adipose tissue., Diabetologia source

In the paper

“Conversely, both genetic and dietinduced obesity result in decreased mitochondrial density and OXPHOS activity in adipose tissue (127, 177, 189 -191), potentially contributing to adipose tissue dysfunction and exacerbation of insulin resistance.”

What the sources say

• Not checked yetcites [127] Crunkhorn, 2007, Peroxisome proliferator activator receptor γ coactivator-1 expression is reduced in obesity: potential pathogenic role of saturated fatty acids and p38 mitogen-activated protein kinase activation., J Biol Chem source
• Not checked yetcites [177] Wilson-Fritch, 2004, Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone., J Clin Invest source
• Not checked yetcites [189] Okamoto, 2007, Comparison of mitochondrial and macrophage content between subcutaneous and visceral fat in db/db mice., Exp Mol Pathol source
• Not checked yetcites [190] Rong, 2007, Adipose mitochondrial biogenesis is suppressed in db/db and high-fat diet-fed mice and improved by rosiglitazone., Diabetes source
• Not checked yetcites [191] Sutherland, 2008, Time course of high-fat diet-induced reductions in adipose tissue mitochondrial proteins: potential mechanisms and the relationship to glucose intolerance, Am J Physiol Endocrinol Metab source

In the paper

“For example, Toh et al. (176) and Nishino,et al. (205) find that mice deficient in Fsp27, a lipid droplet protein that promotes lipid storage in white and brown adipocytes, have increased whole-body energy expenditure, resistance to diet-induced obesity, and enhanced insulin sensitivity.”

What the sources say

• Not checked yetcites [176] Toh, 2008, Up-regulation of mitochondrial activity and acquirement of brown adipose tissue-like property in the white adipose tissue of fsp27 deficient mice, PLoS ONE source
• Not checked yetcites [205] Nishino, 2008, FSP27 contributes to efficient energy storage in murine white adipocytes by promoting the formation of unilocular lipid droplets., J Clin Invest

In the paper

“Protein expression of multiple OXPHOS components and Tfam (expressed per milligram of protein) and citrate synthase activity are also lower in liver (e.g., 7% that of cardiac muscle) (211).”

What the sources say

• Not checked yetcites [211] Benard, 2006, Physiological diversity of mitochondrial oxidative phosphorylation, Am J Physiol Cell Physiol source

In the paper

“Electron microscopy demonstrates that mitochondrial area is 44% lower in liver than in heart (210) with smaller size, fewer cristae, and lower matrix density.”

What the sources say

• Not checked yetcites [210] Veltri, 1990, Distinct genomic copy number in mitochondria of different mammalian organs., J Cell Physiol source

In the paper

“Current reports support the hypothesis that brown adipocytes and myocytes share a common cellular lineage, potentially explaining their similarity with regard to containing mitochondria specialized in fuel oxidation.”

In the paper

“Despite lower OXPHOS capacity, state 3 respiration and respiratory control ratio are equivalent in liver and muscle, indicating differences in relative substrate concentrations and lower”

What the sources say

• Not checked yetcites [211] Benard, 2006, Physiological diversity of mitochondrial oxidative phosphorylation, Am J Physiol Cell Physiol source

In the paper

“Functionally, isolated hepatic mitochondria have relative reductions in OXPHOS proteins, respiratory chain cytochromes, and maximal activity of complexes III and IV (211).”

What the sources say

• Not checked yetcites [211] Benard, 2006, Physiological diversity of mitochondrial oxidative phosphorylation, Am J Physiol Cell Physiol source

In the paper

“In addition, the transcriptional coactivators PGC-1␣ and -1␤ (56) play a critical role in the expansion of the mitochondrial reticulum and in the induction of UCP1 and the brown adipose tissue thermogenic program during the perinatal period (59).”

What the sources say

• Not checked yetcites [56] Wu, 1999, Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1., Cell source
• Not checked yetcites [59] Sonoda, 2007, PGC-1β controls mitochondrial metabolism to modulate circadian activity, adaptive thermogenesis, and hepatic steatosis., Proc Natl Acad Sci USA source

In the paper

“Interestingly, these mice are also dyslipidemic and susceptible to atherosclerosis (209).”

What the sources say

• Not checked yetcites [209] Biddinger, 2008, Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis., Cell Metab source

In the paper

“Thus, mechanisms that induce and maintain active mitochondria in adipocytes can bypass defects in insulin signaling, and indeed, insulin signaling may repress mitochondrial gene expression and/or function.”

In the paper

“The mechanisms whereby obesity results in a reduction in adipose mitochondrial density are not known but could be mediated by decreased expression of PGC-1␣, as observed in obese humans (206).”

What the sources say

• Not checked yetcites [206] Semple, 2004, Expression of the thermogenic nuclear hormone receptor coactivator PGC-1α is reduced in the adipose tissue of morbidly obese subjects., Int J Obes Relat Metab Disord source

In the paper

“For example, liver-specific insulin receptor knockout (LIRKO) mice develop insulin resistance, glucose intolerance, impaired insulin suppression of hepatic glucose production, and altered patterns of hepatic gene expression (208).”

What the sources say

• Not checked yetcites [208] Michael, 2000, Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction., Mol Cell source

In the paper

“Thus, reduced mtDNA content could reduce adipocyte capacity for lipid storage, promoting ectopic lipid accumulation in peripheral tissues such as muscle and liver.”

In the paper

“Mitochondrial levels in white adipocytes are also increased in response to adrenergic stimulation, ␤-3 agonists, and CB1 blockade in mice (195,199,200), again in parallel with enhanced insulin sensitivity.”

What the sources say

• Not checked yetcites [195] Bogacka, 2005, Structural and functional consequences of mitochondrial biogenesis in human adipocytes in vitro., J Clin Endocrinol Metab source
• Not checked yetcites [199] Granneman, 2005, Metabolic and cellular plasticity in white adipose tissue I: effects of β3-adrenergic receptor activation, Am J Physiol Endocrinol Metab source
• Not checked yetcites [200] Tedesco, 2008, Cannabinoid type 1 receptor blockade promotes mitochondrial biogenesis through endothelial nitric oxide synthase expression in white adipocytes., Diabetes source

In the paper

“Although these data cannot address whether such changes are indeed pathogenic, it is interesting that reduced OXPHOS activity in this setting is accompanied by increased tissue long-chain acylcarnitines and reduced short-chain acylcarnitines, despite normal CPT1 activity and increased expression of ␤-oxidation genes (230, 236).”

What the sources say

• Not checked yetcites [230] Misu, 2007, Genes involved in oxidative phosphorylation are coordinately upregulated with fasting hyperglycaemia in livers of patients with type 2 diabetes., Diabetologia source
• Not checked yetcites [236] Kohjima, 2007, Re-evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease., Int J Mol Med

In the paper

“Although these effects could be mediated by accumulation of fatty acyl CoA, diacylglycerols, and ceramides (as in muscle; Section III.A), it is intriguing that effects of fatty acids in liver cells can be prevented by inhibition of CPT1, indicating a critical role for mitochondrial oxidation in inducing lipid-mediated insulin resistance, perhaps via products of incomplete oxidation and/or”

What the sources say

• Not checked yetcites [220] Nakamura, 2009, Palmitate induces insulin resistance in H4IIEC3 hepatocytes through reactive oxygen species produced by mitochondria., J Biol Chem source

In the paper

“Byproducts of incomplete fatty acid oxidation could act in concert with adipose tissue-derived inflammatory signals (e.g., TNF␣), and altered expression and activation of proinflammatory (e.g., IL-1R family) and profibrotic genes (e.g., TGFB1, FGFR2), to increase production of ROS and ultimately contribute to the development of NASH and cirrhosis (235).”

What the sources say

• Not checked yetcites [235] Sanyal, 2001, Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities., Gastroenterology source

In the paper

“In the first (232), severe obesity (mean BMI 52 kg/m 2 ) was associated with reduced ex-pression of seven of 25 genes encoding OXPHOS genes; expression of these genes was inversely correlated with hepatic lipid accumulation and paralleled by reduced expression of PGC-1␣ and genes known to be regulated by thyroid hormone.”

What the sources say

• Not checked yetcites [232] Pihlajamäki, 2009, Thyroid hormone-related regulation of gene expression in human fatty liver., J Clin Endocrinol Metab source

In the paper

“Interestingly, reduced expression of OXPHOS genes (e.g., COX7C, ATP5C1) was also observed in mice fed a high-fat diet and normalized by acute therapy with thyroid hormone T 3suggesting that functional hepatic thyroid hormone resistance could contribute to reduced expression of mitochondrial oxidative genes in this context (232).”

What the sources say

• Not checked yetcites [232] Pihlajamäki, 2009, Thyroid hormone-related regulation of gene expression in human fatty liver., J Clin Endocrinol Metab source

In the paper

“Because accumulation of lipid within hepatocytes is a key marker of insulin resistance in humans (207) and a major contributor to nonalcoholic fatty liver disease, nonalcoholic steatohepatitis (NASH), and cirrhosis, we will first consider relationships between hepatic lipid metabolism and insulin resistance, and in Section III.C.3 will review evidence linking DM and hepatic steatosis to”

What the sources say

• Not checked yetcites [207] Kotronen, 2008, Tissue specificity of insulin resistance in humans: fat in the liver rather than muscle is associated with features of the metabolic syndrome., Diabetologia source

In the paper

“With aging, chronic ROS exposure, and/or the development of insulin resistance related to obesity or sustained lipid accumulation, OXPHOS expression may fall.”

In the paper

“Indeed, a recent paper demonstrated that mice with hepatic insulin resistance due to deletions of the major insulin receptor substrates (IRS-1 and IRS-2) have impaired mitochondrial function and biogenesis, as demonstrated by reduced NADH oxidation, reduced ATP production rates, reduced numbers of mitochondria per cell, reduced fatty acid oxidation, and increased hepatic triglyceride accumulation”

What the sources say

• Not checked yetcites [229] Cheng, 2009, Foxo1 integrates insulin signaling with mitochondrial function in the liver., Nat Med source

In the paper

“We hypothesize that modest obesity may be associated with compensatory up-regulation of OXPHOS gene expression in response to sustained lipid load and/or functional defects in complete fatty acid oxidation.”

In the paper

“Although this may be an appropriate response, limiting oxidative stress, it may also contribute to a vicious cycle of further impairments in oxidative capacity, increased lipid accumulation, and progressive insulin resistance.”

In the paper

“Transgenic mice expressing lipoprotein lipase in the liver have a 2-fold increase in hepatic triglyceride content and are insulin resistant (219).”

What the sources say

• Not checked yetcites [219] Kim, 2001, Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance., Proc Natl Acad Sci USA source

In the paper

“Fatty acid-induced reductions in insulin receptor number and function in the liver (211) may also reduce hepatic insulin clearance (226), causing systemic hyperinsulinemia, itself a contributor to both insulin resistance and reduced mitochondrial function (214,227,228).”

What the sources say

• Not checked yetcites [211] Benard, 2006, Physiological diversity of mitochondrial oxidative phosphorylation, Am J Physiol Cell Physiol source
• Not checked yetcites [226] Seppälä-Lindroos, 2002, Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men., J Clin Endocrinol Metab source
• Not checked yetcites [214] Kotronen, 2008, Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes., Gastroenterology source
• Not checked yetcites [227] Park, 2006, Mechanism of glucose intolerance in mice with dominant negative mutation of CEACAM1, Am J Physiol Endocrinol Metab source
• Not checked yetcites [228] Liu, 2009, Prolonged exposure to insulin suppresses mitochondrial production in primary hepatocytes., J Biol Chem source

In the paper

“Although the relative roles of each of these possibilities is incompletely understood, hepatic lipid accumulation is associated with obesity in humans, particularly central (abdominal) in location (214, 215), and in parallel with low adiponectin levels (216).”

What the sources say

• Not checked yetcites [214] Kotronen, 2008, Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes., Gastroenterology source
• Not checked yetcites [215] Petersen, 2005, Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes., Diabetes source
• Not checked yetcites [216] Koska, 2008, Increased fat accumulation in liver may link insulin resistance with subcutaneous abdominal adipocyte enlargement, visceral adiposity, and hypoadiponectinemia in obese individuals., Am J Clin Nutr source

In the paper

“One possibility is that excessive hepatic lipid accumulation may play a central, pathogenic role in insulin resistance.”

In the paper

“Indeed, enzymatic activity of complexes I-V is reduced in liver extracts from patients with NASH and is inversely correlated with BMI and HOMA-IR (233, 234).”

What the sources say

• Not checked yetcites [233] Pérez-Carreras, 2003, Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis., Hepatology source
• Not checked yetcites [234] Greenfield, 2008, Recent advances in nonalcoholic fatty liver disease., Curr Opin Gastroenterol source

In the paper

“Although these two data sets appear to be discordant (i.e., obesity-linked down-regulation of mitochondrial oxidative gene expression in the first, and up-regulation in the second), several differences in the study population may account for these findings: 1) much greater degree of adiposity and hepatic steatosis in the first; 2) differences in ethnicity (Caucasian-Americans vs. Japanese); and 3)”

In the paper

“Up-regulation of these OXPHOS genes was also positively associated with expression of several genes linked to mitochondrial biogenesis (e.g., PGC-1␤, ERR␣, NRF, thyroid hormone receptor) and both ROS generation (e.g., NADPH oxidase) and attenuation (e.g., glutathione peroxidase).”

What the sources say

• Not checked yetcites [231] Takamura, 2008, Obesity upregulates genes involved in oxidative phosphorylation in livers of diabetic patients., Obesity (Silver Spring) source

In the paper

“Interestingly, mitochondrial diabetes only develops upon aging, with an average age of onset between 35 and 40 yr for MIDD and 48 yr for 14577 TϾC.”

What the sources say

• Not checked yetcites [246] Maassen, 2004, Mitochondrial diabetes: molecular mechanisms and clinical presentation, Diabetes source

In the paper

“However, it also leads to decreased ATP production, which impairs insulin secretion.”

In the paper

“B, In the presence of excess FFA, this normal feedback loop is compromised by a direct activation of UCP2 by FFA, as well as an effect of FFA to increase the amount of UCP2.”

In the paper

“Low levels of ROS are necessary for insulin secretion, but chronic, high mitochondrial ROS production can have a deleterious effect on ␤-cell function (254 -256).”

What the sources say

• Not checked yetcites [254] Li, 2008, The sensitivity of pancreatic β-cells to mitochondrial injuries triggered by lipotoxicity and oxidative stress., Biochem Soc Trans source
• Not checked yetcites [255] Rachek, 2006, Protection of INS-1 cells from free fatty acid-induced apoptosis by targeting hOGG1 to mitochondria., Diabetes source
• Not checked yetcites [256] Simmons, 2005, Progressive accumulation of mitochondrial DNA mutations and decline in mitochondrial function lead to β-cell failure., J Biol Chem source

In the paper

“Thus, UCPs must uncouple respiration sufficiently to mitigate toxic levels of ROS, but not enough to decrease ATP and ROS below the levels necessary for insulin secretion.”

In the paper

“However, these same animals displayed increased liver gluconeogenic enzyme levels and impaired insulin suppression of hepatic glucose production, thus nullifying the potentially beneficial effect of modest muscle PGC-1␣ overexpression on whole-body glucose homeostasis.”

What the sources say

• Not checked yetcites [262] Liang, 2009, Whole body overexpression of PGC-1α has opposite effects on hepatic and muscle insulin sensitivity, Am J Physiol Endocrinol Metab source

In the paper

“Consistent with this view, clonal cytosolic hybrid cells harboring mitochondria derived from MIDD patients exhibit impaired calcium handling and elevated ROS under metabolic stress (247, 248).”

What the sources say

• Not checked yetcites [247] Maechler, 2006, In β-cells, mitochondria integrate and generate metabolic signals controlling insulin secretion., Int J Biochem Cell Biol source
• Not checked yetcites [248] Andrade, 2006, Diabetes-associated mitochondrial DNA mutation A3243G impairs cellular metabolic pathways necessary for β-cell function., Diabetologia source

In the paper

“PGC-1␣ and related coactivators are critical for the regulation of mitochondrial oxidative capacity, as demonstrated by the approximately 2-fold increases in mtDNA and oxygen consumption and a 50% increase in mitochondrial density in myotubes overexpressing PGC-1␣ (56).”

What the sources say

• Not checked yetcites [56] Wu, 1999, Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1., Cell source