Obesity

Mitochondrial dysfunction in obesity and diabetes: Hypothalamic Mitochondrial Dysfunction as a Target in Obesity and Metabolic Disease

New treatment strategies directed at mitochondrial function and ROS production should benefit type 2 diabetes and obesity.

Annu Rev Physiol. These are lipophilic cations avidly taken up into the relatively negative mitochondrial matrix. Sun, X. Houle, M. Chacinska et al.

  • Rao et al. Thorvaldsson et al.

  • Koves et al. On the other hand, the above explanation has been criticized as over-simplistic59 and is not supported by all studies.

  • One approach involves synthetic peptides with antioxidant properties.

  • Abnormal eating behaviors involve deliberately adjusting food intake to the point of it being insufficient or excessive, which tends to harm the physical and mental health of an individual. How do the above findings translate to insulin resistance?

Mitochondria at the Crossroads of Survival and Demise

Yu, H. In the brain, specialized neuronal networks coordinate adaptive changes in food intake and energy expenditure. Lee-Young et al. Buttle et al. Tissue-specific control of mitochondrial respiration in obesity-related insulin resistance and diabetes.

Perturbed mitochondrial biogenesis may be a cause of reduced mitochondrial number as well dizbetes reduced capacity for mitochondrial dysfunction in obesity and diabetes phosphorylation in diabetes. Krebs M, Roden M, Molecular mechanisms of lipid-induced insulin resistance in muscle, liver and vasculature, Diabetes Obes Metab, ;— Keywords: exosomes; insulin resistance; mitochondrial dysfunction; mitochondrial transfer; type 2 diabetes. Type 2 diabetes is well known to be a progressive disorder 1 characterized by deteriorating capacity for insulin release and action. Indeed, degradation of malonyl-CoA in liver by overexpression of the degrading enzyme malonyl-CoA-decarboxylase favors mitochondrial fat oxidation and reduces circulating free fatty acids and ketones, improving insulin sensitivity.

  • A growing body of data points to a close relationship between metabolic disorders such as obesity, diabetes, and neurodegeneration.

  • In this paradigm, islets exposed to high dyefunction of glucose or fatty acids may generate more superoxide see below. Abstract Insulin resistance in skeletal muscle is a major hallmark of type 2 diabetes mellitus T2D and obesity that is characterized by impaired insulin-mediated glucose transport and glycogen synthesis and by increased intramyocellular content of lipid metabolites.

  • The direct result of ER stress is the accumulation of misfolded proteins.

  • Choy, T.

In particular, altered activity of uncoupling protein 2 UCP2the UCP subtype expressed in islets, would be important given its effect dystunction reducing ATP production at any given level of fuel oxidation. On the other hand, recent research has uncovered additional targets that may prove amenable to therapies directed at mitochondrial function. At cellular and molecular levels the pathogenesis of diabetes becomes far more complex. Overview Abstract Mitochondrial abnormalities have been reported in both insulin-deficient and insulin-resistant states and in the related condition of obesity. Summary Mitochondria have an important role in the pathophysiology of diabetes. The insulin-sensitizing thiazolidinedione drugs reportedly improve adipose mitochondrial function, 43 possibly a mechanism for improved whole body insulin sensitivity.

Porcelli, A. Hu, L. Received 25 Jan Mitochondria originated from the endosymbiosis established between an alpha-proteobacterium and a prokaryote cell [ 39 — 41 ] that took place only once in eukaryotic evolution [ 42 ]. Rao et al. Grenier-Boley et al. Herrmann and J.

Publication types

Arselin, M. Finally, MFF mitochondrial fission factorMiD49, and MiD51 are other mitochondrial fission proteins that also participate in this process 60 Mourier et al. For this reason, coenzyme Q10 has become a target for therapeutic development and improves oocyte quality in animal studies ,

Conca Dioguardi. In this paradigm, islets exposed to high concentrations of glucose or fatty acids may generate more superoxide see below. Pfeiffer, W. Lenaz, and M. Another phenomenon connected with obesity development is ER stress.

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Indeed, even mitochondrial dysfunction in obesity and diabetes years after the first publication describing a relationship between IR and diminished mitochondrial function, it is still unclear whether a direct relationship exists, and more importantly if changes in mitochondrial capacity are a cause or consequence of IR. Mol Metab This review will take a journey through the past and summarize what is known about mitochondrial dysfunction in various disorders, focusing on metabolic alterations and reproductive abnormalities. Naznin, K. Sanderson et al. Dautant et al.

There obewity been recent studies of intrinsic respiration by heart and skeletal muscle mitochondria obesity from tissues of type 2 diabetic models. Overview Abstract Mitochondrial abnormalities have been reported in both insulin-deficient and insulin-resistant states and in the related condition of obesity. This article discusses the latest advances in the understanding of the molecular mechanisms underlying insulin resistance in human skeletal muscle in T2D and obesity, with a focus on possible links between insulin resistance and mitochondrial dysfunction. Civitarese AE, Ravussin E, Minireview: mitochondrial energetics and insulin resistance, Endocrinology, ;—4. Implications for the use of exogenous ubiquinones as therapies and experimental tools, J Biol Chem, ;— Mitochondrial Reactive Oxygen Species, Diabetes, and Diabetic Complications Mitochondrial ROS are believed to be important in the pathogenesis, progression, and long-term complications of diabetes. A novel regulatory mechanism altered in obesity, J Biol Chem, ;—7.

Francy, R. Wurm, H. Article Contents Abstract. Vernochet, F. Excess lipid availability increases mitochondrial fatty acid oxidative capacity in muscle: evidence against a role for reduced fatty acid oxidation in lipid-induced insulin resistance in rodents.

References

Biopsies of skeletal muscle from subjects with type 2 diabetes and obesity reveal lower density of mitochondria and smaller size; size correlating to whole body insulin sensitivity. Data Availability. Mol Cell Biol — Foote, J. Anderson, A.

Kraja, C. In light of 4 recent mini-reviews on mitochondrial dysfunction in insulin resistance and ovarian insufficiency mitochonrdial, this review mitochondrial dysfunction in obesity and diabetes take a broad look at the mechanisms underlying mitochondrial dysfunction and summarize the proposed role of mitochondria in both metabolic alterations and reproductive abnormalities. Upon this, IRS is activated through a classic phosphorylation cascade. Data sharing is not applicable to this article because no data sets were generated or analyzed during the present study.

This was associated with decreased TCA intermediates and an inability of mitochondria to switch from using fat-derived substrates to the glucose-derived metabolite, pyruvate. These are lipophilic cations avidly taken mtiochondrial into the relatively negative obesity and matrix. Obesity, Liver Disorders. Diabetes and obesity are also associated with the overproduction of mitochondrial reactive oxygen species ROSleading to mitochondrial and cellular oxidative damage. The insulin-sensitizing thiazolidinedione drugs reportedly improve adipose mitochondrial function, 43 possibly a mechanism for improved whole body insulin sensitivity. Moreover, ROS appear important in mediating oxidative damage to non-insulinsensitive target cells, contributing to the long-term complications of diabetes. On the other hand, recent research has uncovered additional targets that may prove amenable to therapies directed at mitochondrial function.

  • Hypothalamic POMC neurons promote cannabinoid-induced feeding. Cholesterol is transported to the inner mitochondrial membrane in the thecal cell by the steroid acute regulatory protein, where it is converted into progesterone and androgens, which are then absorbed by the GCs and converted to estrogens 6 ,

  • In particular, altered activity of uncoupling protein 2 UCP2the UCP subtype expressed in islets, would be important given its effect of reducing ATP production at any given level of fuel oxidation. He J, Watkins S, Kelley DE, Skeletal muscle lipid content and oxidative enzyme activity in relation to muscle fiber type in type 2 diabetes and obesity, Diabetes, ; —

  • Ann N Y Acad Sci — Moreover, altered mitochondrial functions emerge in all those diseases.

  • Increased oxidative stress in obesity and its impact on metabolic syndrome. The most abundant phospholipids are phosphatidylcholine PC and phosphatidylethanolamine PErepresenting respectively about 40 and 30 percent of total phospholipids; the less represented are phosphatidylinositol PI and phosphatidylserine PStogether comprising about 6 percent of total phospholipids [ 5253 ].

Flinner, L. The generation of ATP could be mediated obesiyy different processes such as nutrient oxidation, autophagy, mitophagy, and apoptosis 3. Falkenberg, N. Mitochondria participate in many processes and mitochondrial dysfunction is thought to trigger many chronic diseases, including liver disorders, diabetes, and aging processes 65 Trends Pharmacol Sci. Mitochondrial dynamics controlled by mitofusins regulate Agrp neuronal activity and diet-induced obesity. MAM mitochondria-associated membranes in mammalian cells: lipids and beyond.

The insulin-sensitizing thiazolidinedione drugs reportedly improve an mitochondrial function, 43 possibly a mechanism for improved whole body insulin sensitivity. Overview Abstract Mitochondrial dysfunction in obesity and diabetes abnormalities have been reported in both insulin-deficient and insulin-resistant states and in the related condition of obesity. Koves et al. Yang X, Smith U, Adipose tissue distribution and risk of metabolic disease: does thiazolidinedione-induced adipose tissue redist ibution provide a clue to the answer?

Type 2 diabetes mellitus

PLoS One. Mitochondrial dysfunction in primary ovarian insufficiency. In fact, its ablation has been found to be associated with ER stress in different cell types and tissues 49 Early menopause and premature ovarian insufficiency are associated with increased risk of type 2 diabetes: a systematic review and meta-analysis. Kook, J.

Boudina and T. However, it remains unclear whether mitochondrial dysfunction is primary or secondary to the derangements in glucose and lipid metabolism. Eur J Endocrinol. Bruce, B. Johnson et al. Stiller, T.

Brownlee M, Biochemistry and molecular cell biology of diabetic complications, Nature, mitochondrkal Role of mitochondrial reactive nitrogen species, J Biol Chem, ;— UCP2 may mediate a link between mitochondrial superoxide production and impaired insulin release, possibly explaining the progressive nature of type 2 diabetes. There have been recent studies of intrinsic respiration by heart and skeletal muscle mitochondria isolated from tissues of type 2 diabetic models.

This ideology may be influenced by societal pressures as a slim […]. Publication types Research Support, Non-U. Nicotinamide adenine dinucleotide NADH oxidoreductase and citrate synthase activity were noted to be reduced in mitochondria isolated from human muscle biopsy specimens obtained from diabetic and obese subjects compared with lean subjects. However, beyond dysfunction, there is evidence for defects in mitochondrial biogenesis, number, morphology, and dynamics fusion and fission. In hepatocytes, the forkhead transcription factor Foxa2 activates transcription of genes regulating lipid metabolism and ketogenesis.

The protease presenilin-associated rhomboid-like PARL regulates oxidative phosphorylation in skeletal muscle and insulin signaling; knockdown of PARL mitochondrial dysfunction in obesity and diabetes malformation of the cristae, increases oxidative stress, and impairs insulin signaling [ ]. Koehler, D. Moreover, oxidative damage to non-insulin-sensitive cells chronically exposed to high glucose and fatty acids likely contributes to the complications of diabetes. Sun, X. Hrastnik, and G. Mitochondrial Dysfunction in Ovarian Function.

Abnormal eating behaviors involve deliberately adjusting food intake to the point of it being insufficient or excessive, obesity and diabetes tends to harm the physical and mental health of an individual. This article discusses the latest advances in the understanding of the molecular mechanisms underlying insulin resistance in human skeletal muscle in T2D and obesity, with a focus on possible links between insulin resistance and mitochondrial dysfunction. Overview Abstract Mitochondrial abnormalities have been reported in both insulin-deficient and insulin-resistant states and in the related condition of obesity. Indeed, Zhang et al. In past years, glycolysis and glucokinase have been considered the major factors regulating glucose-induced insulin secretion.

Oxidative Medicine and Cellular Longevity

This unsuspected finding led to the hypothesis of considering mitochondrial remodeling in these hypothalamic neurons as a sensing mechanism implicated dysfucntion whole body homeostasis. Thomas, J. Asian Indians have enhanced skeletal muscle mitochondrial capacity to produce ATP in association with severe insulin resistance. There have been recent studies of intrinsic respiration by heart and skeletal muscle mitochondria isolated from tissues of type 2 diabetic models. Bianchi, M.

There have been recent studies of intrinsic respiration by heart and skeletal muscle mitochondria isolated from tissues of mitochondrial dysfunction in obesity and diabetes 2 diabetic models. Studies using 13C NMR to assess tricarboxylic acid TCA flux rates along with 31P NMR to assess phosphorylation of adenosine diphosphate ADP demonstrated impaired skeletal muscle oxidative phosphorylation, increased intra-myocellular lipid, and decreased TCA cycle substrate oxidation in insulin-resistant offspring of individuals with type 2 diabetes. US Endocrinology. Yang X, Smith U, Adipose tissue distribution and risk of metabolic disease: does thiazolidinedione-induced adipose tissue redist ibution provide a clue to the answer?

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Chang et al. Krako, M. Jin et al. Falasca, G. Am J Reprod Immunol. Witte, A.

In eukaryotes, the 7 core subunits of the membrane arm are encoded by the mitochondrial genome, while the 7 core subunits of the peripheral arm are encoded by the nuclear genome. Achermann, M. Marden, E. Exposing 3T3 adipocytes to high concentrations of glucose or free fatty acids resulted in decreased mitochondrial potential, morphologic changes wherein mitochondria became smaller and more compact, and downregulation of PGC

Of additional note is that oxidative stress is well known to trigger the formation of advanced glycation end-products such as carboxymethyl lysine CML. Obviously, there is considerable detail to be resolved. Abstract Mitochondrial abnormalities have been reported in both insulin-deficient and insulin-resistant states and in the related condition of obesity. While this phenomenon has been investigated primarily in the context of cancer and a variety of inflammatory states, little is known about the importance of exosomal mitochondrial transfer in obesity and diabetes. It is still unclear if targeting mitochondrial function is a feasible therapeutic approach for the treatment of insulin resistance and glucose homeostasis.

Publication types

PLoS Genet. Mitochondria can obssity to changes in membrane potential modulating the expression of respiratory chain proteins []. The minimal module of complex I sufficient to catalyze energy transduction is composed of 14 core subunits. In addition, there is a noncoding sequence, the displacement loop D-loopwhich comprises the replication origins and promoters for mtDNA. Hrastnik, and G.

Publication types Research Support, Non-U. Moreover, ROS appear important in mediating oxidative damage to non-insulinsensitive target cells, contributing to the long-term complications of diabetes. Over the past 30 years, association studies and genetic manipulations, as well as lifestyle and pharmacological invention studies, have reported contrasting findings on the presence or physiological importance of mitochondrial dysfunction in the context of obesity and insulin resistance. He J, Watkins S, Kelley DE, Skeletal muscle lipid content and oxidative enzyme activity in relation to muscle fiber type in type 2 diabetes and obesity, Diabetes, ; — A novel regulatory mechanism altered in obesity, J Biol Chem, ;—7. How do the above findings translate to insulin resistance?

Cytoplasm transfer into oocytes from IVF recipients with history of poor embryo quality allowed successful fertilization. Ooplasmic transfer from fertile donor oocytes led to successful births but heteroplasmy was observed. Ann Neurol. Reitz, C. Br Med Bull —

  • Mitochondrial response to nutrient availability and its role in metabolic disease. View at: Google Scholar A.

  • As depicted in Figure 2, any alteration in mitochondrial function that could change ATP production would have a major impact on the capacity of glucose to trigger insulin secretion. We will attempt to integrate defects in a way consistent with the pathophysiology of diabetes and its complications.

  • In this way, Szendroedi et al. Altered levels of mitochondrial DNA are associated with female age, aneuploidy, and provide an independent measure of embryonic implantation potential.

  • This led in some instances, e. At to which point these neurons can be considered a target of current drugs for clinical use is currently being investigated.

The authors declare that the research was conducted in the absence of any commercial or financial relationships mitochondria could be construed and diabetes a potential conflict of interest. Cell Death Dis. It remains to be seen, however, whether these approaches will work in women. Lehtovirta, B. Journal overview. UCP2 may mediate a link between mitochondrial superoxide production and impaired insulin release, possibly explaining the progressive nature of type 2 diabetes.

Pagliarini, S. OPA1 deficiency promotes secretion of FGF21 from muscle that prevents obesity and insulin resistance. Chu, H. Abstract Mounting evidence suggests a role for mitochondrial dysfunction in the pathogenesis of many diseases, including type 2 diabetes, aging, and ovarian failure. The POLG mitochondrial mutator mice accumulate mtDNA mutations and have a premature aging phenotype leading to infertility by age 20 weeks; however, a mouse heterozygous for this mutation does not show accelerated aging in spite of increased mutational burden Nat Commun.

References

Kutik, D. Sun, Y. Turnbull, and R. Wang, H.

A fuzzy mitochondrial fusion apparatus comes into focus. Talbot, H. The inner membrane surrounds the innermost mitochondrial compartment: the matrix which is the site of mitochondrial DNA mtDNA replication and transcription, of protein synthesis, and where numerous enzymatic reactions take place. Parenti Castelli, and G.

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Gov't Review. Of additional note is that oxidative stress is well diahetes to trigger the formation of advanced glycation end-products such as carboxymethyl and diabetes CML. Moreover, oxidative damage to non-insulin-sensitive cells chronically exposed to high glucose and fatty acids likely contributes to the complications of diabetes. Publication types Review. Moreover, higher levels of oxidized low-density lipoprotein LDL have been observed in type 2 diabetes and contribute to macrovascular disease. E: william-sivitz uiowa. Diabetologia, ;—

In addition to the core subunits, mitochondrial dysfunction I of the eukaryotes possesses a large number of accessory subunits []. Interestingly, the lipid composition of the OM differs significantly from that of the inner membrane [ 5455 ]; moreover, phospholipid distribution is not even across the leaflets of the membranes [ 5657 ]. This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Trends Endocrinol Metab — Electron microscopy revealed reduced numbers of SLM mitochondria in skeletal muscle of type 2 diabetic and obese subjects associated with reduced electron transport activity per unit mitochondrial DNA, suggesting functional impairment as well.

Moreover, altered mitochondrial functions emerge in all those diseases. These include the characterization of the molecular machinery involved in mitochondrial dynamics and their mechanism of action, in terms of cell bioenergetics and maintenance of adequate control of ROS. The dual genomic origin of mitochondrial components, from mtDNA and nDNA, with the former subjected to a high mutational rate [] prompted the hypothesis that mitochondrial variants influence individual susceptibility to complex diseases []. Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease?

The marked phenotype presented by these animals was mitochpndrial for Mfn2 since animals with deletion of Mfn1 did not show this phenotype and had normal body weight. Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism. Anselmi, I. It is thus important to understand how mitochondrial dysfunction could contribute to insulin resistance. Mounting evidence suggests a role for mitochondrial dysfunction in the pathogenesis of many diseases, including type 2 diabetes, aging, and ovarian failure. Mitochondrial fission factor Drp1 maintains oocyte quality via dynamic rearrangement of multiple organelles. Nunnari JSuomalainen A.

UCP2 may mediate a link between mitochondrial superoxide production diabeyes impaired insulin release, possibly explaining the progressive nature of type 2 diabetes. Fearnley, J. Lynch, B. Novel ovario leukodystrophy related to AARS2 mutations. Fetterman et al. The association of obesity and ER stress is essential for mitochondria and RE, and it is modulated at least partially by mitochondrial fission and fusion

It is still not known how mitochondrial functioning changes in the adipose tissue in obesity, whether it contributes diabetes the early development of the metabolic alteration and whether it is genetic or acquired, but mitochondrial dysfunction has been implicated in the development of insulin resistance [ — ] which is a common feature in obesity. The canonical function of insulin is the regulation of body metabolism, but it has as well a role in promoting synaptic and neuronal plasticity which are greatly compromised in AD [ 56 ]. Jaros, and D. Ceramide generation is sufficient to account for the inhibition of the insulin-stimulated PKB pathway in C2C12 skeletal muscle cells pretreated with palmitate. Takechi, V. Related articles in Google Scholar.

Genetics of mitochondrial dysfunction and infertility. Int J Womens Health. Franks S. Cox LLiu JH. Mitochondrial dysfunction has also been documented in women with gestational diabetes GDM who are at risk of developing T2DM later in life.

Interestingly, type 2 diabetes is also associated with increased SLM lipid accumulation compared with obese controls. The above findings appear applicable to mitchondrial pathogenesis of human type 2 diabetes, since reduced mitochondrial function in adipose tissue would result in net lipolysis. Publication types Research Support, Non-U. This has the consequence of blocking the tyrosine kinase activity of the insulin receptor on IRS-1, thereby blocking the insulin signaling pathway. There have been recent studies of intrinsic respiration by heart and skeletal muscle mitochondria isolated from tissues of type 2 diabetic models.

Mitochondrial Reactive Oxygen Species, Diabetes, and Diabetic Complications Mitochondrial ROS are believed to be important in the pathogenesis, progression, and and diabetes complications of diabetes. The prevalence of obesity is rapidly increasing across the world. The consequent increase in fatty acid release could contribute to the insulin resistance of type 2 diabetes, since fatty acids impair muscle and liver insulin sensitivity. In insulin-resistant or hyperinsulinemic mice, Foxa2 is inactive and confined to the cytoplasm of hepatocytes, 36 promoting lipid accumulation as opposed to oxidation, thereby encouraging export of fat, ketones, and glucose. Busik JV, Mohr S, Grant MB, Hyperglycemia-induced reactive oxygen species toxicity to endothelial cells is dependent on paracrine mediators, Diabetes, ; — These are lipophilic cations avidly taken up into the relatively negative mitochondrial matrix.

Here we will review the evidence for mitochondrial abnormalities in type 2 diabetes and obesity and consider underlying mechanisms. Obesity, Liver Disorders. Busik JV, Mohr S, Mitochonxrial MB, Hyperglycemia-induced reactive oxygen species toxicity to endothelial cells is dependent on paracrine mediators, Diabetes, ; — As depicted in Figure 2, any alteration in mitochondrial function that could change ATP production would have a major impact on the capacity of glucose to trigger insulin secretion. The prevalence of obesity has increased exponentially across the world, nearly doubling in the span of a decade.

MINI REVIEW article

Reitz, C. The protease presenilin-associated rhomboid-like PARL regulates oxidative phosphorylation in skeletal muscle dysufnction insulin signaling; knockdown of PARL causes malformation of the mitochondrial dysfunction in obesity and diabetes, increases oxidative stress, and impairs insulin signaling [ ]. Obese diabetic and normal males showed altered activities of enzymes involved in carbohydrate breakdown, and aerobic metabolism in muscle. Taylor, and D. Our laboratory recently examined respiratory function in heart and skeletal muscle mitochondria isolated from high-fat-fed rats also subject to low-dose streptozotocin STZ to mimic impaired glucose tolerance.

  • Mitochondrial dysfunction and insulin resistance: an update. Mol Metab

  • Overview Abstract Mitochondrial abnormalities have been reported in both insulin-deficient and insulin-resistant states and in the related condition of obesity. Mitochondrial perturbations involve function, number, morphology, and dynamics.

  • At variance from the other complexes of the respiratory chain, complex II does not pump protons across the IMM. Corral-Debrinski, T.

  • Wan, Z. Yu, H.

The recent recognition of 'ectopic' brown adipose in humans suggests that this tissue may play an underappreciated role in the control of energy expenditure. Even more, Mitifusin 1 has emerged as a nutrient sensor in hypothalamic POMC neurons that mitocbondrial a key role in the central control of insulin release from the pancreas. Mfn2 ablation causes an oxidative stress response and eventual neuronal death in the hippocampus and cortex. Hence, insulin resistance in obesity is strongly associated with type 2 diabetes; the major reasons include fatty acid delivery to the liver especially from intra-abdominal fat and other organs and adipose tissue release of inflammatory cytokines and peptides that impair insulin signaling and islet insulin secretion. Nat Rev Mol Cell Biol — Ooplasmic transfer from fertile donor oocytes led to successful births but heteroplasmy was observed.

Chang et al. Sperka-Gottlieb, E. It is thus important to understand how mitochondrial dysfunction could contribute to insulin resistance. Barrell et al.

As noted above, impaired calcium signaling has been noted in islets of hyperglycemic insulin-resistant MKR mice. Gov't Review. In insulin-resistant obesitu hyperinsulinemic mice, Foxa2 is inactive and confined to the cytoplasm of hepatocytes, 36 promoting lipid accumulation as opposed to oxidation, thereby encouraging export of fat, ketones, and glucose. Over the past 30 years, association studies and genetic manipulations, as well as lifestyle and pharmacological invention studies, have reported contrasting findings on the presence or physiological importance of mitochondrial dysfunction in the context of obesity and insulin resistance. Biopsies of skeletal muscle from subjects with type 2 diabetes and obesity reveal lower density of mitochondria and smaller size; size correlating to whole body insulin sensitivity.

  • Rigoni, and M. Moreno-Loshuertos, A.

  • This, in turn, contributes diabetse the development and progression of diabetic complications and to worsening of the diabetic state per se. In particular, altered activity of uncoupling protein 2 UCP2the UCP subtype expressed in islets, would be important given its effect of reducing ATP production at any given level of fuel oxidation.

  • Download other formats More. Among the peripheral signals, there is little doubt about the important role played by leptin.

  • Genetics of mitochondrial dysfunction and infertility. Kipanyula, M.

  • Both Mfn1 and Mfn2 KO mice died in the middle of the gestation period 35as a consequence of mitochondrial fusion failure in the placenta. Mfn2 exerts a key role in the brain, protecting against neurodegeneration in different brain regions, such as the cerebellum, hippocampus, and cortex 45and in different populations such as dopaminergic neurons 46 ,

Koves et al. Overview Abstract Mitochondrial abnormalities have been reported in both insulin-deficient and insulin-resistant states mitochondrial dysfunction in obesity and diabetes in the diabetds condition of obesity. MitoQ also has metabolic effects when added to mitochondria, including uncoupling properties, so one can speculate that mitochondrial-targeted agents like coenzyme Q might be potentially useful in treating obesity. There have been recent studies of intrinsic respiration by heart and skeletal muscle mitochondria isolated from tissues of type 2 diabetic models. E: william-sivitz uiowa.

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Also, a significant relation between obesity in midlife, and the risk of developing dementia later in life has emerged in several epidemiological studies [ — ]. Premature ovarian insufficiency: the context of long-term effects. It comprises two functional domains: the soluble portion, F 1 situated in the matrix, and the F o part embedded in the IMM. Barrett-Connor, C. Porcelli, A.

Mitochondrial Morphology, Fission, and Fusion Beyond, mitochondrial function, type 2 diabetes is associated with changes in imtochondrial size, number, and morphology of muscle mitochondria. In India, about In this context the determination of whether mitochondrial transfer in obesity and diabetes is a friend or foe requires further studies. He J, Watkins S, Kelley DE, Skeletal muscle lipid content and oxidative enzyme activity in relation to muscle fiber type in type 2 diabetes and obesity, Diabetes, ; — The above findings appear applicable to the pathogenesis of human type 2 diabetes, since reduced mitochondrial function in adipose tissue would result in net lipolysis. Matschinsky FM, Glaser B, Magnuson MA, Pancreatic betacell glucokinase: closing the gap between theoretical concepts and experimental realities, Diabetes, ; —

SGLT2-inhibitor and DPP-4 inhibitor improve brain function via attenuating mitochondrial dysfunction, insulin resistance, inflammation, and apoptosis in HFD-induced obese rats. Liu, and H. Diet-induced obesity and the mechanism of leptin resistance. The combination of different events related to mitochondrial movements, such as fusion, fission, mitophagy, and tethering, are responsible for the mitochondrial architecture.

Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice. Roberts and J. Growth differentiation factor 15 is a myomitokine governing systemic energy homeostasis. Cell Cycle —

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While this phenomenon has been investigated primarily in the context of cancer and a variety of inflammatory states, little is known about the importance of exosomal mitochondrial transfer in obesity and diabetes. Diabeges adenine dinucleotide NADH oxidoreductase and citrate synthase activity were mitichondrial to be reduced in mitochondria isolated from human muscle biopsy specimens obtained obesity and diabetic and obese subjects compared with lean subjects. In particular, altered activity of uncoupling protein 2 UCP2the UCP subtype expressed in islets, would be important given its effect of reducing ATP production at any given level of fuel oxidation. The consequent increase in fatty acid release could contribute to the insulin resistance of type 2 diabetes, since fatty acids impair muscle and liver insulin sensitivity. This, in turn, contributes to the development and progression of diabetic complications and to worsening of the diabetic state per se. Pharmacologic efforts to improve mitochondrial function go back to the s when attempts were made to treat human obesity with the mitochondrial chemical uncoupler dinitrophenol. Boudina et al.

Diabetes and obesity are also associated with the overproduction of mitochondrial reactive oxygen species ROSleading to mitochondrial and cellular oxidative damage. These investigators reported decreased respiration on complex I substrates and on palmitoyl—carnitine, associated with proportionally reduced ATP production and decreased content of the F1 alpha-subunit of ATP synthase. Brownlee M, Biochemistry and molecular cell biology of diabetic complications, Nature, ;— Figure 3 represents a simplistic and hypothetical overview of this process. Over the past 30 years, association studies and genetic manipulations, as well as lifestyle and pharmacological invention studies, have reported contrasting findings on the presence or physiological importance of mitochondrial dysfunction in the context of obesity and insulin resistance. Overview Abstract Mitochondrial abnormalities have been reported in both insulin-deficient and insulin-resistant states and in the related condition of obesity. Boudina et al.

Moreover, ROS appear important in mediating oxidative damage to non-insulinsensitive target cells, contributing to the long-term complications of diabetes. This, in turn, contributes to the development and progression of diabetic complications mitochondrial dysfunction in obesity and diabetes to worsening of the diabetic state per se. Hopefully, further understanding will lead to approaches that effectively target mitochondria within multiple tissues in a way that mitigates the pathophysiology involved in the onset and progression of type 2 diabetes. Beyond ROS production, there is evidence for oxidative damage in animals and humans with diabetes. Superoxide is known to activate UCPs, possibly as a feedback means of protection from further radical generation through reduction of membrane potential. Both defects are recognizable early on and present even in non-diabetic offspring of patients with type 2 diabetes.

These are lipophilic cations avidly taken up into the relatively negative mitochondrial matrix. S-nitrosylation of Drp1 mediates beta-amyloid-related mitochondrial fission and neuronal injury. Pappas, B.

Dyefunction, E. The dynamin-related GTPase Dnm1 regulates mitochondrial fission in yeast. Exercise increases mitochondrial biogenesis through effects on PGC-1 86,87 and activates adenosine monophosphate AMP -activated protein kinase AMPKwhich improves both glucose and fat oxidation. Lane and W. Studies investigating mutations showed that an overexpression of FIS1 produced mitochondrial fragmentation, and knock down of this protein caused a highly fused mitochondrial network, indicating that FIS1 activates mitochondrial fission 57 — Yu et al.

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Nicotinamide adenine dinucleotide NADH oxidoreductase and citrate synthase activity were noted to be reduced in mitochondria isolated from human muscle biopsy specimens obtained from diabetic and obese subjects compared with lean subjects. Hopefully, further understanding will lead to approaches that effectively target mitochondria within multiple tissues mitochondrial dysfunction in obesity and diabetes a way that mitigates the pathophysiology involved in the onset and progression of type 2 diabetes. Of additional note is that oxidative stress is well known to trigger the formation of advanced glycation end-products such as carboxymethyl lysine CML. As depicted in Figure 2, any alteration in mitochondrial function that could change ATP production would have a major impact on the capacity of glucose to trigger insulin secretion. This ideology may be influenced by societal pressures as a slim […]. In insulin-resistant or hyperinsulinemic mice, Foxa2 is inactive and confined to the cytoplasm of hepatocytes, 36 promoting lipid accumulation as opposed to oxidation, thereby encouraging export of fat, ketones, and glucose. As noted above, impaired calcium signaling has been noted in islets of hyperglycemic insulin-resistant MKR mice.

In this paradigm, islets exposed to high concentrations of glucose or fatty acids may generate more superoxide see below. In India, about A novel regulatory mechanism altered in obesity, J Biol Chem, ;—7. European Endocrinology.

European Endocrinology. Certain peptides containing tyrosine residues have been found to effectively scavenge oxygen radicals and peroxynitrite and inhibit lipid peroxidation. For example, cultured hepatocytes exposed to high glucose generate more glycogen rather than increase respiration, potential, or reducing equivalents 62 and some studies do not support and effect of glucose to induce ROS at the cell level. Boudina et al. At cellular and molecular levels the pathogenesis of diabetes becomes far more complex.

These are lipophilic cations avidly taken up into the relatively negative mitochondrial matrix. How do the above findings translate to insulin resistance? Over the past 30 years, association studies and genetic manipulations, as dysfuncction as lifestyle and pharmacological invention diabetes, have reported contrasting findings on the presence or physiological importance of mitochondrial dysfunction in the context of obesity and insulin resistance. Studies using 13C NMR to assess tricarboxylic acid TCA flux rates along with 31P NMR to assess phosphorylation of adenosine diphosphate ADP demonstrated impaired skeletal muscle oxidative phosphorylation, increased intra-myocellular lipid, and decreased TCA cycle substrate oxidation in insulin-resistant offspring of individuals with type 2 diabetes. Moreover, ROS appear important in mediating oxidative damage to non-insulinsensitive target cells, contributing to the long-term complications of diabetes.

Other studies of mitochondria or saponin-permeabilized muscle fibers isolated from humans with type 2 diabetes showed impairments in oxygen consumption 14,15 even when normalized for mitochondrial content. Abstract Obesity, insulin resistance and type 2 diabetes are accompanied by a variety of systemic and tissue-specific metabolic defects, including inflammation, oxidative and endoplasmic reticulum stress, lipotoxicity, and mitochondrial dysfunction. Several studies have provided evidence for mitochondrial dysfunction in skeletal muscle of type 2 diabetic and prediabetic subjects, primarily due to a lower content of mitochondria mitochondrial biogenesis and possibly to a reduced functional capacity per mitochondrion. Hopefully, further understanding will lead to approaches that effectively target mitochondria within multiple tissues in a way that mitigates the pathophysiology involved in the onset and progression of type 2 diabetes.

  • Trajectories of glycaemia, insulin sensitivity and insulin secretion in South Asian and white individuals before diagnosis of type 2 diabetes: a longitudinal analysis from the Whitehall II cohort study.

  • As noted above, impaired calcium signaling has been noted in islets of hyperglycemic insulin-resistant MKR mice. US Endocrinology.

  • Martone, S. The evidence regarding the relevance of mitochondrial function in glucose homeostasis is extensive.

  • Int Health. The protease presenilin-associated rhomboid-like PARL regulates oxidative phosphorylation in skeletal muscle and insulin signaling; knockdown of PARL causes malformation of the cristae, increases oxidative stress, and impairs insulin signaling [ ].

  • Exercise increases mitochondrial biogenesis through effects on PGC-1 86,87 and activates adenosine monophosphate AMP -activated protein kinase AMPKwhich improves both glucose and fat oxidation.

Koves et al. In this way, Szendroedi et al. Obesity, insulin resistance and type 2 diabetes daibetes accompanied by a variety of systemic and tissue-specific metabolic defects, including inflammation, oxidative and endoplasmic reticulum stress, lipotoxicity, and mitochondrial dysfunction. Pharmacologic efforts to improve mitochondrial function go back to the s when attempts were made to treat human obesity with the mitochondrial chemical uncoupler dinitrophenol. These are lipophilic cations avidly taken up into the relatively negative mitochondrial matrix.

Mayeda, E. Similarly, melatonin can reduce mitochondrial oxidative stress and prevent fertility decline Measurement of plasma glucose, free fatty acid, lactate, and insulin for 24 h in patients with NIDDM. Even more, Mitifusin 1 has emerged as a nutrient sensor in hypothalamic POMC neurons that plays a key role in the central control of insulin release from the pancreas. Schwall, V.

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