review article mitochondrial dysfunction: a basic...

Hindawi Publishing CorporationMediators of InflammationVolume 2013 Article ID 135698 13 pageshttpdxdoiorg1011552013135698

Review ArticleMitochondrial Dysfunction A Basic Mechanism inInflammation-Related Non-Communicable Diseases andTherapeutic Opportunities

Anna Hernaacutendez-Aguilera1 Anna Rull1 Esther Rodriacuteguez-Gallego1 Marta Riera-Borrull1

Fedra Luciano-Mateo1 Jordi Camps1 Javier A Meneacutendez2 and Jorge Joven1

1 Unitat de Recerca Biomedica Hospital Universitari Sant Joan Institut drsquoInvestigacio Sanitaria Pere VirgiliUniversitat Rovira i Virgili carrer Sant Llorenc 21 43201 Reus Spain

2 Catalan Institute of Oncology and Girona Biomedical Research Institute Avda de Francia sn 1707 Girona Spain

Correspondence should be addressed to Jorge Joven jjovengrupsagessacom

Received 5 December 2012 Revised 1 February 2013 Accepted 1 February 2013

Academic Editor Fabio Santos Lira

Copyright copy 2013 Anna Hernandez-Aguilera et al This is an open access article distributed under the Creative CommonsAttribution License which permits unrestricted use distribution and reproduction in any medium provided the original work isproperly cited

Obesity is not necessarily a predisposing factor for disease It is the handling of fat andor excessive energy intake that encompassesthe linkage of inflammation oxidation and metabolism to the deleterious effects associated with the continuous excess of foodingestion The roles of cytokines and insulin resistance in excessive energy intake have been studied extensively Tobacco use andobesity accompanied by an unhealthy diet and physical inactivity are the main factors that underlie noncommunicable diseasesThe implication is that the management of energy or food intake which is the main role of mitochondria is involved in the mostcommon diseases In this study we highlight the importance of mitochondrial dysfunction in the mutual relationships betweencausative conditions Mitochondria are highly dynamic organelles that fuse and divide in response to environmental stimulidevelopmental status and energy requirementsThese organelles act to supply the cell with ATP and to synthesise key molecules inthe processes of inflammation oxidation and metabolism Therefore energy sensors and management effectors are determinantsin the course and development of diseases Regulating mitochondrial function may require a multifaceted approach that includesdrugs and plant-derived phenolic compounds with antioxidant and anti-inflammatory activities that improve mitochondrialbiogenesis and act to modulate the AMPKmTOR pathway

1 Background

The burden of noncommunicable diseases is increasing assuch diseases are now responsible for more than three infive deaths worldwide Atherosclerosis and cancer in whichtobacco use and excessive energy intake are determiningfactors are the most frequently occurring of these diseasesand are potentially preventable [1 2] Obesity and associ-ated metabolic disturbances which have been increasingworldwide in recent years are the main factors that underlienoncommunicable diseases and are the consequences ofunhealthy diets and physical inactivity [3] Approximately10ndash20 of patients with severe obesity defined as a bodymass index (BMI) gt 40 present with no other metabolic

complications These patients are referred to by the oxy-moronic designation of ldquometabolically healthyrdquo obese [4ndash7] Such a designation implies that most obese patients arenot ldquometabolically healthy rdquo Hence risk factors for theappearance of noncommunicable diseases have emergedThe reasons for these two phenotypes are unknown thephenotypes might represent different transitions on a diseasetimeline and different levels of either chronic inflammationor insulin resistance are likely contributors Other con-tributors include gradual differences in glucose toleranceinflammatory responses adipose tissue distribution patternsof adipokine secretion and age

Emerging obesogenic factors are likely to present withsignificant differences in the elderly and consequently the

2 Mediators of Inflammation

prevalence of obesity is expected to increase with increasingage Therefore it is likely not coincidental that most co-morbidity associated with obesity and hence with non-communicable diseases correlates with aging the processesmay share basic mechanisms particularly mitochondrial agewithin an individual [7] Of note the prevalence of obesity islower in people over 70 years of age an effect attributed to theselective mortality of middle-aged people [8]

Current recommendations to decrease food intake andincrease physical exercise do result in metabolic improve-ments but such lifestyle changes are rarely sustaineddespite strong motivation However several communitieshave undertaken initiatives to prevent noncommunicablediseases and the lessons learned from the implementation ofsuch initiatives should be examined further [9] The activemanipulation of energy sensors and effectors might be apossible alternative therapeutic procedure Our aim is toprovide a succinct review of the scarce and disseminateddata that link mitochondrial dysfunction to the pathogenesisof energy-related complications and to discuss a possiblemultifaceted therapeutic approach

2 Food Availability Links MitochondrialDysfunction and the Vicious Cycle ofOxidative Stress and Inflammation

Mitochondrial defects systemic inflammation and oxidativestress are at the root of most noncommunicable diseases suchas cancer atherosclerosis Parkinsonrsquos disease Alzheimerrsquosdisease other neurodegenerative diseases heart and lungdisturbances diabetes obesity and autoimmune diseases[10ndash16] Obesity and obesity-related complications as wellas impairment of mitochondrial function which is requiredfor normal metabolism and health (Figure 1) are universallyassociated with these conditions The exact mechanisms thatassociate mitochondrial dysfunction obesity and aging withmetabolic syndrome remain a topic of debate [17ndash22]

Body weight is controlled by molecular messengers thatregulate energy status in a limited number of susceptibletissues including the liver adipose tissue skeletal musclespancreas and the hypothalamus [7 23] Mouse models ofdiet-induced obesity have revealed important morphologicaland molecular differences with respect to humans particu-larly those related to the development of fatty liver (NAFLDnonalcoholic fatty liver disease) or nonalcoholic steatohep-atitis (NASH) [24ndash30] (Figure 2) High expectations fora human therapy after the generation of leptin-deficientanimals (ObOb) were countered by the determination thatleptin is not a therapeutic option in humans [28]

Endoplasmic reticulum (ER) and mitochondrial stresswith the consequent oxidative stress are immediate conse-quences of attempts to store excess food energy [23 29]Under normal weight conditions adipose tissue-derivedadipokines maintain the homeostasis of glucose and lipidmetabolism however in obese conditions the dysregu-lated production of adipokines favours the development ofmetabolic syndrome and related complications particularlythe accumulation of triglycerides in nonadipose organs that

are not designed to store energy [19] Other adipokines maycause inflammation and oxidative stress [31] but unknownfactors are involved because interventions to ameliorateinsulin resistance do not lead uniformly to clinical improve-ment [32] It is of paramount importance to understand themechanisms that disrupt ER homeostasis and lead to the acti-vation of the unfolded protein response and mitochondrialdefects in metabolic diseases in order to correctly managenoncommunicable diseases [33]

Incidentally the role of genetics in low-energy expendi-ture and chronic food intake although potentially significantremains poorly understood [29 30] The genetic-selectionhypothesis which attempts to explain the high prevalenceof obesity and diabetes in humans remains controversialsince the recent abandonment of the ldquothriftyrdquo gene hypothesis[34ndash38] As a result the roles of oxidative stress inflam-mation mitochondrial dysfunction nutritional status andmetabolism might be reinforced in hypotheses regarding thepathogenesis of noncommunicable diseases (Figures 3 and 4)

Inflammation plays a vital role in host defence Tissuedamage fibrosis and losses of function occur under chronicinflammatory conditions Growing evidence links a low-grade chronic inflammatory state to obesity and its coexist-ing conditions as well as to noncommunicable diseases [10ndash16] This low-grade inflammatory state is aggravated by therecruitment of inflammatory cells mainly macrophages toadipose tissue Inflammatory cell recruitment is likely due tothe combined effects of the complex regulatory network ofcells and mediators that are designed to resolve inflamma-tory responses [7] Anti-inflammatory drugs have shown toreverse insulin resistance and other related conditions thatresult from circulating cytokines that cause and maintaininsulin resistance [19 23 39ndash42] Therefore it is likely thatinflammation per se is a causal factor for noncommunicablediseases rather than an associated risk factor

It is also important to highlight that adipose tissueis comprised of multiple types of cells that have intrin-sic and important endocrine functions particularly thosemediated by leptin and adiponectin Recruited and res-ident macrophages secrete the majority of inflammatoryadipokines specifically tumour necrosis factor 120572 (TNF120572)interleukin-6 (IL-6) andmonocyte chemoattractant protein-1 (MCP-1) among others The major roles of TNF120572 andother inflammatory cytokines in the progression ofmetaboliccomplications are likely related to oxidative stress [43 44]In adipose tissue macrophages increased concentrations ofsaturated free fatty acids (FFAs) stimulate the synthesis ofTNF120572 directly through the Toll-like receptor 4 (TLR4) orindirectly through cellular accumulation Both macrophagesand adipocytes possess TLR4 receptors that upon lipid-dependent activation induce NF-KB translocation to thenucleus and the subsequent synthesis of TNF120572 and IL-6[7 43 44] However recruited macrophages have uniqueinflammatory properties that are not observed in residenttissue macrophages and the recruitment of these cells ismainly modulated by MCP-1 the most important moleculeof the CC chemokine family [7] In this setting the rolesand polarisation of adipose tissue macrophages (ATMs)seem established [45] M1 or ldquoclassically activatedrdquo ATMs

Mediators of Inflammation 3

Oxidative burst InflammationLow cellular functionInsulin resistance

Mild Severe

Oxidative stressInflammationAgingHigh-fat diets

Mitochondrial dysfunction

Health

Figure 1Mutations inmitochondrial DNA are accompanied by different disease-suggestive phenotypes (myopathies neuropathies diabetesand signs of reduced lifespan and premature aging) Severe mitochondrial dysfunction triggers a high level of oxidative and inflammatorydamage impairs tissue function and promotes age-related diseases

(a)

(b)

Figure 2 Clinically it is evident that in severe obesity (a) the presence of liver steatosis may vary from more than 80 to less than 5 ofpatients Conversely in most obese patients with some degree of liver steatosis (b) this condition disappeared in a relatively brief period oftime after significant weight loss due to bariatric surgery

are increased and M2 or ldquoalternatively activatedrdquo ATMs aredecreased in the adipose tissues of both obesemice and obesehumans as discussed below [46 47]

It is frequently assumed that in contrast to hormoneschemokines influence cellular activities in an autocrine orparacrine fashion However chemokines may be relevant

effectors in chronic systemic inflammation as the confine-ment of these molecules to well-defined environments isunlikely Specifically alterations in plasmaMCP-1 concentra-tions in metabolic disease states the presence of circulatingchemokine reservoirs recent evidence of novel mechanismsof action and certain unexplained responses associated with


Electron transport chainMalate-aspartate shuttle

High caloric intake


TAC cycle120573-oxidationHeme synthesis

Mitochondrial efficiencyHealth

Disease

Matrix

Inner membraneMetabolic syndrome Aging

Apoptosis

Adipocyte Stem cells

Caloric restriction

Figure 3 The mitochondrial matrix hosts the mitochondrial metabolic pathways (TAC cycle 120573-oxidation and haem synthesis) and theinner membrane contains the electron transport chain complexes and ATP synthase Exchange carriers such as the malate-aspartate shuttleare also essential Under caloric restriction the mitochondrion achieves the highest efficiency and high caloric intake produces dysfunctionand a consequent increase in apoptosis which promotes metabolic syndrome and age-related diseases

Mitochondria

Iron-sulfurclusters

Catabolicreactions

AnabolicreactionsAgeing

Apoptosis regulation

Figure 4 Schematic and abridged representation of the multipleroles of mitochondria in cellular processes that are associated withthe pathogenesis of the more prevalent diseases

metabolic disturbances suggest that MCP-1 might have asystemic role inmetabolic regulation [48ndash50]How andwhenobesity might initiate an inflammatory response remainscontroversial but the underlying mechanism likely dependson the activation of the c-Jun N-terminal kinase (JNK)in insulin-sensitive tissues as JNK is likely the principalmechanism through which inflammatory signals interferewith insulin activity [7]

ER stress responses and mitochondrial defects are alsolinked to the mTOR pathway discussed below which isessential for the regulation of numerous processes includingthe cell cycle energy metabolism the immune response andautophagy Therefore the specific cellular changes associatedwith metabolic alterations particularly mitochondrial dys-function require further attention

3 Mitochondria Bioenergy CouplesMetabolism Oxidation and Inflammation

Mitochondria are essential organelles that among otherfunctions supply the cell with ATP through oxidative phos-phorylation synthesise key molecules and buffer calciumgradients however they are also a source of free radicals(Figures 1 3 and 4) It is not surprising that mitochondrialhealth is tightly regulated and associated with the home-ostasis and aging of the organism Within these processesthe antagonistic and balanced activities of the fusion andfission machineries constantly provide adequate responsesto events caused by inflammation (Figure 5) [23 50ndash54]A shift towards fusion favours the generation of intercon-nected mitochondria which contribute to the dissipationand rapid provision of energy A shift towards fissionresults in numerous mitochondrial fragments Apparentlythe mixing of the matrix and the inner membrane allowsthe respiratory machinery components to cooperate mostefficiently Furthermore fusion maximises ATP synthesisIn quiescent cells mitochondria are frequently present asnumerous morphologically and functionally distinct smallspheres or short rods [51 55 56] Upon the exposure ofcells to stress fusion optimises mitochondrial function and


5 120583m

(a)

5 120583m

(b)

Figure 5 Mitochondrial fusion (a) and fission (b) processes in the liver (arrows) Mitochondrial morphology is basically controlled bymetabolism and inflammation and each change in morphology is mediated by large guanosine triphosphatases of the dynamin familyconsistent with a model in which the capacity for oxidative phosphorylation is maximised under stressful conditions

500 nm

Figure 6 The complete elimination of mitochondria by autophagy(arrow) is a process linked to mitochondrial fission and fusionMitochondria also employ quality-control proteases to eliminatedamaged molecules through the transcriptional induction of chap-erones or the ubiquitin proteasome quality-control pathway

plays a beneficial role in the maintenance of long-termbioenergetics capacities In contrast the mitochondrial fis-sion machinery contributes to the elimination of irreversiblydamaged mitochondria through autophagy [55ndash58] Thisprocess also called mitophagy is extremely important underboth physiological and pathological conditions (Figure 6)A detailed discussion of the importance of mitophagy isbeyond the scope of this review however as an exampleof its importance recall that amino acids are not storedin the body but are instead mobilised by proteolysis underconditions such as starvation reduced physical activity anddisease [59] Furthermore intense exercise may modulatehepatic metabolism through similar mechanisms [60] Morerecently the mitochondrial E3 ubiquitin protein ligase 1 (Mul1) was identified as a key protein that promotes mitophagyand skeletal muscle loss [61] Mitochondrial fission per setriggers organelle dysfunction and muscle loss The oppositeis observedwhenmitochondrial fission is inhibitedThe same

authors [61] also demonstrated that the overexpression ofForkhead box O3 (FoxO3) induces mitochondrial disruptionvia mitophagy

Therefore it is not surprising that mitochondrial diseasesoften have an associated metabolic component and con-sequently mitochondrial defects are expected in inflamma-tion aging and other energy-dependent disturbances [5862] In such disturbances cellular oxidative damage causedby the generation of reactive oxygen species (ROS) thatexceed the natural antioxidant activity is likely an initiatingfactor in inflammation and aging [63 64] Several poten-tial therapeutic approaches are currently available to slowdown age-related functional declines [65] including antiox-idant treatments [66] however the effectiveness of existingantioxidants is likely suboptimal because these antioxidantsare not selective for mitochondria [67] However recentexperiments with a mitochondria-targeted antioxidant havebeen successful in animal models [67] Similar assumptionscan be made for endothelial cells in which oxidation andthe accompanying inflammation are recognised factors foratherosclerosis Oxidative stress which is mainly derivedfrom mitochondrial dysfunction decreases NO synthesiscontributes to hypertension upregulates the secretion ofadhesion molecules and inflammatory cytokines and isresponsible for the oxidation of low-density lipoproteins [6869]

Defective mitochondrial function in muscle tissues leadsto reduced fatty acid oxidation and the inhibition of glucosetransport indicating that insulin-stimulated glucose trans-port is reduced This is a hallmark of insulin resistance andtype 2 diabetes The chronic production of excess ROS andinflammation result inmitochondrial dysfunction potentiallyinducing lipid accumulation in these tissues and the endlessvicious cycle of insulin resistance [70ndash74] MitochondrialROS have also been related to the increased activity ofuncoupling proteins (UCP) which uncouple ATP synthesisfromelectron transport UCP activity leads to heat generationwithout ATP production and long-term reductions in ATP


levels affect cellular insulin signalling The roles of the UCPsand the metabolically relevant differences between brownand white adipose tissues were reviewed recently [75ndash77]

The mitochondria of obese individuals are different fromthose of lean individuals Alterations in mitochondrial mor-phology impaired mitochondrial bioenergetics increasedmitochondrial lipid peroxides decreased ATP content andmitochondrial dysfunction further increase the risks of devel-oping metabolic complications [78 79] In comparison tothose of lean individuals mitochondria in obese individualshave lower energy-generating capacities less clearly definedinner membranes and reduced fatty acid oxidation Thesedifferences might promote the development and progressionof obesity and might also have therapeutic implications [8081] Impaired mitochondrial function could account for theinsulin resistance that is closely associated with increasedlipid content in the muscles of patients with type 2 diabetesAltered mitochondrial function is the major factor that leadsto increased muscular lipid accumulation and decreasedinsulin sensitivity [80 81]More recently amodel was createdin which the amount of mitochondrial activity in adipocytesand hepatocytes can be altered based on the properties ofthe mitochondrial protein mitoNEET which is located atthe outer membrane [70] Despite the prevalence of obesityin this model mitoNEET overexpression during periodsof high caloric intake resulted in systemwide improve-ments in insulin sensitivity thereby providing a model ofa ldquometabolically healthyrdquo obese state with minimal tissuelipotoxicity that is similar to the clinically observed condition[82] Alterations in mitoNEET expression might modulateROS concentrations and mitochondrial iron transport intothe matrix [70 82 83] The mitochondrial fusion proteinmitofusin-2 (Mfn-2) another useful protein in studies ofmitochondrial dysfunction regulates cellular metabolismand controls mitochondrial metabolism In cultured cellsmitochondrial metabolism was activated in Mfn-2 gain-of-function experiments whereas Mfn-2 loss-of-functionreduced glucose oxidation mitochondrial membrane poten-tial oxygen consumption and mitochondrial proton leakage[84] It is defective in themuscles of obese and type 2 diabetespatients in which mitochondrial size is reduced [71]

Therefore a detailed characterisation of the proteinsinvolved in mitochondrial fusion and fission and studies ofthemechanisms that regulate these two processes are relevantto human pathology and might have a great therapeuticpotential to improve metabolism and to decrease the genera-tion of oxidative stress and excessive inflammatory response[85]

4 Is There a Link between Mitochondria andNutrient Availability The Possible Roles ofInflammation and Apoptosis

Apoptosis is another basic process to consider in metabolicdiseases Excess food intake leads to mitochondrial dysfunc-tion and higher apoptotic susceptibility Mitochondria spe-cialise in energy production and cell killing Only 13 proteinsare encoded by the mitochondrial DNA a circular molecule

of 16 Kb The remaining necessary proteins are encoded inthe nuclear DNA [86] Mitochondria are composed of outerand inner specialised membranes that define two separatecomponents the matrix and the intermembrane space [87]Mitochondria regulate apoptosis in response to cellular stresssignals and determine whether cells live or die [88] Thus itis conceivable that the availability or ingestion of nutrientscould be a main candidate in the regulation of cell deathand that mitochondria could have been selected as a nutrientsensor and effector This could explain the influence ofapoptosis-related proteins onmitochondrial respiration [89]

A common laboratory finding is that the morphologyof the mitochondria changes when mice are supplied witha high-fat diet (Figure 7) and that optimal mitochondrialperformance is achieved under conditions of calorie restric-tion Excess food intake impairs respiratory capacities likelythrough mTOR and increases the susceptibility of thecell to apoptosis and additional stress [90 91] Of noteapoptotic protein levels are increased in the adipocytes ofobese humans and the depletion of proapoptotic proteinsprotects against liver steatosis and insulin resistance in micefed a high-fat high-cholesterol diet [92] These conditionsare relevant to the development of metabolic syndrome asnutritional imbalances inWestern diets lead tomitochondrialdysfunction and higher susceptibilities to inflammationapoptosis and aging [22]

5 AMP-Activated Protein Kinase (AMPK) NotOnly Influences Metabolism in Adipocytesbut Also Suppresses the ProinflammatoryEnvironment

AMPKhas anti-inflammatory actions that are independent ofits effects on glucose and lipid metabolism [93]The action ofAMPK is not necessarily identical in all tissues In adipose tis-sues the role ofAMPK is largely unknownbecause laboratorytechniques to explore the action of this kinase in terminallydifferentiated adipocytes have not been fully establishedSeveral agents have been used to activate AMPK experimen-tally including AICAR (51015840-aminoimidazole-4-carboxamideribonucleoside) metformin rosiglitazone resveratrol andother polyphenols statins and several adipocytokines Inadipocytes AMPK appears to increase the insulin-stimulateduptake of glucose likely by increasing the expression ofGLUT4 yet inhibits glucose metabolism [94] Studies of theeffects of AMPK on lipolysis in adipocytes have been con-troversial some authors have reported an antilipolytic effectwhile others have suggested that AMPK stimulates lipolysis[95 96] However the activation of AMPK by metforminin human adipose tissues increases the phosphorylation ofacetyl-CoA carboxylase (ACC) and decreases the expressionof lipogenic genes leading to reductions in malonyl-CoAwhich is the precursor for fatty acid synthesis malonyl-CoAalso regulates fatty acid oxidation through the inhibition ofcarnitine palmitoyl-transferase 1 the rate-limiting enzymefor fatty acid entry into the mitochondria [97 98] Adiposetissue secretes adipocytokines which influence metabolicand inflammatory pathways through the recruitment of


200 nm

(a)

200 nm

(b)

Figure 7 The nutrient availability of food in ldquonaturalrdquo conditions for mice is likely low and near the condition known as calorie restrictionIn the laboratory however mice are usually fed ad libitum and certain biases cannot be discarded However mitochondria from mice fed achow diet (a) display rapid morphological changes when mice are fed with high-fat diets (b)

macrophages and the consequent transition from the M2state to M1 [7 41] These actions contribute to the develop-ment of disease (Figure 8) Conversely adiponectin has beenreported to induce adiposemacrophages to switch to the anti-inflammatory M2 state [99] AMPK is anti-inflammatoryas it inhibits the synthesis of proinflammatory cytokinesand promotes the expression of IL-10 in macrophagesadiponectin and leptin levels may also be regulated by AMPK[100] (Figure 8) Finally brown adipocytes contain highnumbers of mitochondria that express UCP1 which permitthermogenesis Exposure to cold temperatures stimulatesAMPK and may play a role in the differentiation of fattyoxidising brown adipose tissue thus leading to greater energyexpenditure [101] Therefore we hypothesise that the chronicmanipulation of the AMPKmechanistic target of rapamycin(mTOR) pathway might represent a therapeutic approachfor preventing noncommunicable diseases (Figure 8) Met-formin along with salicylate polyphenols and rapamycinhas a long history of safe and effective use but othermodulators are currently under development and will likelypermit the design of tissue-specific activators of this pathway

6 Metformin andor Rapamycin andPlant-Derived Polyphenols An ApparentTreatment of Choice for MetabolicSyndrome and Obesity-RelatedComplications

The first therapeutic approaches to metabolic disturbancesare reduced caloric ingestion and increased physical activityThe effects are based mainly on weight reduction but useful-ness in other common complications remains incompletelyexplored [102] Bariatric surgery is also effective even inldquometabolically healthyrdquo patients [103 104] The effectivenessof surgery for the treatment of metabolic disturbances is sur-prisingly higher than expected and mechanisms associatedwith surgical effects are not completely understood

Insulin resistance and mitochondrial dysfunction appearto be the most significant alternative therapeutic targetsMetabolic abnormalities are associated with inflammationNormally glycolysis yields pyruvate which is further oxi-dised in the mitochondria When oxygen becomes limit-ing mitochondrial oxidative metabolism is restricted Theinduction of an inflammatory response is an energy-intensiveprocess and the involved cells rapidly switch from restingto highly active states This is observed in diseases suchas cancer atherosclerosis or autoimmune diseases andmechanistic insights suggest the common involvement of thetranscription factor hypoxia-inducible factor 1120572 AMPK andthe mTOR pathway In addition the activation of sirtuinswhich act as NAD+ sensors that connect nutrition andmetabolism to chromatin structure is anti-inflammatory[105] (Figure 8)

The use of metformin an AMPK activator used exten-sively to treat type 2 diabetes has been indicated for othermetabolic conditions based on the rationale that insulin-sensitising agents might be effective [106] and the mode ofaction ofmetformin has guided our own experiments on can-cer aging and viral infection [65 107 108] We have shownthat the beneficial effects of this biguanide class drug whichwas initially obtained from Galega officinalis are universalin patients with metabolic complications and negligible inpatients without such complications The primary effect isthought to be the suppression of hepatic glucose productionand hepatic lipogenesis [109] Metformin activates AMPKin hepatocytes resulting in the phosphorylation and inacti-vation of ACA a rate-limiting enzyme in lipogenesis [110]and theoretically might be useful and safe in the treatmentof NAFLD [111] Surprisingly the beneficial clinical effectsseem to be limited despite the effects of metformin oninsulin resistance most likely because long-term treatmentis an absolute requirement for the prevention of progressivedisease Our own current experiments in animal modelssuggest new insights into this phenomenon Metforminactivates AMPK but AMPK deficiency does not abolish


Adiponectin

Anti-inflammatoryenvironment Proinflammatory

environment

Obese

Lean

Blood vesselBlood vessel

Excessive energy intake

TNF-120572IL-6

MCP-1

IL-10

(a)

FOXOs

Polyphenols

Polyphenols

Inflammation

Rapamycin

Metformin

AMPK

mTOR Sirtuins

p53

(b)

Figure 8 Activation of AMPK inmacrophages promotes the switch from a proinflammatory to an anti-inflammatory phenotype by inducinga shift from glycolysis towards mitochondrial oxidative metabolism In obesity there may be a shift towards proinflammatory states whereasin dietary restriction the balance may shift towards anti-inflammatory phenotypes through the activation of AMPK (a) The activation ofAMPK implies the inhibition of mTOR and several compounds are known to regulate this pathway (b) The inhibition of mTOR extendslifespan in model organisms and confers protection against a growing list of age-related pathologies Several characterised inhibitors arealready clinically approved and others are under development

the effects of metformin on hepatic glucose productionindicating that the role of AMPK is dispensable as indicatedpreviously [112] This suggests that the overall effect ofmetformin is mediated through actions on mitochondrialfunction through decreases in the hepatic energy state andintracellular ATP content Other studies suggest that met-formin inhibits Complex I of the mitochondrial respiratorychain but the exact mechanisms and pathways involved areunclear [113] Sirtuin 3 (SIRT 3) a member of the familyof nicotinamide adenine dinucleotide (NAD+) dependentdeacetylase proteins is a crucial regulator of mitochondrialfunction that controls the global acetylation of the organelle(all sirtuins regulate energy production and the cell cycleFigure 8) SIRT3 induces the activity of Complex I and pro-motes oxidative phosphorylation In SIRT3 knockout micemitochondrial proteins are hyperacetylated and cellular ATPlevels are reduced effects that are aggravated by fasting[114] As a complement peroxisome proliferator-activatedreceptor gamma coactivator 1-alpha induces the expressionof SIRT3 in the liver [115] Therefore mitochondrial functionappears to be the key target of metformin reductions in ATPproduction may mediate the hepatic and antihyperglycemicactions of the drug and downregulate SIRT3 expression [116]However metformin distinctively regulates the expressionof different sirtuin family members [117 118] In summarymetformin acts against both insulin resistance andmitochon-drial dysfunction and is currently an attractive candidateagent of choice in the management of metabolic disordersWe have recently reviewed this complex scenario and foundthe following (1) the unique ability of metformin to activateAMPK while leading to the increased utilisation of energyoccurs because metformin inhibits AMP deaminase and(2) in metabolic tissues metformin can inhibit cell growth

by functionally mimicking the effects of a multitargetedantifolate [119]

Based on these and other findings we have also demon-strated that plant-derived phenolic compounds interact withnumerous targets and multiple deregulated signalling path-ways that may be useful in the management of metabolicconditions [120ndash123] The proposed mechanisms are directantioxidant activity attenuation of endoplasmic reticulumstress blockade of proinflammatory cytokines and block-ade of transcription factors related to metabolic diseases[120] Most polyphenols modulate oxidative stress andinflammatory responses through relevant actions in theprocess of macrophage recruitment Interactions betweenthe chemokinecytokine network and bioenergetics likelythrough the mTOR pathway may also represent potentialmechanisms for the prevention of metabolic disturbances[121] Moreover polyphenols attenuate the metabolic effectsof high-fat high-cholesterol diets when administered contin-uously at high doses andwe have described beneficial actionsassociated with the expression of selected microRNAs [122]

Inflammation lies at the heart of many diseases becausethe entire body is under metabolic stress which inducessymptoms and causes morbidity Targeting altered metabolicpathways in inflammation may enhance our understandingof disease pathogenesis and point the way to new therapiesAs mentioned metformin polyphenols AICAR salicylatesand corticoids all activate the AMPKmTOR pathway Newcompounds such as A-769662 are under scrutiny Finallyrapamycin which is also known as sirolimus and wasfirst isolated from Streptomyces hygroscopicus and severalderivative compounds including everolimus temsirolimusridaforolimus umirolimus and zotarolimus have beenapproved for a variety of uses including posttransplantation


therapy the prevention of restenosis following angioplastyand as a treatment for certain forms of cancer Drugs thatinhibit the mTOR pathway could one day be used widelyto slow aging and reduce age-related pathologies in humans[124] The development of chemical inhibitors of mTOR aswell as drugs that target other components of the mTORpathway promises to aid research greatlywhile also providingdrugs with potential therapeutic value

7 Perspectives and Implications

Obesity metabolic alterations and age-related diseases arecomplex conditions that require a multifaceted approachthat includes action on both the chemokine network andenergy metabolism [123 125] The underlying mechanismsare far from being understood [126] although the associationbetween obesity and insulin resistance seems to be wellsubstantiated However obesity is not distributed normallythroughout the population and type 2 diabetes mellitus isnot associated closely with increased body weight also therelationship with noncommunicable diseases is not straight-forward A working hypothesis is that adipose tissue hasa limited maximum capacity to increase in mass Oncethe adipose tissue has reached the expansion limit fat isdeposited in the liver and muscle tissues and causes insulinresistance This process is also associated with the activationof macrophages oxidative stress and inflammation whichproduce cytokines that have negative effects on insulinsensitivity induce the secretion of adipokines that causeinsulin resistance and suppress those that promote insulinsensitivity However a host of other mechanisms must beinvolved because metabolic responses are different amongpatients with maximum adipose tissue expansion A morepopular and recent hypothesis suggests a differential effectof lipophagy which implies a tissue-selective autophagy withcellular consequences from the mobilisation of intracellularlipids Defective lipophagy is linked to fatty liver tissues andobesity and might be the basis for age-related metabolicsyndrome [127] Increased adipose tissue autophagy maybe responsible for more efficient storage Autophagy alsoaffectsmetabolism oxidation and proinflammatory cytokineproduction Very recent evidence suggests that autophagyis increased in the adipose tissues of obese patients [128]Inexpensive and well-tolerated molecules such as chloro-quine metformin and polyphenols already exist and couldbe used to fine-tune the metabolic alterations derived froman excess of energy and more specifically to modulateautophagy in the liver Whether these therapies will dampenthe genetic expression of factors that affect the developmentof noncommunicable diseases remains to be ascertained

Acknowledgments

The Unitat de Recerca Biomedica is currently being sup-ported by Grants from the Fondo de Investigacion Sanitaria(FIS PI081032 PI1100130) E Rodrıguez-Gallego is therecipient of a fellowship from the Generalitat de Catalunya(2012FI B 00389) and M Riera-Borrull is the recipient of

a fellowship from the Universitat Rovira i Virgili (2010PFR-URV-B2-58)

References

[1] K Strong CMathers S Leeder and R Beaglehole ldquoPreventingchronic diseases how many lives can we saverdquoThe Lancet vol366 no 9496 pp 1578ndash1582 2005

[2] M Cecchini F Sassi J A Lauer Y Y Lee V Guajardo-Barron andD Chisholm ldquoTackling of unhealthy diets physicalinactivity and obesity health effects and cost-effectivenessrdquoTheLancet vol 376 no 9754 pp 1775ndash1784 2010

[3] T A Gaziano G Galea and K S Reddy ldquoScaling up interven-tions for chronic disease prevention the evidencerdquoThe Lancetvol 370 no 9603 pp 1939ndash1946 2007

[4] E A H Sims ldquoAre there persons who are obese but metaboli-cally healthyrdquoMetabolism vol 50 no 12 pp 1499ndash1504 2001

[5] N Stefan K Kantartzis J Machann et al ldquoIdentification andcharacterization of metabolically benign obesity in humansrdquoArchives of Internal Medicine vol 168 no 15 pp 1609ndash16162008

[6] G Iacobellis M C Ribaudo A Zappaterreno C V Iannucciand F Leonetti ldquoPrevalence of uncomplicated obesity in anItalian obese populationrdquo Obesity Research vol 13 no 6 pp1116ndash1122 2005

[7] A Rull J Camps C Alonso-Villaverde and J Joven ldquoInsulinresistance inflammation and obesity role of monocytechemoattractant protein-1 (orCCL2) in the regulation ofmetabolismrdquo Mediators of Inflammation vol 2010 Article ID326580 11 pages 2010

[8] J B Meigs I Lipinska S Kathiresan et al ldquoVisceral and subcu-taneous adipose tissue volumes are cross-sectionally related tomarkers of inflammation and oxidative stress the framinghamheart studyrdquo Circulation vol 116 no 11 pp 1234ndash1241 2007

[9] D Dowell and T A Farley ldquoPrevention of non-communicablediseases in New York Cityrdquo The Lancet vol 380 no 9855 pp1787ndash1792 2012

[10] DMArduıno A R Esteves and SMCardoso ldquoMitochondriadrive autophagy pathology via microtubule disassembly a newhypothesis for Parkinson diseaserdquo Autophagy vol 9 no 1 pp112ndash114 2013

[11] H Kumar HW Lim S V More et al ldquoThe role of free radicalsin the aging brain and Parkinsonrsquos disease convergence andparallelismrdquo International Journal of Molecular Science vol 13no 8 pp 10478ndash10504 2012

[12] G Medina-Gomez ldquoMitochondria and endocrine function ofadipose tissuerdquo Best Practice amp Research Clinical Endocrinologyamp Metabolism vol 26 no 6 pp 791ndash804 2012

[13] G Pagano G Castello and F V Pallardo ldquoSjoslashgrenrsquos syndrome-associated oxidative stress and mitochondrial dysfunctionprospects for chemoprevention trialsrdquo Free Radical Researchvol 47 no 2 pp 71ndash73 2013

[14] J OuyangMWuCHuang L Cao andG Li ldquoOverexpressionof oxidored-nitro domain containing protein 1 inhibits humannasopharyngeal carcinoma and cervical cancer cell prolifer-ation and induces apoptosis involvement of mitochondrialapoptotic pathwaysrdquoOncology Reports vol 29 no 1 pp 79ndash862013

[15] L D Osellame T S Blacker and M R Duchen ldquoCellularand molecular mechanisms of mitochondrial functionrdquo BestPractice amp Research Clinical Endocrinology amp Metabolism vol26 no 6 pp 711ndash723 2012


[16] I Enache A L Charles J Bouitbir et al ldquoSkeletal muscle mito-chondrial dysfunction precedes right ventricular impairment inexperimental pulmonary hypertensionrdquoMolecular and CellularBiochemistry vol 373 no 1-2 pp 161ndash170 2013

[17] L W Chol ldquoMetabolic syndromerdquo Singapore Medical Journalvol 52 no 11 pp 779ndash785 2011

[18] M R Souza F D Mde J E Medeiros-Filho and M S AraujoldquoMetabolic syndrome and risk factors for non-alcoholic fattyliver diseaserdquo Arquivos de Gastroenterologia vol 49 no 1 pp89ndash96 2012

[19] M S Mirza ldquoObesity visceral fat and NAFLD querying therole of adipokines in the progression of nonalcoholic fatty liverdiseaserdquo ISRN Gastroenterology vol 2011 Article ID 592404 11pages 2011

[20] G Tarantino S Savastano and A Colao ldquoHepatic steatosislow-grade chronic inflammation and hormonegrowth fac-toradipokine imbalancerdquo World Journal of Gastroenterologyvol 16 no 38 pp 4773ndash4783 2010

[21] C Vernochet and C R Kahn ldquoMitochondria obesity andagingrdquo Aging vol 4 no 12 pp 1ndash2 2012

[22] F Pintus G Floris and A Rufini ldquoNutrient availability linksmitocondria apoptosis and obesityrdquo Aging vol 4 no 11 pp 1ndash8 2012

[23] M M Rogge ldquoThe role of impaired mitochondrial lipidoxidation in obesityrdquo Biological Research for Nursing vol 10 no4 pp 356ndash373 2009

[24] M Vinaixa M A Rodrıguez A Rull et al ldquoMetabolomicassessment of the effect of dietary cholesterol in the progres-sive development of fatty liver diseaserdquo Journal of ProteomeResearch vol 9 no 5 pp 2527ndash2538 2010

[25] A Rull M Vinaixa M Angel Rodrıguez et al ldquoMetabolic phe-notyping of genetically modified mice an NMR metabonomicapproachrdquo Biochimie vol 91 no 8 pp 1053ndash1057 2009

[26] J Joven A Rull N Ferre et al ldquoThe results in rodent modelsof atherosclerosis are not interchangeable The influence of dietand strainrdquo Atherosclerosis vol 195 no 2 pp e85ndashe92 2007

[27] M Tous N Ferre J Camps F Riu and J Joven ldquoFeed-ing apolipoprotein E-knockout mice with cholesterol and fatenriched diets may be amodel of non-alcoholic steatohepatitisrdquoMolecular and Cellular Biochemistry vol 268 no 1-2 pp 53ndash582005

[28] P Lindstrom ldquo120573-cell function in obese-hyperglycemic mice[obob mice]rdquo Advances in Experimental Medicine and Biologyvol 654 pp 463ndash477 2010

[29] S de Ferranti and D Mozaffarian ldquoThe perfect storm obesityadipocyte dysfunction and metabolic consequencesrdquo ClinicalChemistry vol 54 no 6 pp 945ndash955 2008

[30] L Xu X Ma B Cui X Li G Ning and S Wang ldquoSelection ofreference genes for qRT-PCR in high fat diet-induced hepaticsteatosis mice modelrdquo Molecular Biotechnology vol 48 no 3pp 255ndash262 2011

[31] M V Machado J Coutinho F Carepa A Costa H Proencaand H Cortez-Pinto ldquoHow adiponectin leptin and ghrelinorchestrate together and correlate with the severity of nonalco-holic fatty liver diseaserdquo European Journal of Gastroenterologyand Hepatology vol 24 no 10 pp 1166ndash1172 2012

[32] J C Cohen J D Horton and H H Hobbs ldquoHuman fatty liverdisease old questions and new insightsrdquo Science vol 332 no6037 pp 1519ndash1523 2011

[33] M J Pagliassotti ldquoEndoplasmic reticulum stress in nonalco-holic fatty liver diseaserdquo Annual Review of Nutrition vol 32 pp17ndash33 2012

[34] J V Neel ldquoDiabetes mellitus a ldquothriftyrdquo genotype rendereddetrimental by lsquoprogressrsquordquo The American Journal of HumanGenetics vol 14 pp 352ndash353 1962

[35] J V Neel ldquoUpdate to lsquoThe study of natural selection in primitiveand civilized human populationsrsquordquo Human Biology vol 61 no5-6 pp 811ndash823 1989

[36] A R Frisancho ldquoReduced rate of fat oxidation a metabolicpathway to obesity in the developing nationsrdquo The AmericanJournal of Human Biology vol 15 no 4 pp 522ndash532 2003

[37] J R Speakman ldquoA novel non-adaptive scenario explainingthe genetic pre-disposition to obesity the ldquopredation releaserdquohypothesisrdquo Cell Metabolism vol 6 no 1 pp 5ndash12 2007

[38] J R Speakman and S OrsquoRahilly ldquoFat an evolving issuerdquoDiseaseModels and Mechanisms vol 5 no 5 pp 569ndash573 2012

[39] B Rius C Lopez-Vicario A Gonzalez-Periz et al ldquoResolutionof inflammation in obesity-induced liver diseaserdquo Frontiers inImmunology vol 3 article 257 2012

[40] A Paul L Calleja J Camps et al ldquoThe continuous administra-tion of aspirin attenuates atherosclerosis in apolipoprotein E-deficient micerdquo Life Sciences vol 68 no 4 pp 457ndash465 2000

[41] M Tous N Ferre A Rull et al ldquoDietary cholesterol and dif-ferential monocyte chemoattractant protein-1 gene expressionin aorta and liver of apo E-deficient micerdquo Biochemical andBiophysical Research Communications vol 340 no 4 pp 1078ndash1084 2006

[42] L Masana M Camprubi P Sarda R Sola J Joven and P RTurner ldquoThemediterranean-type diet is there a need for furthermodificationrdquo The American Journal of Clinical Nutrition vol53 no 4 pp 886ndash889 1991

[43] A P Rolo J S Teodoro and C M Palmeira ldquoRole of oxidativestress in the pathogenesis of nonalcoholic steatohepatitisrdquo FreeRadical Biology and Medicine vol 52 no 1 pp 59ndash69 2012

[44] B Mlinar and J Marc ldquoNew insights into adipose tissuedysfunction in insulin resistancerdquo Clinical Chemistry and Lab-oratory Medicine vol 29 no 12 pp 1925ndash1935 2011

[45] C N Lumeng J L Bodzin and A R Saltiel ldquoObesity induces aphenotypic switch in adipose tissue macrophage polarizationrdquoJournal of Clinical Investigation vol 117 no 1 pp 175ndash184 2007

[46] M E Shaul G Bennett K J Strissel A S Greenberg andM S Obin ldquoDynamic M2-like remodeling phenotypes ofCD11c+ adipose tissue macrophages during high-fat dietmdashinduced obesity in micerdquo Diabetes vol 59 no 5 pp 1171ndash11812010

[47] J M Wentworth G Naselli W A Brown et al ldquoPro-inflammatory CD11c+CD206+ adipose tissue macrophages areassociated with insulin resistance in human obesityrdquo Diabetesvol 59 no 7 pp 1648ndash1656 2010

[48] A Rull R Beltran-Debon G Aragones et al ldquoExpression ofcytokine genes in the aorta is altered by the deficiency in MCP-1 effect of a high-fat high-cholesterol dietrdquo Cytokine vol 50no 2 pp 121ndash128 2010

[49] M L Batista S B Peres M E McDonald et al ldquoAdipose tissueinflammation and cancer cachexia possible role of nucleartranscription factorsrdquo Cytokine vol 57 no 1 pp 9ndash16 2012

[50] A Rull J C Escola-Gil J Julve et al ldquoDeficiency in mono-cyte chemoattractant protein-1 modifies lipid and glucosemetabolismrdquoExperimental andMolecular Pathology vol 83 no3 pp 361ndash366 2007

[51] B Coll C Alonso-Villaverde and J Joven ldquoMonocyte chemoat-tractant protein-1 and atherosclerosis Is there room for anadditional biomarkerrdquo Clinica Chimica Acta vol 383 no 1-2pp 21ndash29 2007


[52] B Westermann ldquoMitochondrial fusion and fission in cell lifeand deathrdquo Nature Reviews Molecular Cell Biology vol 11 no12 pp 872ndash884 2010

[53] D C Chan ldquoMitochondrial fusion and fission in mammalsrdquoAnnual Review of Cell and Developmental Biology vol 22 pp79ndash99 2006

[54] D HMargineantuW G Cox L Sundell SW Sherwood J MBeechem andR A Capaldi ldquoCell cycle dependentmorphologychanges and associated mitochondrial DNA redistribution inmitochondria of human cell linesrdquoMitochondrion vol 1 no 5pp 425ndash435 2002

[55] A E Frazier C Kiu D Stojanovski N J Hoogenraad andM T Ryan ldquoMitochondrial morphology and distribution inmammalian cellsrdquoBiological Chemistry vol 387 no 12 pp 1551ndash1558 2006

[56] BWestermann ldquoBioenergetic role of mitochondrial fusion andfissionrdquo Biochimica et Biophysica Acta vol 1817 no 10 pp 1833ndash1838 2012

[57] J C Chang S J Kou W T Lin and C S Liu ldquoRegulatory roleof mitochondria in oxidative stress and atherosclerosisrdquo WorldJournal of Cardiology vol 2 no 6 pp 150ndash159 2010

[58] D C Chan ldquoMitochondria dynamic organelles in diseaseaging and developmentrdquo Cell vol 125 no 7 pp 1241ndash12522006

[59] K C Fearon D J Glass and D C Guttridge ldquoCancer cachexiamediators signaling andmetabolic pathwaysrdquoCellMetabolismvol 16 no 2 pp 153ndash166 2012

[60] F S Lira L C Carnevali N E Zanchi R V T Santos J MLavoie and M Seelaender ldquoExercise intensity modulation ofhepatic lipid metabolismrdquo Journal of Nutrition and Metabolismvol 2012 Article ID 809576 8 pages 2012

[61] S Lokireddy I W Wijesoma S Teng et al ldquoThe ubiquitinligase mul1 induces mitophagy in skeletal muscle in responseto muscle-wasting stimulirdquo Cell Metabolism vol 16 no 5 pp613ndash624 2012

[62] M Banasch M Ellrichmann A Tannapfel W E Schmidtand O Goetze ldquoThe non-invasive 13C-methionine breath testdetects hepatic mitochondrial dysfunction as a marker of dis-ease activity in non-alcoholic steatohepatitisrdquo European Journalof Medical Research vol 16 no 6 pp 258ndash264 2011

[63] W Droge and H M Schipper ldquoOxidative stress and aberrantsignaling in aging and cognitive declinerdquo Aging Cell vol 6 no3 pp 361ndash370 2007

[64] M E Witte J J G Geurts H E de Vries P van der Valkand J vanHorssen ldquoMitochondrial dysfunction a potential linkbetween neuroinflammation and neurodegenerationrdquo Mito-chondrion vol 10 no 5 pp 411ndash418 2010

[65] J AMenendez S Cufi C Oliveras-Ferraros L Vellon J Jovenand A Vazquez-Martin ldquoGerosuppressant metformin less ismorerdquo Aging vol 3 no 4 pp 348ndash362 2011

[66] S I Rattan ldquoAnti-ageing strategies prevention or therapyShowing ageing from withinrdquo EMBO Reports vol 6 pp S25ndashS29 2005

[67] V B Saprunova M A Lelekova N G Kolosova and L EBakeeva ldquoSkQ1 slows development of age-dependent destruc-tive processes in retina and vascular layer of eyes of wistar andOXYS ratsrdquo Biochemistry vol 77 no 6 pp 648ndash658 2012

[68] T F Liu C M Brown M El Gazzar et al ldquoFueling the flamebioenergy couples metabolism and inflammationrdquo Journal ofLeukocyte Biology vol 92 no 3 pp 499ndash507 2012

[69] E Profumo B Buttari L Petrone et al ldquoRedox imbalance of redblood cells impacts T lymphocyte homeostasis implication incarotid atherosclerosisrdquo Journal ofThrombosis andHaemostasisvol 106 no 6 pp 1117ndash1126 2011

[70] C M Kusminski W L Holland K Sun et al ldquoMitoNEET-driven alterations in adipocyte mitochondrial activity reveal acrucial adaptative process that preserves insulin sensitivity inobesityrdquo Nature Medicine vol 18 no 10 pp 1539ndash1549 2012

[71] A Zorzano M Liesa and M Palacın ldquoRole of mitochondrialdynamics proteins in the pathophysiology of obesity and type 2diabetesrdquo International Journal of Biochemistry and Cell Biologyvol 41 no 10 pp 1846ndash1854 2009

[72] C Aguer and M E Harper ldquoSkeletal muscle mitochondrialenergetics in obesity and type 2 diabetes mellitus endocrineaspectsrdquo Best Practice amp Research Clinical Endocrinology ampMetabolism vol 26 no 6 pp 805ndash819 2012

[73] Z AMa ldquoThe role of peroxidation ofmitochondrialmembranephospholipids in pancreatic 120573-cell failurerdquo Current DiabetesReviews vol 8 no 1 pp 69ndash75 2012

[74] C Tang K Koulajian I Schuiki et al ldquoGlucose-induced betacell dysfunction in vivo in rats link between oxidative stress andendoplasmic reticulum stressrdquo Diabetologia vol 55 no 5 pp1366ndash1379 2012

[75] A Lde Brondani T S Assmann G C Duarte J L Gross L HCanani and D Crispim ldquoThe role of the uncoupling protein1 (UCP1) on the development of obesity and type 2 diabetesmellitusrdquo Arquivos Brasileiros de Endocrinologia e Metabologiavol 56 no 4 pp 215ndash225 2012

[76] A Fedorenko P V Lishko and Y Kirichok ldquoMechanism offatty-acid-dependent UCP1 uncoupling in brown fat mitochon-driardquo Cell vol 151 no 2 pp 400ndash413 2012

[77] B Cannon and J Nedergaard ldquoCell biology neither brown norwhiterdquo Nature vol 488 no 7411 pp 286ndash287 2012

[78] I Grattagliano O de Bari T C Bernardo P J OliveiraD Q Wang and P Portincasa ldquoRole of mitochondria innonalcoholic fatty liver diseasemdashfrom origin to propagationrdquoClinical Biochemistry vol 45 no 9 pp 610ndash618 2012

[79] G Serviddio F Bellanti G Vendemiale and E AltomareldquoMitochondrial dysfunction in nonalcoholic steatohepatitisrdquoExpert Review of Gastroenterology and Hepatology vol 5 no2 pp 233ndash244 2011

[80] N C Sadler T E Angel M P Lewis et al ldquoActivity-based protein profiling reveals mitochondrial oxidative enzymeimpairment and restoration in diet-induced obese micerdquo PLoSONE vol 7 no 10 Article ID e47996 2012

[81] M Carrer N Liu C E Grueter et al ldquoControl ofmitochondrialmetabolism and systemic energy homeostasis by microRNAs378 and 378rdquo Proceedings of the National Academy of Sciencesof the United States of America vol 109 no 38 pp 15330ndash153352012

[82] A D Karelis M Faraj J P Bastard et al ldquoThe metabolicallyhealthy but obese individual presents a favorable inflammationprofilerdquo Journal of Clinical Endocrinology and Metabolism vol90 no 7 pp 4145ndash4150 2005

[83] C M Kusminski and P E Scherer ldquoMitochondrial dysfunc-tion in white adipose tissuerdquo Trends in Endocrinology andMetabolism vol 23 no 9 pp 435ndash443 2012

[84] A Zorzano M I Hernandez-Alvarez M Palacın and G Min-grone ldquoAlterations in the mitochondrial regulatory pathwaysconstituted by the nuclear co-factors PGC-1120572 or PGC-1120573 andmitofusin 2 in skeletal muscle in type 2 diabetesrdquo Biochimica etBiophysica Acta vol 1797 no 6-7 pp 1028ndash1033 2010


[85] A Zorzano D Sebastian J Segales and M Palacın ldquoThemolecular machinery of mitochondrial fusion and fission anopportunity for drug discoveryrdquo Current Opinion in DrugDiscovery and Development vol 12 no 5 pp 597ndash606 2009

[86] X J Chen and R A Butow ldquoThe organization and inheritanceof the mitochondrial genomerdquo Nature Reviews Genetics vol 6no 11 pp 815ndash825 2005

[87] A M Distler J Kerner and C L Hoppel ldquoProteomics ofmitochondrial inner and outer membranesrdquo Proteomics vol 8no 19 pp 4066ndash4082 2008

[88] L Galluzzi I Vitale J M Abrams et al ldquoMolecular def-initions of cell death subroutines recommendations of thenomenclature committee on cell death 2012rdquo Cell Death andDifferentiation vol 19 pp 107ndash120 2012

[89] N Joza G Y Oudit D Brown et al ldquoMuscle-specific loss ofapoptosis-inducing factor leads to mitochondrial dysfunctionskeletalmuscle atrophy and dilated cardiomyopathyrdquoMolecularand Cellular Biology vol 25 no 23 pp 10261ndash10272 2005

[90] J R Speakman and S E Mitchell ldquoCaloric restrictionrdquo Molec-ular Aspects of Medicine vol 32 no 3 pp 159ndash221 2011

[91] A Raffaello and R Rizzuto ldquoMitochondrial longevity path-waysrdquo Biochimica et Biophysica Acta vol 1813 no 1 pp 260ndash268 2011

[92] N Alkhouri A Gornicka M P Berk et al ldquoAdipocyte apop-tosis a link between obesity insulin resistance and hepaticsteatosisrdquoThe Journal of Biological Chemistry vol 285 no 5 pp3428ndash3438 2010

[93] I P Salt and T M Palmer ldquoExploiting the anti-inflammatoryeffects of AMP-activated protein kinase activationrdquo ExpertOpinion on Investigational Drugs vol 21 no 8 pp 1155ndash11672012

[94] J G Boyle P J Logan G C Jones et al ldquoAMP-activated proteinkinase is activated in adipose tissue of individuals with type2 diabetes treated with metformin a randomised glycaemia-controlled crossover studyrdquo Diabetologia vol 54 no 7 pp1799ndash1809 2011

[95] J E Sullivan K J Brocklehurst A E Marley F Carey D Car-ling and R K Beri ldquoInhibition of lipolysis and lipogenesis inisolated rat adipocytes with AICAR a cell-permeable activatorof AMP-activated protein kinaserdquo FEBS Letters vol 353 no 1pp 33ndash36 1994

[96] W Yin J Mu and M J Birnbaum ldquoRole of AMP-activatedprotein kinase in cyclic AMP-dependent lipolysis in 3T3-L1adipocytesrdquoThe Journal of Biological Chemistry vol 278 no 44pp 43074ndash43080 2003

[97] M P Gaidhu S Fediuc and R B Ceddia ldquo5-Aminoimidazole-4-carboxamide-1-120573-D-ribofuranoside-induced AMP-activatedprotein kinase phosphorylation inhibits basal and insulin-stimulated glucose uptake lipid synthesis and fatty acid oxi-dation in isolated rat adipocytesrdquo The Journal of BiologicalChemistry vol 281 no 36 pp 25956ndash25964 2006

[98] M P Gaidhu S Fediuc N M Anthony et al ldquoProlongedAICAR-inducedAMP-kinase activation promotes energy dissi-pation in white adipocytes novel mechanisms integrating HSLandATGLrdquo Journal of Lipid Research vol 50 no 4 pp 704ndash7152009

[99] A T Turer and P E Scherer ldquoAdiponectin mechanistic insightsand clinical implicationsrdquo Diabetologia vol 55 no 9 pp 2319ndash2326 2012

[100] S Galic M D Fullerton J D Schertzer et al ldquoHematopoieticAMPK 1205731 reduces mouse adipose tissue macrophage inflam-mation and insulin resistance in obesityrdquo Journal of ClinicalInvestigation vol 121 no 12 pp 4903ndash4915 2011

[101] R Vila-BedmarM Lorenzo and S Fernandez-Veledo ldquoAdeno-sine 51015840-monophosphate-activated protein kinase-mammaliantarget of rapamycin cross talk regulates brown adipocyte dif-ferentiationrdquo Endocrinology vol 151 no 3 pp 980ndash992 2010

[102] O Horakova D Medrikova E M van Schothorst et alldquoPreservation of metabolic flexibility in skeletal muscle by acombined use of n-3 PUFA and rosiglitazone in dietary obesemicerdquo PLoS ONE vol 7 no 8 Article ID e43764 2012

[103] V T To T P Huttl R Lang K Piotrowski and K G ParhoferldquoChanges in body weight glucose homeostasis lipid profilesand metabolic syndrome after restrictive bariatric surgeryrdquoExperimental and Clinical Endocrinology and Diabetes vol 120no 9 pp 547ndash552 2012

[104] H M Heneghan S Nissen and P R Schauer ldquoGastrointestinalsurgery for obesity and diabetes weight loss and control ofhyperglycemiardquo Current Atherosclerosis Reports vol 14 no 6pp 579ndash587 2012

[105] A Luke J OrsquoNeill andDHardie ldquoMetabolism of inflammationlimited by AMPK and pseudo-starvationrdquo Nature vol 493 pp346ndash355 2013

[106] C Finelli and G Tarantino ldquoIs there any consensus as to whatdiet of lifestyle approach is the right one for NAFLD patientsrdquoJournal of Gastrointestinal and Liver Diseases vol 21 pp 293ndash302 2012

[107] J Joven J Menendez L Fernandez-Sender et al ldquoMetformina cheap and well-tolerated drug that provides benefits for viralinfectionsrdquo HIV Medicine 2012

[108] S Del Barco A Vazquez-Martin S Cufı et al ldquoMetforminmulti-faceted protection against cancerrdquo Oncotarget vol 2 no12 pp 896ndash917 2011

[109] B Viollet B Guigas N Sanz Garcia J Leclerc M Foretz and FAndreelli ldquoCellular and molecular mechanisms of metforminan overviewrdquo Clinical Science vol 122 no 6 pp 253ndash270 2012

[110] S Nair A M Diehl M Wiseman G H Farr and R P PerrilloldquoMetformin in the treatment of non-alcoholic steatohepatitis apilot open label trialrdquo Alimentary Pharmacology and Therapeu-tics vol 20 no 1 pp 23ndash28 2004

[111] ADuseja ADas R KDhiman et al ldquoMetformin is effective inachieving biochemical response in patients with nonalcoholicfatty liver disease (NAFLD) not responding to lifestyle interven-tionsrdquo Annals of Hepatology vol 6 no 4 pp 222ndash226 2007

[112] J W Haukeland Z Konopsi H B Eggesbo et al ldquoMetforminin patients with non-alcoholic fatty liver disease a randomizedcontrolled trialrdquo Scandinavian Journal of Gastroenterology vol44 no 7 pp 853ndash860 2009

[113] M Foretz S Hebrard J Leclerc et al ldquoMetformin inhibits hep-atic gluconeogenesis inmice independently of the LKB1AMPKpathway via a decrease in hepatic energy staterdquo Journal ofClinical Investigation vol 120 no 7 pp 2355ndash2369 2010

[114] M R Owen E Doran and A P Halestrap ldquoEvidence thatmetformin exerts its anti-diabetic effects through inhibition ofcomplex 1 of the mitochondrial respiratory chainrdquo BiochemicalJournal vol 348 no 3 pp 607ndash614 2000

[115] BH AhnH S Kim S Song et al ldquoA role for themitochondrialdeacetylase Sirt3 in regulating energy homeostasisrdquo Proceedingsof the National Academy of Sciences of the United States ofAmerica vol 105 no 38 pp 14447ndash14452 2008


[116] X Kong R Wang Y Xue et al ldquoSirtuin 3 a new target ofPGC-1120572 plays an important role in the suppression of ROS andmitochondrial biogenesisrdquo PLoS ONE vol 5 no 7 Article IDe11707 2010

[117] M Buler S M Aatsinki V Izzi and J Hakkola ldquoMet-formin reduces hepatic expression of SIRT3 the mitochondrialdeacetylase controlling energy metabolismrdquo PLoS ONE vol 7no 11 Article ID e49863 2012

[118] P W Caton N K Nayuni J Kieswich N Q Khan M MYaqoob and R Corder ldquoMetformin suppresses hepatic gluco-neogenesis through induction of SIRT1 and GCN5rdquo Journal ofEndocrinology vol 205 no 1 pp 97ndash106 2010

[119] B Corominas-Faja R Quirantes-Pine C Oliveras-Ferraros etal ldquoMetabolomic fingerprint reveals that metformin impairsone-carbon metabolism in a manner similar to the antifolateclass of chemotherapy drugsrdquo Aging vol 4 no 7 pp 480ndash4982012

[120] R Beltran-Debon A Rull F Rodrıguez-Sanabria et alldquoContinuous administration of polyphenols from aqueousrooibos (Aspalathus linearis) extract ameliorates dietary-induced metabolic disturbances in hyperlipidemic micerdquo Phy-tomedicine vol 18 no 5 pp 414ndash424 2011

[121] J Joven A Rull E Rodrıguez-Gallego et al ldquoMultifunc-tional targets of dietary polyphenols in disease a case forthe chemokine network and energy metabolismrdquo Food andChemical Toxicology vol 51 pp 267ndash279 2013

[122] J Joven E Espinel A Rull et al ldquoPlant-derived polyphenolsregulate expression of miRNA paralogs miR-103107 and miR-122 and prevent diet-induced fatty liver disease in hyperlipi-demic micerdquo Biochimica et Biophysica Acta no 7 pp 894ndash8991820

[123] A Segura-Carretero M A Puertas-Mejıa S Cortacero-Ramırez et al ldquoSelective extraction separation and identifi-cation of anthocyanins from Hibiscus sabdariffa L using solidphase extraction-capillary electrophoresis-mass spectrometry(time-of-flightion trap)rdquo Electrophoresis vol 29 no 13 pp2852ndash2861 2008

[124] S C Johnson P S Rabinovitch and M Kaeberlein ldquomTOR isa key modulator of ageing and age-related diseaserdquo Nature vol493 pp 338ndash345 2013

[125] M Herranz-Lopez S Fernandez-Arroyo A Perez-Sanchez etal ldquoSynergism of plant-derived polyphenols in adipogenesisperspectives and implicationsrdquo Phytomedicine vol 19 no 3-4pp 253ndash261 2012

[126] S Virtue and A Vidal-Puig ldquoItrsquos not how fat you are itrsquos whatyou do with it that countsrdquo PLoS Biology vol 6 no 9 articlee237 2008

[127] R Singh and A M Cuervo ldquoLipophagy connecting autophagyand lipid metabolismrdquo International Journal of Cell Biology vol2012 Article ID 282041 12 pages 2012

[128] H J Jansen P van Essen T Koenen L A Joosten M G Neteaand C J Tack ldquoAutophagy activity is up-regulated in adiposetissue of obese individuals and modulates proinflammatorycytokine expressionrdquo Endocrinology vol 153 no 12 pp 5866ndash5874 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


prevalence of obesity is expected to increase with increasingage Therefore it is likely not coincidental that most co-morbidity associated with obesity and hence with non-communicable diseases correlates with aging the processesmay share basic mechanisms particularly mitochondrial agewithin an individual [7] Of note the prevalence of obesity islower in people over 70 years of age an effect attributed to theselective mortality of middle-aged people [8]

Current recommendations to decrease food intake andincrease physical exercise do result in metabolic improve-ments but such lifestyle changes are rarely sustaineddespite strong motivation However several communitieshave undertaken initiatives to prevent noncommunicablediseases and the lessons learned from the implementation ofsuch initiatives should be examined further [9] The activemanipulation of energy sensors and effectors might be apossible alternative therapeutic procedure Our aim is toprovide a succinct review of the scarce and disseminateddata that link mitochondrial dysfunction to the pathogenesisof energy-related complications and to discuss a possiblemultifaceted therapeutic approach

2 Food Availability Links MitochondrialDysfunction and the Vicious Cycle ofOxidative Stress and Inflammation

Mitochondrial defects systemic inflammation and oxidativestress are at the root of most noncommunicable diseases suchas cancer atherosclerosis Parkinsonrsquos disease Alzheimerrsquosdisease other neurodegenerative diseases heart and lungdisturbances diabetes obesity and autoimmune diseases[10ndash16] Obesity and obesity-related complications as wellas impairment of mitochondrial function which is requiredfor normal metabolism and health (Figure 1) are universallyassociated with these conditions The exact mechanisms thatassociate mitochondrial dysfunction obesity and aging withmetabolic syndrome remain a topic of debate [17ndash22]

Body weight is controlled by molecular messengers thatregulate energy status in a limited number of susceptibletissues including the liver adipose tissue skeletal musclespancreas and the hypothalamus [7 23] Mouse models ofdiet-induced obesity have revealed important morphologicaland molecular differences with respect to humans particu-larly those related to the development of fatty liver (NAFLDnonalcoholic fatty liver disease) or nonalcoholic steatohep-atitis (NASH) [24ndash30] (Figure 2) High expectations fora human therapy after the generation of leptin-deficientanimals (ObOb) were countered by the determination thatleptin is not a therapeutic option in humans [28]

Endoplasmic reticulum (ER) and mitochondrial stresswith the consequent oxidative stress are immediate conse-quences of attempts to store excess food energy [23 29]Under normal weight conditions adipose tissue-derivedadipokines maintain the homeostasis of glucose and lipidmetabolism however in obese conditions the dysregu-lated production of adipokines favours the development ofmetabolic syndrome and related complications particularlythe accumulation of triglycerides in nonadipose organs that

are not designed to store energy [19] Other adipokines maycause inflammation and oxidative stress [31] but unknownfactors are involved because interventions to ameliorateinsulin resistance do not lead uniformly to clinical improve-ment [32] It is of paramount importance to understand themechanisms that disrupt ER homeostasis and lead to the acti-vation of the unfolded protein response and mitochondrialdefects in metabolic diseases in order to correctly managenoncommunicable diseases [33]

Incidentally the role of genetics in low-energy expendi-ture and chronic food intake although potentially significantremains poorly understood [29 30] The genetic-selectionhypothesis which attempts to explain the high prevalenceof obesity and diabetes in humans remains controversialsince the recent abandonment of the ldquothriftyrdquo gene hypothesis[34ndash38] As a result the roles of oxidative stress inflam-mation mitochondrial dysfunction nutritional status andmetabolism might be reinforced in hypotheses regarding thepathogenesis of noncommunicable diseases (Figures 3 and 4)

Inflammation plays a vital role in host defence Tissuedamage fibrosis and losses of function occur under chronicinflammatory conditions Growing evidence links a low-grade chronic inflammatory state to obesity and its coexist-ing conditions as well as to noncommunicable diseases [10ndash16] This low-grade inflammatory state is aggravated by therecruitment of inflammatory cells mainly macrophages toadipose tissue Inflammatory cell recruitment is likely due tothe combined effects of the complex regulatory network ofcells and mediators that are designed to resolve inflamma-tory responses [7] Anti-inflammatory drugs have shown toreverse insulin resistance and other related conditions thatresult from circulating cytokines that cause and maintaininsulin resistance [19 23 39ndash42] Therefore it is likely thatinflammation per se is a causal factor for noncommunicablediseases rather than an associated risk factor

It is also important to highlight that adipose tissueis comprised of multiple types of cells that have intrin-sic and important endocrine functions particularly thosemediated by leptin and adiponectin Recruited and res-ident macrophages secrete the majority of inflammatoryadipokines specifically tumour necrosis factor 120572 (TNF120572)interleukin-6 (IL-6) andmonocyte chemoattractant protein-1 (MCP-1) among others The major roles of TNF120572 andother inflammatory cytokines in the progression ofmetaboliccomplications are likely related to oxidative stress [43 44]In adipose tissue macrophages increased concentrations ofsaturated free fatty acids (FFAs) stimulate the synthesis ofTNF120572 directly through the Toll-like receptor 4 (TLR4) orindirectly through cellular accumulation Both macrophagesand adipocytes possess TLR4 receptors that upon lipid-dependent activation induce NF-KB translocation to thenucleus and the subsequent synthesis of TNF120572 and IL-6[7 43 44] However recruited macrophages have uniqueinflammatory properties that are not observed in residenttissue macrophages and the recruitment of these cells ismainly modulated by MCP-1 the most important moleculeof the CC chemokine family [7] In this setting the rolesand polarisation of adipose tissue macrophages (ATMs)seem established [45] M1 or ldquoclassically activatedrdquo ATMs



Mild Severe



Health


(a)

(b)







High caloric intake




Disease

Matrix


Apoptosis


Caloric restriction


Mitochondria

Iron-sulfurclusters

Catabolicreactions









5 120583m

(a)

5 120583m

(b)


500 nm

















200 nm

(a)

200 nm

(b)








Adiponectin


environment

Obese

Lean



TNF-120572IL-6

MCP-1

IL-10

(a)

FOXOs

Polyphenols

Polyphenols

Inflammation

Rapamycin

Metformin

AMPK

mTOR Sirtuins

p53

(b)










Acknowledgments



References










































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















Mild Severe



Health


(a)

(b)







High caloric intake




Disease

Matrix


Apoptosis


Caloric restriction


Mitochondria

Iron-sulfurclusters

Catabolicreactions









5 120583m

(a)

5 120583m

(b)


500 nm

















200 nm

(a)

200 nm

(b)








Adiponectin


environment

Obese

Lean



TNF-120572IL-6

MCP-1

IL-10

(a)

FOXOs

Polyphenols

Polyphenols

Inflammation

Rapamycin

Metformin

AMPK

mTOR Sirtuins

p53

(b)










Acknowledgments



References










































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















High caloric intake




Disease

Matrix


Apoptosis


Caloric restriction


Mitochondria

Iron-sulfurclusters

Catabolicreactions









5 120583m

(a)

5 120583m

(b)


500 nm

















200 nm

(a)

200 nm

(b)








Adiponectin


environment

Obese

Lean



TNF-120572IL-6

MCP-1

IL-10

(a)

FOXOs

Polyphenols

Polyphenols

Inflammation

Rapamycin

Metformin

AMPK

mTOR Sirtuins

p53

(b)










Acknowledgments



References










































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















5 120583m

(a)

5 120583m

(b)


500 nm

















200 nm

(a)

200 nm

(b)








Adiponectin


environment

Obese

Lean



TNF-120572IL-6

MCP-1

IL-10

(a)

FOXOs

Polyphenols

Polyphenols

Inflammation

Rapamycin

Metformin

AMPK

mTOR Sirtuins

p53

(b)










Acknowledgments



References










































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























200 nm

(a)

200 nm

(b)








Adiponectin


environment

Obese

Lean



TNF-120572IL-6

MCP-1

IL-10

(a)

FOXOs

Polyphenols

Polyphenols

Inflammation

Rapamycin

Metformin

AMPK

mTOR Sirtuins

p53

(b)










Acknowledgments



References










































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Adiponectin


environment

Obese

Lean



TNF-120572IL-6

MCP-1

IL-10

(a)

FOXOs

Polyphenols

Polyphenols

Inflammation

Rapamycin

Metformin

AMPK

mTOR Sirtuins

p53

(b)










Acknowledgments



References










































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















Acknowledgments



References










































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of










































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article mitochondrial dysfunction: a basic...

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