CoChat
Sign Up
Cited by 246Adipose Tissue and MetabolismMitochondrial Function and PathologyPeroxisome Proliferator-Activated Receptors

Mitochondrial fatty acid oxidation in obesity

Open access
Serra, Dolors, Mera, Paula, Malandrino, Maria Ida, Mir, Joan Francesc, Herrero, Laura·2013·Antioxidants & Redox Signaling
DOI 10.1089/ars.2012.4875PMC PMC3691913
Open this paper in CoChat — free account

Abstract

SIGNIFICANCE: Current lifestyles with high-energy diets and little exercise are triggering an alarming growth in obesity. Excess of adiposity is leading to severe increases in associated pathologies, such as insulin resistance, type 2 diabetes, atherosclerosis, cancer, arthritis, asthma, and hypertension. This, together with the lack of efficient obesity drugs, is the driving force behind much research. RECENT ADVANCES: Traditional anti-obesity strategies focused on reducing food intake and increasing physical activity. However, recent results suggest that enhancing cellular energy expenditure may be an attractive alternative therapy. CRITICAL ISSUES: This review evaluates recent discoveries regarding mitochondrial fatty acid oxidation (FAO) and its potential as a therapy for obesity. We focus on the still controversial beneficial effects of increased FAO in liver and muscle, recent studies on how to potentiate adipose tissue energy expenditure, and the different hypotheses involving FAO and the reactive oxygen species production in the hypothalamic control of food intake. FUTURE DIRECTIONS: The present review aims to provide an overview of novel anti-obesity strategies that target mitochondrial FAO and that will definitively be of high interest in the future research to fight against obesity-related disorders.

AI snapshot

Written from the paper’s full text.

TL;DR

This review evaluates mitochondrial fatty acid oxidation (FAO) and its potential as an anti-obesity therapy, focusing on the controversial beneficial effects of increased FAO in liver and muscle, strategies to potentiate adipose tissue energy expenditure, and hypotheses linking FAO and reactive oxygen species (ROS) to hypothalamic control of food intake. It concludes that targeting FAO and cellular energy expenditure may offer future therapies for obesity and its associated diseases, though several open questions remain.

Key findings

  • Enhancing liver FAO via overexpression of a malonyl-CoA-insensitive CPT1A mutant (CPT1AM) in obese rodents rescues impaired hepatic, muscle, and WAT insulin signaling and reduces steatosis, inflammation, and adiposity, without increasing ROS derivatives or liver injury.
  • In skeletal muscle, the role of FAO is contested: exercise, direct CPT1 overexpression, and indirect CPT1 activation (AMPK activators, ACC2 knockout) improve insulin sensitivity, but a high-fat diet also induces muscle mitochondrial biogenesis and β-oxidation, and incomplete FAO with acylcarnitine accumulation correlates negatively with glucose tolerance.
  • In WAT, direct CPT1A overexpression improves insulin sensitivity and suppresses inflammatory signaling, but there is still no evidence that increasing adipose tissue FAO decreases FFA-induced ROS production.
  • In the hypothalamus, pharmacological and genetic inhibition of CPT1A reduces food intake; malonyl-CoA, LCFA-CoA, and ROS are all proposed mediators, with UCP2 acting as a ROS scavenger to maintain physiological NPY/AgRP expression.

Methods

This is a narrative review; no primary data, sample, or statistical analysis are reported. It synthesizes in vitro, rodent, and human studies on mitochondrial FAO across liver, WAT, BAT, skeletal muscle, and hypothalamus, and discusses CPT1/AMPK/sirtuin regulation, ROS biology, and anti-obesity drug status (Orlistat and Lorcaserin as the only FDA-approved weight-loss drugs at the time).

Limitations

The paper states several open questions: whether long-term increased energy expenditure triggers compensatory appetite enhancement; whether increased FAO could induce pathological ROS or incomplete oxidation products; whether FAO enhancement reaches a tissue-specific limit (e.g., BAT thermogenesis tied to environmental temperature); and whether improved mitochondrial FAO is physiologically relevant if the individual remains sedentary or warm. The text also makes evident that data on hepatic FAO rates and CPT1A activity in NAFLD/NASH are inconclusive due to differing models and parameters, and that the role of ROS in hypothalamic food-intake control requires further research.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1089/ars.2012.4875

Cites

182 of 182 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 126 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    In a NASH rat model fed a methionine-choline-deficient diet, CPT1A activity and mitochondrial FAO were notably reduced despite increased CPT1A mRNA expression.

    “In this study, a NASH rat model fed a methionine-choline-deficient diet had a notable reduction in CPT1A activity and mitochondrial FAO despite increased CPT1A mRNA expression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [150] source

      Not checked in the free run.

  • Premisecitation

    When adipose tissue cannot store excess fat, lipids accumulate inappropriately in the liver, muscle, and pancreas.

    “When the adipose tissue cannot store excess fat, lipids accumulate inappropriately in the liver, muscle, and pancreas.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [145] source

      Not checked in the free run.

  • Interpretationreasoning

    Reduction in malonyl-CoA levels leads to an increase in CPT1 activity and FAO.

    “In consequence, the reduction in malonyl-CoA levels leads to an increase in CPT1 activity and FAO.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Formation of a 4-hydroxynonenal-CPT1 adduct caused by lipid peroxidation as a consequence of ROS overproduction is the main cause of impaired FAO and lipid removal from hepatocytes.

    “The formation of a 4-hydroxynonenal-CPT1 adduct caused by lipid peroxidation as a consequence of ROS overproduction is the main cause of impaired FAO and lipid removal from hepatocytes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [150] source

      Not checked in the free run.

  • Interpretationreasoning

    The liver can deal with an increased flux of fatty acids into mitochondria, thus escaping liver injury.

    “It seems that the liver can deal with an increased flux of FA into the mitochondria, thus escaping from liver injury.”
    Quote in the paperSubstantial claim
  • May combine two claims. 37
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Premisecitation

    Malonyl-CoA regulates FAO by inhibiting CPT1, making CPT1 the rate-limiting step in mitochondrial oxidation of fatty acids.

    “Malonyl-CoA, a molecule derived from glucose metabolism and the first intermediate in lipogenesis, regulates FAO by inhibiting CPT1, thus making this enzyme the rate-limiting step in mitochondrial oxidation of FAs.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    CPT1 overexpression and increased CPT1 activity occur in liver during onset of steatosis as a mechanism to compensate for increased fatty acid levels.

    “The observations listed above suggest that CPT1 overexpression and increased CPT1 activity occur in liver during the onset of steatosis as a mechanism to compensate for increased FA levels.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Imbalance between lipid inputs and outputs results in lipid accumulation in hepatocytes, causing hepatosteatosis and insulin resistance.

    “The imbalance between these inputs and outputs results in lipid accumulation in hepatocytes, which causes hepatosteatosis and insulin resistance.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Accelerated mitochondrial FAO might cause excessive electron flux in the ETC and ROS overproduction.

    “Accelerated mitochondrial FAO might cause excessive electron flux in the ETC and ROS overproduction.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Infiltrated immune cells contribute to chronic low-grade inflammation, and increased inflammatory cytokines cause insulin resistance elsewhere in the body.

    “Infiltrated immune cells also contribute to this chronic low-grade inflammatory milieu, whereby the increase in inflammatory cytokines causes insulin resistance elsewhere in the body.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Increased ROS might initiate lipid peroxidation, damage mitochondrial DNA and proteins, and alter mitochondrial morphology and function.

    “As lipids, proteins, and mitochondrial DNA are the main ROS targets, increased ROS might initiate lipid peroxidation, damage mitochondrial DNA and proteins, and alter mitochondrial morphology and function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    BAT thermogenesis takes place in its numerous, densely packed mitochondria, which contain BAT-specific UCP1.

    “BAT thermogenesis takes place in its numerous, densely packed mitochondria, which contain the BAT-specific UCP1.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Adipocytes exceed their oxygen diffusion limit, promoting hypoxia, ER stress, and cell death.

    “Consequently, adipocytes exceed their oxygen diffusion limit, thereby promoting hypoxia ([73](#B73)), ER stress ([132](#B132)), and cell death”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [73] source

      Not checked in the free run.

    • cites [132] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased circulating free fatty acids and triglyceride accumulation in ectopic sites is produced.

    “and increased circulating FFA and TG accumulation in ectopic sites is produced ([145](#B145)).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [145] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In these studies, enhanced mitochondrial FAO did not increase ROS derivatives or liver injury.

    “Furthermore, in these studies, enhanced mitochondrial FAO did not increase ROS derivatives or liver injury.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [117] source

      Not checked in the free run.

    • cites [130] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In rodents, BAT generates heat mainly for two reasons: to protect against cold exposure via nonshivering thermogenesis and to burn excess calories and reduce fat accumulation.

    “In rodents, BAT generates heat mainly for two reasons; namely, to protect against cold exposure *via* nonshivering thermogenesis and to burn the excess calories and reduce fat accumulation ([54](#B54), [72](#B72)).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [54] source

      Not checked in the free run.

    • cites [72] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This rise in lipid utilization improves insulin sensitivity in these cells and suppresses inflammatory signaling.

    “In fact, this rise in lipid utilization improves insulin sensitivity in these cells and suppresses inflammatory signaling ([50](#B50)).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Physiological ROS production in adipocytes is a relevant cellular signaling mechanism in the insulin response and depends mainly on NADPH oxidase (NOX) family activity.

    “Physiological ROS production in adipocytes is a relevant cellular signaling mechanism in the insulin response and it depends mainly on the NADPH oxidase (NOX) family activity ([9](#B9)).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    All groups showed major depots of metabolically active fat in the cervical-supraclavicular region, a slightly different site from that in rodents and children, where BAT is found mainly in the interscapular area.

    “All the groups showed major depots of metabolically active fat in the cervical–supraclavicular region, a slightly different site from that in rodents and children, where BAT is found mainly situated in the interscapular area.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [30] source

      Not checked in the free run.

    • cites [143] source

      Not checked in the free run.

    • cites [165] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These events cause insulin resistance in adipocytes, exacerbation of the inflammatory state, and systemic insulin resistance.

    “These events cause insulin resistance in adipocytes, exacerbation of the inflammatory state, and systemic insulin resistance ([59](#B59), [147](#B147))”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [59] source

      Not checked in the free run.

    • cites [147] source

      Not checked in the free run.

    • Rests on an assumption: The induction of JNK leads to serine phosphorylation of IRS-1 and 2, crucial molecules in insulin signaling, and consequently inhibits insulin action.

  • May combine two claims.

    Premisecitation

    A high-fat diet causes insulin resistance in rodents, while inducing an increase in skeletal muscle mitochondrial biogenesis and β-oxidation.

    “And finally, a HFD causes insulin resistance in rodents, while inducing an increase in SkM mitochondrial biogenesis and β-oxidation ([164](#B164)).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [164] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exercise in obese humans increases muscle mitochondrial fatty acid oxidation and improves glucose tolerance and insulin sensitivity.

    “exercise in obese humans increases muscle mitochondrial FAO and improves glucose tolerance and insulin sensitivity ([16](#B16)).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Human studies showed that BAT is reduced in obese and diabetic patients, indicating that this tissue participates in both cold-induced and diet-induced thermogenesis.

    “Interestingly, human studies showed that BAT is reduced in obese and diabetic patients, thus indicating that this tissue participates in both cold-induced and diet-induced thermogenesis ([30](#B30)).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Skeletal muscle accounts for approximately 80% of total glucose uptake after insulin stimulation.

    “It accounts for ∼80% of total glucose uptake after insulin stimulation ([34](#B34))”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Macrophages and the bone morphogenetic protein BMP8B have the capacity to regulate BAT thermogenesis.

    “In addition, recent articles reported that macrophages ([125](#B125)) and the bone morphogenetic protein BMP8B ([172](#B172)) have also the capacity to regulate BAT thermogenesis.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [125] source

      Not checked in the free run.

    • cites [172] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A moderate increase (threefold) in irisin blood levels in mice enhanced energy expenditure and improved obesity and glucose homeostasis.

    “Interestingly, a moderate increase (threefold) in irisin blood levels in mice enhanced energy expenditure and improved obesity and glucose homeostasis ([12](#B12)).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Different laboratories have demonstrated that a decrease in the size and number of mitochondria, the activity of proteins in the electron transport chain, and, in general, impaired oxidative capacity in skeletal muscle are associated with obesity and insulin resistance in humans and animals.

    “Different laboratories have demonstrated that a decrease in the size and number of mitochondria, the activity of proteins in the ETC and, in general, impaired oxidative capacity in SkM are associated with obesity and insulin resistance in humans and animals ([102](#B102), [139](#B139), [153](#B153)).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [102] source

      Not checked in the free run.

    • cites [139] source

      Not checked in the free run.

    • cites [153] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    This suggests that fatty acid oxidation might already be enhanced during obesity, contributing to the development of insulin resistance.

    “This suggests that FAO might already be enhanced during obesity, contributing to the development of insulin resistance ([121](#B121)).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [121] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased malonyl-CoA levels, which are generated by activated (i.e., dephosphorylated) ACC, act as abundance indicators, thereby diminishing food intake and consequently body weight.

    “Strong evidence shows that increased malonyl-CoA levels, which are generated by activated (*i.e.,* dephosphorylated) ACC, act as abundance indicators, thereby diminishing food intake and consequently body weight ([173](#B173)).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [173] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ROS are produced normally during mitochondrial respiration and are essential signal transducers that regulate several cell processes in skeletal muscle, including the insulin pathway.

    “However, these molecules are produced normally during mitochondrial respiration and are essential signal transducers that regulate several cell processes in SkM ([8](#B8)), including the insulin pathway ([64](#B64), [65](#B65)).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [8] source

      Not checked in the free run.

    • cites [64] source

      Not checked in the free run.

    • cites [65] Heffetz D, 1990, J Biol Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Specific hypothalamic nuclei sense nutrients and modify energy intake and expenditure to maintain a balance, and are responsible for regulating food intake.

    “Specific hypothalamic nuclei, which sense nutrients and modify energy intake and expenditure to maintain a balance, are responsible for regulating this intake ([48](#B48)).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ROS show insulin-like effects, stimulating skeletal muscle glucose uptake during muscle contraction via the activation of AMPK and the induction of PGC-1α expression in vitro and in vivo.

    “ROS show insulin-like effects, stimulating SkM glucose uptake during muscle contraction *via* the activation of AMPK ([81](#B81)) and the induction of PGC-1α expression *in vitro* and *in vivo* ([57](#B57), [79](#B79)).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [81] source

      Not checked in the free run.

    • cites [57] source

      Not checked in the free run.

    • cites [79] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The main problems associated with an increase in fatty acid oxidation are high rates of incomplete fat oxidation and an increase in oxidative stress associated with mitochondrial overload.

    “The main problems associated with an increase in FAO are: (i) the high rates of incomplete fat oxidation and (ii) the increase in oxidative stress associated with a mitochondrial overload ([Fig. 6C](#f6)) ([89](#B89)).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Koves et al. postulated that a high-fat diet induces the expression of fatty acid oxidation-related genes, but not those associated with the electron transport chain and TCA cycle.

    “Koves *et al.* ([89](#B89)) postulated that HFD induces the expression of FAO-related genes, but not those associated with the ETC and TCA cycle.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The mechanism of leptin action also appears to be related to increases in physiological malonyl-CoA in the arcuate nucleus, which promotes a reduction in food intake and body weight, using different mechanisms from those previously reported for ghrelin action, during energetically wealthy states.

    “The mechanism of leptin action also appears to be related to increases in physiological malonyl-CoA in the arcuate nucleus, which promotes a reduction in food intake and body weight, using different mechanisms to those previously reported for ghrelin action, during energetically wealthy states ([49](#B49), [141](#B141)).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [49] source

      Not checked in the free run.

    • cites [141] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Under physiological conditions, ROS are generated in response to insulin and are required for its action.

    “On the one hand, under physiological conditions, ROS are generated in response to insulin and are required for its action ([69](#B69)), since the activity of different enzymes that participate in the insulin cascade are dependent on their oxidation state.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SIRT3 knockout mice have high acylcarnitines and increased acylated mitochondrial proteins and develop metabolic syndrome.

    “This along with the observation that SIRT3 knockout mice have high acylcarnitines and increased acylated mitochondrial proteins and develop metabolic syndrome, implies that mitochondrial accumulation of FAO intermediates triggers metabolic complications *via* protein modification ([71](#B71), [80](#B80)).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [71] source

      Not checked in the free run.

    • cites [80] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    This causes a mismatch between fatty acid oxidation and TCA cycle activity, leading to the accumulation of incomplete fatty acids and other intermediates (i.e., acylcarnitines) that correlate negatively with glucose tolerance.

    “This causes a mismatch between FAO and TCA cycle activity, thus leading to the accumulation of incomplete FAs and other intermediates (*i.e.,* acylcarnitines) that correlate negatively with glucose tolerance ([2](#B2)).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A recent finding is that hypothalamic autophagy is a source of endogenous free fatty acids to regulate AgRP levels.

    “In addition to all these considerations, the recent finding that hypothalamic autophagy is a source of endogenous FFA to regulate AgRP levels ([82](#B82))”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    UCP2 acts as a ROS scavenger to keep a physiological ROS level that allows correct NPY and AgRP expression in the hypothalamus.

    “This notion may explain the importance of UCP2 as a ROS scavenger to keep a physiological ROS level that allows correct NPY and AgRP expression in the hypothalamus ([6](#B6)).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The presence of such small but functional fatty acid oxidation could be explained by its essential role in neuronal fatty acid turnover and its action as a lipid-sensing mediator for energy homeostasis.

    “Additionally, the presence of such small, but functional FAO could be explained by its essential role in neuronal FA turnover and its action as a lipid-sensing mediator for energy homeostasis ([113](#B113)).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationnone given

    There is no doubt regarding the involvement of ROS in pathophysiological processes related to obesity, and CPT1 seems to be a good molecular target for ROS and FAO modulation.

    “There is no doubt regarding the involvement of ROS in pathophysiological processes related to obesity, and CPT1 seems to be a good molecular target for ROS and FAO modulation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Some authors pointed to complex I as the most relevant site for single electron reduction in brain mitochondria.

    “Concretely, some authors pointed to complex I as the most relevant site for single electron reduction in brain mitochondria ([90](#B90)).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Various kinases and transcription factors involved in neuropeptide regulation have been reported to be modulated by redox signaling.

    “Various kinases and transcription factors, involved in neuropeptide regulation, have been reported to be modulated by redox signaling ([33](#B33), [91](#B91)).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [33] source

      Not checked in the free run.

    • cites [91] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    All of these could well alleviate the mitochondrial pressure found in lipid overload states.

    “All of these could well alleviate the mitochondrial pressure found in lipid overload states.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Mitochondrial ROS have been put forward as a mediator in response to nutrient availability.

    “Along with malonyl-CoA and LCFA-CoA, mitochondrial ROS have been put forward as a mediator in response to nutrient availability ([140](#B140))”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [140] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Increased fatty acid oxidation may also decrease glucose oxidation to maintain energy homeostasis, augment mitochondrial burning capacity through an increase in the number of mitochondria and/or the increased expression of UCPs, and thus dissipate the excess of energy as heat and ATP.

    “Increased FAO may also decrease glucose oxidation to maintain energy homeostasis, augment mitochondrial burning capacity through an increase in the number of mitochondria and/or the increased expression of UCPs, and thus dissipate the excess of energy as heat and ATP.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationcitation

    Potential mechanisms to explain the beneficial effects of targeting mitochondrial fatty acid oxidation could be the concomitant enhancement of hepatic ketone bodies, CO2, acid soluble products, ATP production, and endergonic processes (e.g., gluconeogenesis) seen in previous publications.

    “Potential mechanisms to explain the beneficial effects of targeting mitochondrial FAO could be the concomitant enhancement of hepatic ketone bodies, CO2, acid soluble products, ATP production, and endergonic processes (*e.g.,* gluconeogenesis) seen in previous publications ([38](#B38), [130](#B130), [158](#B158)).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [38] source

      Not checked in the free run.

    • cites [130] source

      Not checked in the free run.

    • cites [158] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Mitochondrial fatty acid oxidation is the cell source of energy from fatty acids.

    “Mitochondrial FAO is the cell source of energy from FAs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Hypothalamic neurons have the capacity to sense glucose and free fatty acids simultaneously and to integrate other nutritional and hormonal inputs.

    “and the capacity of hypothalamic neurons to sense glucose and FFA simultaneously and to integrate other nutritional and hormonal inputs ([95](#B95), [99](#B99))”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [95] source

      Not checked in the free run.

    • cites [99] source

      Not checked in the free run.

45 of 45

  • The paper relies on this without support.

    Obesity develops when energy intake exceeds energy expenditure.

    “Obesity develops when energy intake exceeds energy expenditure.”

  • The paper relies on this without support.

    Mammals have evolved mechanisms to store energy to survive during periods of starvation.

    “mammals have evolved mechanisms to store energy to survive during periods of starvation”

  • The paper relies on this without support.

    Homeostatic mechanisms increase caloric efficiency, making further weight loss more difficult.

    “Such homeostatic mechanisms increase caloric efficiency, thus making further weight loss even more difficult.”

  • The paper relies on this without support.

    Hormones such as insulin, glucagon, and noradrenaline control the extracellular uptake and intracellular release of carbohydrates and fatty acids.

    “Hormones, such as insulin, glucagon, and noradrenaline, control the extracellular uptake and intracellular release of the main cell fuels; namely, carbohydrates and FAs.”

  • The paper relies on this without support.

    Once inside the cell, fatty acids are esterified, metabolized to lipid second messengers, or β-oxidized in mitochondria.

    “Once inside the cell, FAs are esterified, metabolized to lipid second messengers, or β-oxidized in mitochondria.”

  • The paper relies on this without support.

    AMPK is one of the main regulators of the metabolic signaling network involving ACC, MCD, and CPT1.

    “One of the main regulators of this network is the AMP-activated protein kinase (AMPK).”

  • The paper relies on this without support.

    AMPK inhibits ATP-consuming processes while activating catabolic pathways.

    “In general, AMPK inhibits ATP-consuming processes, while activating catabolic pathways.”

  • The paper relies on this without support.

    Sirtuins are critical modulators of lipid metabolism and specifically of FAO.

    “In recent years, sirtuins have emerged as critical modulators of lipid metabolism and specifically of FAO.”

  • The paper relies on this without support.

    Energy flow in living cells (bioenergetics) takes place mainly in mitochondria.

    “Energy flow in living cells (bioenergetics) takes place mainly in mitochondria.”

  • The paper relies on this without support.

    Oxidative phosphorylation is the main source of reactive oxygen species (ROS) in the cell.

    “This process is the main source of reactive oxygen species (ROS) in the cell.”

  • The paper relies on this without support.

    In the ETC, the energy of electrons from NADH and FADH2 is used to pump protons from the mitochondrial matrix to the intermembrane space and generate the electrochemical gradient necessary for ATP synthesis.

    “In the ETC, the energy of electrons from NADH and FADH2 is used to pump protons (H+) from the mitochondrial matrix to the intermembrane space and generate the electrochemical gradient necessary for ATP synthesis.”

  • The paper relies on this without support.

    When electrons escape the ETC, ROS are produced in the mitochondria.

    “However, when these electrons escape the ETC, ROS are produced in the mitochondria.”

  • The paper relies on this without support.

    Mitochondrial ROS production is highly regulated and important for various cell functions, as ROS can act as signaling molecules.

    “Mitochondrial ROS production is highly regulated and important for various cell functions, as ROS can act as signaling molecules.”

  • The paper relies on this without support.

    In mitochondria, ETC complexes remain electron-bounded when the proton gradient is high, preventing outward pumping of H+ and increasing ROS production.

    “In the mitochondria, the ETC complexes remain electron-bounded when the proton gradient between the mitochondrial matrix and the intermembrane space is high, preventing the outward pumping of H+ and increasing ROS production.”

  • The paper relies on this without support.

    In BAT, UCP1 dissipates energy as heat and plays a key role in adaptive thermogenesis.

    “In BAT, UCP1 dissipates energy as heat and plays a key role in adaptive thermogenesis.”

  • The paper relies on this without support.

    The liver plays a central role in both energy expenditure and lipid/glucose homeostasis.

    “The liver plays a central role in both energy expenditure and lipid/glucose homeostasis.”

  • The paper relies on this without support.

    In conditions associated with prolonged excess of energy or impaired fatty acid metabolism, the liver stores considerable amounts of lipids in a process that leads to nonalcoholic fatty liver disease (NAFLD).

    “In conditions associated with prolonged excess of energy or impaired FA metabolism, the liver stores considerable amounts of lipids in a process that leads to nonalcoholic fatty liver disease (NAFLD).”

  • The paper relies on this without support.

    The mechanisms underlying NAFLD to NASH progression are not completely understood.

    “The mechanisms underlying NAFLD to NASH progression are not completely understood.”

  • The paper relies on this without support.

    Mitochondria play a vital role in the oxidation of fatty acids and ROS production.

    “Mitochondria play a vital role in the oxidation of FAs and ROS production.”

  • The paper relies on this without support.

    In the liver, mitochondrial FAO results either in complete oxidation to carbon dioxide or in partial oxidation to ketone bodies, which are exported to provide fuel for other tissues.

    “In the liver, mitochondrial FAO results either in complete oxidation to carbon dioxide or in partial oxidation to ketone bodies, which are exported to provide fuel for other tissues.”

  • The paper relies on this without support.

    Data on the rates of mitochondrial FAO and CPT1A activity in NAFLD/NASH are not conclusive, possibly because of the use of different models and parameters.

    “Data on the rates of mitochondrial FAO and CPT1A activity in NAFLD/NASH are not conclusive, possibly because of the use of different models and parameters.”

  • The paper relies on this without support.

    Results on CPT1A expression and activity are controversial.

    “Similarly controversial results were obtained with CPT1A expression and activity.”

  • The paper relies on this without support.

    The side effect of hepatic steatosis has interrupted the development of systemic CPT1 inhibitors such as etomoxir and 2-tetradecylglycidic acid as a therapeutic tool.

    “This side effect has interrupted the development of other systemic inhibitors, such as etomoxir and 2-tetradecylglycidic acid, as a therapeutic tool.”

  • The paper relies on this without support.

    Ketone bodies produced by enhanced FAO are easily consumed by other tissues, increasing the flux of carbons from liver to other organs.

    “The ketone bodies produced by enhanced FAO are easily consumed by other tissues, increasing the flux of carbons from liver to other organs.”

  • The paper relies on this without support.

    FGF21 has emerged as a key regulator in FAO and ketogenic activation.

    “Recently, a new hepatic factor, fibroblast growth factor 21 (FGF21), has emerged as a key regulator in FAO and ketogenic activation.”

  • The paper relies on this without support.

    WAT stores lipids mainly in the form of triglycerides, which can be mobilized and used to generate ATP through the mitochondrial β-oxidation pathway in peripheral organs during periods of caloric need.

    “This long-term energy reservoir stores lipids mainly in the form of TGs, which can be mobilized and used to generate ATP through the mitochondrial β-oxidation pathway in peripheral organs during periods of caloric need.”

  • The paper relies on this without support.

    Obesity is characterized by the expansion of white adipose tissue mass due to an increase in both adipocyte number (hyperplasia) and size (hypertrophy).

    “Obesity is characterized by the expansion of WAT mass due to an increase in both adipocyte number (hyperplasia) and size (hypertrophy)”

  • The paper relies on this without support.

    Obesity is closely associated with insulin resistance in peripheral tissues, such as skeletal muscle and liver.

    “and it is closely associated with insulin resistance in peripheral tissues, such as SkM and liver.”

  • The paper relies on this without support.

    The induction of JNK leads to serine phosphorylation of IRS-1 and 2, crucial molecules in insulin signaling, and consequently inhibits insulin action.

    “The induction of JNK leads to serine phosphorylation of IRS-1 and 2, crucial molecules in insulin signaling, and consequently inhibits insulin action.”

  • The paper relies on this without support.

    BAT is the only tissue to express UCP1.

    “BAT is the only tissue to express UCP1, a protein found in the inner mitochondrial membrane that orchestrates the uncoupled reaction of allowing protons to re-enter the mitochondrial matrix without generating ATP.”

  • The paper relies on this without support.

    UCP1 is a protein found in the inner mitochondrial membrane that orchestrates the uncoupled reaction of allowing protons to re-enter the mitochondrial matrix without generating ATP.

    “BAT is the only tissue to express UCP1, a protein found in the inner mitochondrial membrane that orchestrates the uncoupled reaction of allowing protons to re-enter the mitochondrial matrix without generating ATP.”

  • The paper relies on this without support.

    Body temperature changes stimulate norepinephrine release by sympathetic nervous endings that activate β-adrenergic receptors and trigger a signal transduction cascade that converts nutrients into acetyl-CoA.

    “Body temperature changes stimulate norepinephrine release by sympathetic nervous endings that activate β-adrenergic receptors and trigger a signal transduction cascade that converts nutrients into acetyl-CoA.”

  • The paper relies on this without support.

    Obesity is characterized by a greater breakdown and uptake of fatty acids.

    “Obesity is characterized by a greater breakdown and uptake of FAs.”

  • The paper relies on this without support.

    Mitochondrial members of the sirtuin family deacetylate/activate several proteins involved in fat oxidation.

    “Mitochondrial members of the sirtuin family are known to deacetylate/activate several proteins involved in fat oxidation.”

  • The paper relies on this without support.

    Ghrelin-mediated activation (i.e., phosphorylation) of AMPK is done via SIRT1-mediated activation (i.e., deacetylation) of p53.

    “Concretely, ghrelin-mediated activation (*i.e.,* phosphorylation) of AMPK is done *via* SIRT1-mediated activation (*i.e.,* deacetylation) of p53.”

  • The paper relies on this without support.

    Changes in feeding behavior and peripheral metabolism are conducted via the action of neuropeptides, such as agouti-related protein (AgRP), neuropeptide Y (NPY), and melanocortins.

    “Regardless of whether malonyl-CoA or LCFA-CoA is the main actor, changes in feeding behavior and peripheral metabolism are conducted *via* the action of neuropeptides, such as agouti-related protein (AgRP), neuropeptide Y (NPY), and melanocortins.”

  • The paper relies on this without support.

    ROS in the hypothalamus are produced chiefly in mitochondria electron transport chain complexes.

    “ROS in the hypothalamus are produced chiefly in mitochondria ECT complexes.”

  • The paper relies on this without support.

    Mitochondrial fatty acid oxidation is the cell source of energy from fatty acids.

    “Mitochondrial FAO is the cell source of energy from FAs.”

  • The paper relies on this without support.

    Current therapeutic strategies, focused mainly on controlling food intake, have met limited success, probably due to the inherent resistance of the human body to weight loss.

    “Current therapeutic strategies, focused mainly on controlling food intake, have met limited success, probably due to the inherent resistance of the human body to weight loss.”
39 of 39

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Secreted proteins stimulate brown adipocyte thermogenesis and recruit brown or beige adipocytes to white adipose tissue.

    “recent studies have identified secreted proteins that stimulate brown adipocyte thermogenesis and recruit brown (or beige) adipocytes to white adipose tissue [60] [61].”

    From Regulation of obesity and insulin resistance by nitric oxide (2014) · cites this paper as [60]

  • FAO is activated in insulin resistance, in which free fatty acids provide a compensatory fuel for repressed glucose uptake.

    “Likewise, FAO is activated in insulin resistance, in which free fatty acids provide a compensatory fuel for repressed glucose uptake.62,63”

    From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [63]

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. Khan A, 2012, Recent Pat Endocr Metab, 6, 117
  2. Nakamuta M, 2005, Int J Mol Med, 16, 631
  3. Pizer ES, 1996, Cancer Res, 56, 2745

Cited by

Sorted by citations

Related

Authors
Serra, D., Mera, P., Malandrino, M. I., Mir, J. F., & Herrero, L.
Affiliations
Instituto de Salud Carlos III (ES)
Corresponding author
Herrero, Laura
ORCID
Venue
Antioxidants & Redox Signaling
Publisher
SAGE Publications
Published
2013-07-20
Volume
19
Issue
3
Pages
269-284
ISSN
  • 1523-0864 (ISSN-L)
  • 1557-7716
DOI
10.1089/ars.2012.4875
PMC
PMC3691913
OpenAlex
W2119314929
Semantic Scholar
4a19e0b958be726b0812b91b568837097ddfa0dc
Cited by
246
References
182
Citations by year
2026: 13 · 2025: 20 · 2024: 25 · 2023: 29 · 2022: 15 · 2021: 17 · 2020: 31 · 2019: 21 · 2018: 22 · 2017: 16 · 2016: 10 · 2015: 11 · 2014: 12 · 2013: 4
FWCI
0.93
Type
journal article
Language
en
Open access
Locations
  • Antioxidants and Redox Signaling (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (publishedVersion)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion)
  • RECERCAT (Consorci de Serveis Universitaris de Catalunya) (publishedVersion)
  • RECERCAT (Consorci de Serveis Universitaris de Catalunya) (submittedVersion)
  • RECERCAT (Consorci de Serveis Universitaris de Catalunya) (submittedVersion, public-domain)
Funders
  • Eli Lilly and Company
  • European Foundation for the Study of Diabetes
  • Ministerio de Ciencia e Innovación (CB06/03)
  • Universitat de Barcelona
  • Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CB06/03)
  • Instituto de Salud Carlos III (CB06/03, CB06/03/0026)
Topics
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Keywords
mitochondrial fatty acid oxidation, obesity, obesity treatment, energy expenditure, liver, skeletal muscle, adipose tissue, reactive oxygen species, insulin resistance, type 2 diabetes
MeSH terms
Animals, Adipose Tissue, Brown, Fatty Acids, Humans, Hypothalamus, Liver, Mitochondria, Obesity, Oxidation-Reduction, Oxidative Phosphorylation, Anti-Obesity Agents, Lipid Metabolism, Adipose Tissue, White

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review