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Cited by 274Nitric Oxide and Endothelin EffectsAdipokines, Inflammation, and Metabolic DiseasesAdipose Tissue and Metabolism

Regulation of obesity and insulin resistance by nitric oxide

Open access
Sansbury, Brian E., Hill, Bradford G.·2014·Free Radical Biology and Medicine
DOI 10.1016/j.freeradbiomed.2014.05.016PMC PMC4112002
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Abstract

Obesity is a risk factor for developing type 2 diabetes and cardiovascular disease and has quickly become a worldwide pandemic with few tangible and safe treatment options. Although it is generally accepted that the primary cause of obesity is energy imbalance, i.e., the calories consumed are greater than are utilized, understanding how caloric balance is regulated has proven a challenge. Many "distal" causes of obesity, such as the structural environment, occupation, and social influences, are exceedingly difficult to change or manipulate. Hence, molecular processes and pathways more proximal to the origins of obesity-those that directly regulate energy metabolism or caloric intake-seem to be more feasible targets for therapy. In particular, nitric oxide (NO) is emerging as a central regulator of energy metabolism and body composition. NO bioavailability is decreased in animal models of diet-induced obesity and in obese and insulin-resistant patients, and increasing NO output has remarkable effects on obesity and insulin resistance. This review discusses the role of NO in regulating adiposity and insulin sensitivity and places its modes of action into context with the known causes and consequences of metabolic disease.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that nitric oxide (NO) is a central regulator of energy metabolism, body composition, and insulin sensitivity, with NO bioavailability reduced in obesity and diabetes. It proposes that NOS3-derived NO is largely anti-obesogenic and insulin-sensitizing, whereas NOS1 and NOS2-derived NO can promote hyperphagia and insulin resistance.

Key findings

  • NO bioavailability is decreased in animal models of obesity/diabetes and in obese and diabetic humans; diminished NO may arise from lower NOS expression, impaired NOS activity, NOS uncoupling, or NO quenching by reactive species such as superoxide.
  • NOS3-derived NO appears anti-obesogenic and insulin-sensitizing: NOS3 knockout causes insulin resistance, hyperlipidemia, and hypertension, while NOS3 overexpression prevents diet-induced obesity, raises metabolic rate, and lowers plasma free fatty acids and triglycerides.
  • NOS2 promotes insulin resistance: NOS2 ablation improves glucose tolerance and insulin sensitivity in high-fat-fed mice, and NOS2 expression is linked to S-nitrosation of insulin receptor, IRS-1, and Akt; NOS1 in the brain promotes hyperphagia.
  • Pharmacological studies show context-dependent effects: L-arginine increases food intake but reduces fat mass and improves insulin sensitivity in mice, rats, and pigs; chronic NOS inhibition reduces food intake/adiposity and improves insulin sensitivity in obese models, but acute NOS inhibition causes systemic insulin resistance.
  • The review cites obesity statistics: U.S. obesity prevalence rose from 13% to 36% (1962–2010); as of 2008, ~1.5 billion adults were overweight and 10% obese; >33% of U.S. adults and 17% of children were obese; estimated obesity-related health care costs were $147 billion per year.

Methods

  • Design: narrative review of the role of NO in regulating obesity, adiposity, and insulin sensitivity, integrating pharmacological, human, and genetic mouse studies.
  • Data/sample: no primary dataset or systematic sample; the paper synthesizes cited animal models, human studies, and genetic interventions, including NOS isoform knockout/overexpression models.
  • Main analysis: narrative synthesis and a proposed model (Figure 3) in which NOS3-derived NO is beneficial for metabolism while NOS1 and NOS2-derived NO contribute to deleterious metabolic changes.

Limitations

  • The paper does not state formal limitations.
  • It explicitly notes unresolved issues, including the identity of hepatic insulin-sensitizing substance (HISS), whether obesity itself decreases NO availability, the specific contribution of peroxynitrite and other reactive species to endothelial function, and the controversy over NO’s dual role in insulin secretion.
  • Evident from the text: as a narrative review, it lacks a systematic search strategy, formal quality assessment, meta-analysis, or new primary data, so conclusions depend on the cited literature and the proposed model.

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

Integrity signals

Registry

Crossref · 10.1016/j.freeradbiomed.2014.05.016

Cites

369 of 369 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 155 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    NO bioavailability is decreased in animal models of diet-induced obesity and in obese and insulin-resistant patients.

    “NO bioavailability is decreased in animal models of diet-induced obesity and in obese and insulin resistant patients”
    • Also stated in: § 4. NO bioavailability is diminished in obese and diabetic states · plain
      “NO bioavailability is decreased in animal models of obesity and diabetes [116, 117] and in obese and diabetic humans [118, 119].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [116] Bender, 2007, Diet-induced obesity and diabetes reduce coronary responses to nitric oxide due to reduced bioavailability in isolated mouse hearts, Diabetes Obes. Metab. source

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    • cites [119] Gruber, 2008, Obesity reduces the bioavailability of nitric oxide in juveniles, Int. J. Obes. source

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    • Rests on an assumption: Findings from animal models of obesity and diabetes are informative about human obesity and diabetes.
  • Premisecitation

    Release of cholecystokinin in combination with neural signaling in response to gut distension are potent signals of satiety and trigger an end to feeding.

    “Release of cholecystokinin (CCK) in combination with neural signaling in response to gut distension are potent signals of satiety and trigger an end to feeding [34].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Spiegelman, 2001, Obesity and the regulation of energy balance, Cell source

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  • Interpretationreasoning

    Increasing NO output has remarkable effects on obesity and insulin resistance.

    “increasing NO output has remarkable effects on obesity and insulin resistance”
    Quote in the paperNot a substantial claim
  • Interpretationnone given

    NO is emerging as a central regulator of energy metabolism and body composition.

    “nitric oxide (NO) is emerging as a central regulator of energy metabolism and body composition”
    Quote in the paperSubstantial claim
  • Interpretationnone given

    NO plays an important role in many proximal causes of obesity.

    “nitric oxide (NO) plays an important role in many of these proximal causes of obesity”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 25
  • May combine two claims. 48

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    Premisecitation

    The principal cause of obesity is energy imbalance: calories consumed exceed calories utilized by bodily processes.

    “The principal cause of obesity is energy imbalance: the calories consumed are greater than that utilized by bodily processes, e.g., breathing, digestion, thermogenesis [7].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Tseng, 2010, Cellular bioenergetics as a target for obesity therapy, Nat. Rev. Drug Discovery source

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    Premisereasoning

    Any effective obesity treatment must decrease energy intake, increase energy expenditure, or both.

    “Any effective obesity treatment must decrease energy intake, increase energy expenditure or both.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Weight loss via caloric restriction faces difficulties including an evolution-engendered guard against low fat mass and a propensity to increase caloric efficiency during dieting.

    “Even weight loss via caloric restriction faces difficulties, including an evolution-engendered guard against low fat mass [7, 31] and the propensity of the body to increase caloric efficiency during dieting [32, 33].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [7] Tseng, 2010, Cellular bioenergetics as a target for obesity therapy, Nat. Rev. Drug Discovery source

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    Premisecitation

    Neuropeptide Y directly affects feeding behavior, metabolism, and body composition.

    “neuropeptide Y (NPY) directly affects feeding behavior, metabolism and body composition [37, 38]”
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    • cites [37] Stanley, 1986, Neuropeptide Y chronically injected into the hypothalamus: a powerful neurochemical inducer of hyperphagia and obesity, Peptides source

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    Corticotropin-releasing hormone, growth-hormone-releasing hormone, galanin, and ghrelin function in hunger and satiety signaling.

    “corticotropin-releasing hormone, growth-hormone-releasing hormone, galanin and ghrelin, some of which are expressed in both the stomach and the brain, function in hunger and satiety signaling [39].”
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    Leptin is crucial to integrate the melanocortin neuronal circuit of the hypothalamus with the energy stores of the body.

    “The adipose tissue-derived hormone, leptin, is crucial to integrate the melanocortin neuronal circuit of the hypothalamus with the energy stores of the body [34-36].”
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    • cites [34] Spiegelman, 2001, Obesity and the regulation of energy balance, Cell source

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    • cites [35] Ahima, 2000, Leptin, Annu. Rev. Physiol. source

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    • cites [36] Schwartz, 2000, Central nervous system control of food intake, Nature source

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    Norepinephrine, dopamine, and serotonin are important in central energy balance.

    “The neurotransmitters norepinephrine, dopamine and serotonin are also important in central energy balance [34, 36]”
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    • cites [34] Spiegelman, 2001, Obesity and the regulation of energy balance, Cell source

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    • cites [36] Schwartz, 2000, Central nervous system control of food intake, Nature source

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    Premisecitation

    Mitochondria are central to the regulation of energy expenditure, and targeting their activity has been a prospect for obesity therapies for decades.

    “Mitochondria are central to the regulation of energy expenditure, and targeting their activity has been a prospect for obesity therapies for decades [47, 48], [49].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [47] Cutting, 1934, Relationship between blood cholesterol and increased metabolism from dinitrophenol and thyroid, J. Clin. Invest. source

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    Inhibition of gastric and pancreatic lipases via orlistat decreases triglyceride hydrolysis, inhibits absorption of ingested fat by about 30%, and contributes to a caloric deficit of approximately 200 calories per day.

    “Inhibition of gastric and pancreatic lipases via orlistat treatment decreases triglyceride hydrolysis and is able to inhibit absorption of ingested fat by ~30% and contributes to a caloric deficit of approximately 200 calories per day [45].”
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    The basal metabolic rate is the largest contributor to obligatory energy expenditure.

    “The largest contributor to obligatory energy expenditure is the basal metabolic rate (BMR), which is defined as the resting energy expenditure at thermoneutrality in the unfed state [46].”
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    • cites [46] Harper, 2008, The efficiency of cellular energy transduction and its implications for obesity, Annu. Rev. Nutr. source

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    BMR includes cellular turnover, repair and basic functions, basal synthetic reactions, mitochondrial proton leak, and obligatory thermogenesis.

    “BMR includes cellular turnover, repair and basic functions (e.g., maintenance of ion gradients, transmembrane metabolite transfer), basal synthetic reactions (e.g., RNA, DNA protein synthesis) and mitochondrial proton leak; it also includes obligatory thermogenesis (e.g., digestion and absorption) [7, 46].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] Tseng, 2010, Cellular bioenergetics as a target for obesity therapy, Nat. Rev. Drug Discovery source

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    • cites [46] Harper, 2008, The efficiency of cellular energy transduction and its implications for obesity, Annu. Rev. Nutr. source

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    Inhibiting reuptake of norepinephrine, dopamine, and serotonin is the strategy employed by drugs such as sibutramine, which are effective but have side effects such as increased blood pressure and heart rate.

    “inhibiting their reuptake is the strategy employed by drugs such as sibutramine, which have proven effective but have side effects such as increased blood pressure and heart rate [40].”
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    • cites [40] Bray, 2000, Medicinal strategies in the treatment of obesity, Nature source

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    Orlistat promotes weight loss, but side effects caused discontinuation of the medication in many patients.

    “orlistat promotes weight loss; however, side effects caused discontinuation of the medication in many patients [40].”
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    • cites [40] Bray, 2000, Medicinal strategies in the treatment of obesity, Nature source

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    Premisecitation

    PGC-1α is a known regulator of energy metabolism and of mitochondrial biogenesis.

    “PGC-1α is a known regulator of energy metabolism and of mitochondrial biogenesis [59]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    The three isoforms of NOS generate NO at different rates.

    “The three isoforms of NOS generate NO at different rates [62].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Hill, 2010, What part of NO don׳t you understand? Some answers to the cardinal questions in nitric oxide biology, J. Biol. Chem. source

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    Premisecitation

    The most common route of NO production is through the action of the nitric oxide synthase family of enzymes.

    “The most common route of NO production is through the action of the nitric oxide synthase (NOS) family of enzymes [62, 64].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [62] Hill, 2010, What part of NO don׳t you understand? Some answers to the cardinal questions in nitric oxide biology, J. Biol. Chem. source

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    • cites [64] Alderton, 2001, Nitric oxide synthases: structure, function and inhibition, Biochem. J. source

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    Premisecitation

    NO synthesis depends on the availability of cofactors such as FAD, FMN, tetrahydrobiopterin, and heme.

    “Such synthesis of NO depends on the availability of cofactors such as FAD, FMN, tetrahydrobiopterin (BH4), as well as the prosthetic group, heme [65].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Li, 2005, Structure–function studies on nitric oxide synthases, J. Inorg. Biochem. source

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    Premisecitation

    NOS3 is expressed at highest relative abundance in vascular endothelium, but is also found in neurons, epithelial cells, cardiomyocytes, adipocytes, and hepatocytes.

    “NOS3 (commonly called endothelial NOS or eNOS) is expressed to highest relative abundance in the vascular endothelium, but has also been found in neurons, epithelial cells, and cardiomyocytes [66] as well as adipocytes [67, 68] and hepatocytes [69-71].”
    Quote in the paperNot a substantial claim0 of 6 sources checked
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    Premisecitation

    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].”
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    Premisecitation

    Nitric oxide and related nitrogen oxides have emerged as critical regulators of cell and tissue function.

    “Nitric oxide and related nitrogen oxides have emerged as critical regulators of cell and tissue function [62].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Hill, 2010, What part of NO don׳t you understand? Some answers to the cardinal questions in nitric oxide biology, J. Biol. Chem. source

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

    Premisecitation

    NOS1 is a calcium/calmodulin-dependent isoform that can be activated by agonists of the NMDA receptor.

    “NOS1 (frequently called neuronal NOS or nNOS) is also a Ca2+/calmodulin-dependent isoform that can be activated by agonists of the N-methyl-D-aspartate (NMDA) receptor [75].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] Kone, 2003, Protein interactions with nitric oxide synthases: controlling the right time, the right place, and the right amount of nitric oxide, Am. J. Physiol. Renal Physiol source

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    Premisecitation

    NO can be produced endogenously from nitrite, and reduction of nitrite to NO is increased under acidic and hypoxic conditions by heme proteins such as deoxyhemoglobin or deoxymyoglobin.

    “In addition to direct production via NOS enzymes, NO can be produced endogenously from the more oxidized nitrogen oxide, nitrite. Reduction of nitrite to NO is increased under acidic and hypoxic conditions, with the reduction occurring enzymatically by heme proteins such as deoxyhemoglobin or deoxymyoglobin [79].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Vitturi, 2011, Current perspectives and challenges in understanding the role of nitrite as an integral player in nitric oxide biology and therapy, Free Radic. Biol. Med. source

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    Premisecitation

    The endogenous half-life of NO is in the range of 2 ms to greater than 2 s and appears to depend on the availability of reactants.

    “The endogenous half-life of NO has been found to be in the range of 2 ms to > 2 s and appears to depend on the availability of reactants [81].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Thomas, 2001, The biological lifetime of nitric oxide: implications for the perivascular dynamics of NO and O2, Proc. Natl. Acad. Sci. USA source

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    Premisecitation

    NOS3 produces relatively low quantities of NO, and its activity is controlled by calcium/calmodulin, post-translational modifications, and physical forces such as shear stress.

    “It produces relatively low quantities of NO, and its activity is controlled by Ca2+ and calmodulin, post-translational modifications [72, 73], and physical forces such as shear stress [74, 75].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
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    Premisecitation

    Peroxynitrite and reactive species derived from it are important in inflammatory responses and can modulate cell signaling, in part by promoting oxidation or nitration of biomolecules.

    “Peroxynitrite and reactive species derived from it (e.g., nitrogen dioxide) are important in inflammatory responses [85] and can modulate cell signaling [87-90], in part by promoting the oxidation or nitration of a broad range of biomolecules [62].”
    Quote in the paperNot a substantial claim0 of 6 sources checked
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    Premisecitation

    NOS2 has the highest capacity to generate NO and is expressed in multiple cell types in response to inflammatory stimuli.

    “NOS2 (also termed inducible NOS or iNOS), which has the highest capacity to generate NO, is expressed in multiple cell types in response to inflammatory stimuli [75, 76].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [75] Kone, 2003, Protein interactions with nitric oxide synthases: controlling the right time, the right place, and the right amount of nitric oxide, Am. J. Physiol. Renal Physiol source

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    • cites [76] Kleinert, 2004, Regulation of the expression of inducible nitric oxide synthase, Eur. J. Pharmacol. source

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    Premisecitation

    The presence of free radicals such as superoxide changes the fate of NO: once reacted, it forms peroxynitrite and can no longer bind to ferrous heme.

    “The presence of free radicals such as superoxide (O2.−) [82-85] changes the fate of NO: once reacted, it forms peroxynitrite [82, 84, 85] and can no longer bind to ferrous heme [86].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
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    Premisecitation

    NO synthesized by NOS in the endothelium diffuses into the vessel wall, activates soluble guanylate cyclase in vascular smooth muscle, raises cyclic GMP, and elicits relaxation of the vessel.

    “NO synthesized by NOS in the endothelium diffuses into the vessel wall where it activates sGC in vascular smooth muscle; this leads to a rise in cyclic GMP (cGMP) and elicits relaxation of the vessel [96-102].”
    Quote in the paperNot a substantial claim0 of 7 sources checked
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    Premisecitation

    NOS1 activity in the medulla and hypothalamus is important for systemic regulation of blood pressure.

    “NOS1 activity in the medulla and hypothalamus is important for systemic regulation of blood pressure [104-107]”
    Quote in the paperNot a substantial claim0 of 4 sources checked
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      Not checked in the free run.

    • cites [105] Sakuma, 1992, NG-methyl-L-arginine, an inhibitor of L-arginine-derived nitric oxide synthesis, stimulates renal sympathetic nerve activity in vivo: a role for nitric oxide in the central regulation of sympathetic tone?, Circ. Res. source

      Not checked in the free run.

    • cites [106] el Karib, 1993, The central effects of a nitric oxide synthase inhibitor (N omega-nitro-L-arginine) on blood pressure and plasma renin, Clin. Exp. Hypertens. source

      Not checked in the free run.

    • cites [107] Toda, 2009, Control of systemic and pulmonary blood pressure by nitric oxide formed through neuronal nitric oxide synthase, J. Hypertens. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic exposure to relatively high levels of NO results in mitochondrial biogenesis, which could reprogram a cell or tissue to have a higher metabolic capacity.

    “Chronic exposure to relatively high levels of NO results in mitochondrial biogenesis [113-115], which could reprogram a cell or tissue to have a higher metabolic capacity.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [113] Kelly, 2004, Transcriptional regulatory circuits controlling mitochondrial biogenesis and function, Genes Dev. source

      Not checked in the free run.

    • cites [114] Nisoli, 2003, Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide, Science source

      Not checked in the free run.

    • cites [115] Nisoli, 2004, Mitochondrial biogenesis by NO yields functionally active mitochondria in mammals, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

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

    Premisecitation

    NO derived from the integration of NOS3 and NOS1 activities plays key roles in regulating systemic blood pressure and acutely regulating organ blood flow, whereas NOS2-derived NO species are most recognized for their impact on pathogen killing and inflammatory processes.

    “Overall, NO derived from the integration of NOS3 and NOS1 activities play key roles in regulating systemic blood pressure and acutely regulating organ blood flow, whereas NOS2-derived NO species are most well recognized for their impact on pathogen killing and inflammatory processes [82].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Pacher, 2007, Nitric oxide and peroxynitrite in health and disease, Physiol. Rev. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Diminished levels of NO in obese states may be due to decreased expression of NOS, impairments in NOS activity, or reaction of NO with reactive species such as superoxide.

    “diminished levels of NO in obese states may be due to decreased expression of NOS, impairments in NOS activity, or by the reaction of NO with reactive species (e.g., superoxide) (Figure 2).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    NOS3 and NOS1 have distinct roles in regulating microvascular tone.

    “NOS3 and NOS1 were found to have distinct roles in regulating microvascular tone [103]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Melikian, 2009, Neuronal nitric oxide synthase and human vascular regulation, Trends Cardiovasc. Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A key function of NO is to modulate oxygen gradients in cells and tissues by regulating hemoglobin action and by inhibiting oxygen consumption in respiring mitochondria.

    “Thus, a key function of NO is to modulate O2 gradients in cells and tissues by regulating hemoglobin action and by inhibiting O2 consumption in respiring mitochondria [81].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Thomas, 2001, The biological lifetime of nitric oxide: implications for the perivascular dynamics of NO and O2, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TNFα is increased in obesity and implicated in the etiology of insulin resistance.

    “tumor necrosis factor-α (TNFα), which is increased in obesity and implicated in the etiology of insulin resistance [130]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [130] Hotamisligil, 1993, Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In rodents, L-arginine increases food intake and NOS inhibitors decrease food intake.

    “In rodents, L-arginine was shown to increase, and NOS inhibitors to decrease, food intake [155, 251-254].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [155] Sadler, 2004, Reduced ventromedial hypothalamic neuronal nitric oxide synthase and increased sensitivity to NOS inhibition in dietary obese rats: further evidence of a role for nitric oxide in the regulation of energy balance, Brain Res. source

      Not checked in the free run.

    • cites [251] Morley, 1991, Evidence that nitric oxide modulates food intake in mice, Life Sci. source

      Not checked in the free run.

    • cites [252] Morley, 1992, Competitive antagonism of nitric oxide synthetase causes weight loss in mice, Life Sci. source

      Not checked in the free run.

    • cites [253] Morley, 1994, Effect of competitive antagonism of NO synthetase on weight and food intake in obese and diabetic mice, Am. J. Physiol.

      Not checked in the free run.

    • cites [254] Squadrito, 1993, Anorectic activity of NG-nitro-L-arginine, an inhibitor of brain nitric oxide synthase, in obese Zucker rats, Eur. J. Pharmacol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Systemic administration of NG-nitro-L-arginine reduces food intake in obese rats and increases serotonin metabolism in the cortex, diencephalon, and medulla pons.

    “Systemic administration of the NOS inhibitor, NG-nitro-L-arginine, reduced food intake in obese rats and increased serotonin metabolism in the cortex, diencephalon, and medulla pons, thereby implicating the central serotoninergic system in mediating the anorexic effect of NOS inhibitors [257].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [257] Squadrito, 1994, Central serotoninergic system involvement in the anorexia induced by NG-nitro-L-arginine, an inhibitor of nitric oxide synthase, Eur. J. Pharmacol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Intracranial leptin diminishes diencephalic NOS activity and decreases food intake and body weight gain in rodents.

    “Leptin, given intracranially, was found to diminish diencephalic NOS activity and decrease food intake and body weight gain, and intracranial co-administration of L-arginine antagonized this effect [255].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [255] Calapai, 1998, Effects of intracerebroventricular leptin administration on food intake, body weight gain and diencephalic nitric oxide synthase activity in the mouse, Br. J. Pharmacol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    L-NAME promotes weight loss and diminishes food intake in ob/ob and db/db mice and obese rats.

    “Other NOS inhibitors, such as L-NAME, promote weight loss and diminish food intake in ob/ob and db/db mice [253] and obese rats [258]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [253] Morley, 1994, Effect of competitive antagonism of NO synthetase on weight and food intake in obese and diabetic mice, Am. J. Physiol.

      Not checked in the free run.

    • cites [258] Stricker-Krongrad, 1996, Nitric oxide mediates hyperphagia of obese Zucker rats: relation to specific changes in the microstructure of feeding behavior, Life Sci.

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    NO produced in the brain antagonizes anorectic signals and stimulates food intake.

    “Taken together with numerous other studies demonstrating a role for NO in the regulation of hunger [266-270], it would appear that NO produced in the brain antagonizes anorectic signals and stimulates food intake.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [266] Yamada, 1996, Effects of a nitric oxide synthase inhibitor on 5-HT1A receptor agonist 8-OH-DPAT-induced hyperphagia in rats, Eur. J. Pharmacol. source

      Not checked in the free run.

    • cites [267] Sugimoto, 1999, A neuronal nitric oxide synthase inhibitor 7-nitroindazole reduces the 5-HT1A receptor against 8-OH-DPAT-elicited hyperphagia in rats, Eur. J. Pharmacol. source

      Not checked in the free run.

    • cites [268] Sugimoto, 1999, Involvement of nitric oxide in the 5-HT1A autoreceptor-mediated hyperphagia in rats, Adv. Exp. Med. Biol. source

      Not checked in the free run.

    • cites [269] Czech, 2003, A nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester, attenuates lipoprivic feeding in mice, Physiol. Behav. source

      Not checked in the free run.

    • cites [270] Li, 2006, The weight loss elicited by cobalt protoporphyrin is related to decreased activity of nitric oxide synthase in the hypothalamus, J. Appl. Physiol. (1985) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NOS inhibitors reduce adiposity and improve insulin sensitivity in high fat-fed mouse models.

    “as well as reduce adiposity and improve insulin sensitivity in high fat-fed mouse models [259]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [259] Tsuchiya, 2007, Chronic blockade of nitric oxide synthesis reduces adiposity and improves insulin resistance in high fat-induced obese mice, Endocrinology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Intracerebroventricular administration of LNMMA regulates insulin secretion and peripheral insulin sensitivity.

    “Interestingly, intracerebroventricular administration of NG-monomethyl-L-arginine (LNMMA) was shown also to regulate insulin secretion and peripheral insulin sensitivity [260]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [260] Shankar, 1998, Central nervous system nitric oxide synthase activity regulates insulin secretion and insulin action, J. Clin. Invest. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Restoration of NOS3 phosphorylation in endothelial-specific IRS-2 knockout mice using beraprost rescues capillary recruitment and promotes adequate insulin and glucose delivery to skeletal muscle.

    “Restoration of NOS3 phosphorylation in endothelial-specific insulin receptor substrate 2 (IRS-2) knockout mice using beraprost (a stable prostaglandin analog) was sufficient to rescue capillary recruitment and to promote adequate insulin and glucose delivery to skeletal muscle [179].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [179] Kubota, 2011, Impaired insulin signaling in endothelial cells reduces insulin-induced glucose uptake by skeletal muscle, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    L-arginine feeding reduces white adipose tissue mass, improves insulin sensitivity, and increases energy expenditure in mice despite promoting hyperphagia.

    “Despite promoting hyperphagia, L-arginine feeding reduced white adipose tissue mass, improved insulin sensitivity, and increased energy expenditure in mice [278].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [278] Clemmensen, 2012, L-Arginine improves multiple physiological parameters in mice exposed to diet-induced metabolic disturbances, Amino Acids source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Collective data suggest L-arginine, and by inference NO, has the capacity to reduce fat mass by increasing mitochondrial biogenesis, regulating brown adipose tissue signaling, and increasing expression of genes that promote oxidation of energy substrates.

    “Overall, the collective data suggest that L-arginine, and by inference, NO, has the capacity to reduce fat mass by increasing mitochondrial biogenesis, regulating brown adipose tissue signaling, and increasing the expression of genes that promote oxidation of energy substrates [282].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [282] McKnight, 2010, Beneficial effects of L-arginine on reducing obesity: potential mechanisms and important implications for human health, Amino Acids source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    NO derived from NOS3 is pivotal for regulating systemic glucose metabolism and insulin delivery to peripheral tissues.

    “Hence, NO derived from NOS3 appears to be pivotal for regulating systemic glucose metabolism and insulin delivery to peripheral tissues.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Dietary L-arginine supplementation in rats reduces fat mass, increases skeletal muscle and brown fat mass, and reduces serum concentrations of glucose, triglycerides, free fatty acids, homocysteine, dimethylarginines, and leptin.

    “In rats, not only has dietary L-arginine supplementation been shown to reduce fat mass, but it appears to increase skeletal muscle and brown fat mass and reduce serum concentrations of glucose, triglycerides, free fatty acids, homocysteine, dimethylarginines, and leptin as well [279, 280].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [279] Fu, 2005, Dietary L-arginine supplementation reduces fat mass in Zucker diabetic fatty rats, J. Nutr. source

      Not checked in the free run.

    • cites [280] Jobgen, 2009, Dietary L-arginine supplementation reduces white fat gain and enhances skeletal muscle and brown fat masses in diet-induced obese rats, J. Nutr. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic treatment with sildenafil improves insulin action and diminishes obesity in high fat-fed mice.

    “Chronic treatment with sildenafil, which prevents the degradation of cGMP and is commonly prescribed to improve erectile function, improved insulin action and diminished obesity in high fat-fed mice [283].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [283] Ayala, 2007, Chronic treatment with sildenafil improves energy balance and insulin action in high fat-fed conscious mice, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Administration of BH4 to STZ-induced diabetic mice lowers fasting blood glucose levels in an NOS3-dependent manner and improves glucose tolerance and insulin sensitivity in ob/ob mice.

    “Administration of BH4, which is known to be oxidized to BH2 in the diabetic state [289-291] and plays an important role in regulating coupled NOS3 activity (vide supra), to STZ-induced diabetic mice lowered fasting blood glucose levels in an NOS3-dependent manner and improved glucose tolerance and insulin sensitivity in ob/ob mice [292].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [292] Abudukadier, 2013, Tetrahydrobiopterin has a glucose-lowering effect by suppressing hepatic gluconeogenesis in an endothelial nitric oxide synthase-dependent manner in diabetic mice, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Deletion of NOS3 in mice causes insulin resistance, hyperlipidemia, and hypertension.

    “In mice, it has been reported that deletion of NOS3 causes insulin resistance, hyperlipidemia, and hypertension [326].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [326] Duplain, 2001, Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase, Circulation source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Intraportal administration of NOS inhibitors causes insulin resistance, which is rescued by intraportal delivery of SIN-1.

    “For example, intraportal administration of NOS inhibitors was shown to cause insulin resistance, which was rescued by intraportal delivery of the NO and superoxide donor, SIN-1 [293, 294].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [293] Sadri, 1999, Blockade of hepatic nitric oxide synthase causes insulin resistance, Am. J. Physiol.

      Not checked in the free run.

    • cites [294] Guarino, 2003, Hepatic glutathione and nitric oxide are critical for hepatic insulin-sensitizing substance action, Am. J. Physiol. Gastrointest. Liver Physiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice overexpressing NOS3 show an anti-obesogenic phenotype characterized by resistance to accumulation of white adipose tissue in response to a high fat diet, a higher metabolic rate, resistance to diet-induced hyperinsulinemia, and remarkably lower plasma levels of free fatty acids and triglycerides.

    “Furthermore, mice overexpressing NOS3 show an anti-obesogenic phenotype characterized by resistance to accumulation of white adipose tissue in response to a high fat diet, a higher metabolic rate, resistance to diet-induced hyperinsulinemia, and remarkably lower plasma levels of free fatty acids and triglycerides [335].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [335] Atochin, 2010, Endothelial nitric oxide synthase transgenic models of endothelial dysfunction, Pflugers Arch. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ablation of the NOS2 gene has no effect on weight gain but improves glucose tolerance, normalizes insulin sensitivity, and prevents derangements in PI3K/Akt signaling in high fat-fed mice.

    “Although ablation of the NOS2 gene has no effect on weight gain, its absence was shown to improve glucose tolerance, normalize insulin sensitivity, and prevent derangements in PI3K/Akt signaling in high fat-fed mice [346].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [346] Carvalho-Filho, 2005, S-nitrosation of the insulin receptor, insulin receptor substrate 1, and protein kinase B/Akt: a novel mechanism of insulin resistance, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    NO stimulates early, glucose-induced insulin release, while it is responsible for cytokine (e.g., IL-1β)-mediated inhibition of insulin secretion.

    “With respect to insulin release, it appears that NO stimulates early, glucose-induced insulin release, while it is responsible for cytokine (e.g., IL-1β)-mediated inhibition of insulin secretion.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    NOS3 KO mice have markedly lower energy expenditure and decreases in mitochondrial content and fatty acid oxidation in muscle compared with WT mice.

    “Supporting evidence supplied by NOS3 KO mice include a markedly lower energy expenditure and decreases in mitochondrial content and fatty acid oxidation in muscle compared with WT mice [332]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [332] Le Gouill, 2007, Endothelial nitric oxide synthase (eNOS) knockout mice have defective mitochondrial beta-oxidation, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The inhibitory actions of NO on insulin release appear to be due to NOS2-derived NO, which is implicated in the destruction of islet cells in type 1 diabetes.

    “The inhibitory actions of NO on insulin release appear to be due to NOS2-derived NO, which is implicated in the destruction of islet cells in type 1 diabetes [309, 310].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [309] Broniowska, 2014, A. beta-Cell responses to nitric oxide, Vitam. Horm. source

      Not checked in the free run.

    • cites [310] Takamura, 1998, Transgenic mice overexpressing type 2 nitric-oxide synthase in pancreatic beta cells develop insulin-dependent diabetes without insulitis, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Selective overexpression of NOS2 in liver is sufficient to cause hepatic insulin resistance, hyperglycemia, and hyperinsulinemia.

    “Selective overexpression of NOS2 in liver is sufficient to cause hepatic insulin resistance, hyperglycemia and hyperinsulinemia [355]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [355] Handa, 2011, Reduced vascular nitric oxide–cGMP signaling contributes to adipose tissue inflammation during high-fat feeding, Arterioscler. Thromb. Vasc. Biol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    NOS2 promotes insulin resistance in both liver and skeletal muscle and is critical in inflammatory responses in multiple tissues, most notably the adipose organ.

    “The NOS2 isoform promotes insulin resistance in both liver and skeletal muscle and is critical in inflammatory responses in multiple tissues, most notably, the adipose organ.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    NO derived from NOS3 has both anti-obesogenic and insulin-sensitizing properties.

    “NO derived from NOS3 appears to have both anti-obesogenic and insulin-sensitizing properties.”
    Quote in the paperSubstantial claim
59 of 59

  • The paper relies on this without support.

    Findings from animal models of obesity and diabetes are informative about human obesity and diabetes.

    “NO bioavailability is decreased in animal models of obesity and diabetes [116, 117] and in obese and diabetic humans [118, 119].”

  • The paper relies on this without support.

    HISS is a liver-produced hormone that mediates a substantial portion of insulin's glucose disposal and peripheral vasodilation.

    “The answer has been suggested to lie in a hormone called ‘hepatic insulin-sensitizing substance (HISS)’. This substance, for which there are only suggestive candidates (e.g., bone morphogenetic protein-9 [296]), has been suggested to account for 55% of the glucose disposal effect of insulin.”
2 of 2

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Authors
Sansbury, B. E., & Hill, B. G.
Affiliations
University of Louisville (US)
Corresponding author
Hill, Bradford G.
ORCID
Venue
Free Radical Biology and Medicine
Publisher
Elsevier BV
Published
2014-08
Volume
73
Pages
383-399
ISSN
0891-5849 (ISSN-L)
DOI
10.1016/j.freeradbiomed.2014.05.016
PMC
PMC4112002
OpenAlex
W2004580431
Semantic Scholar
9be401aa7d5b93ae5de0b586336e2131cd5e4e17
Cited by
274
References
368
Citations by year
2026: 14 · 2025: 29 · 2024: 18 · 2023: 22 · 2022: 28 · 2021: 28 · 2020: 34 · 2019: 23 · 2018: 25 · 2017: 23 · 2016: 11 · 2015: 13 · 2014: 5
FWCI
2.04
Type
journal article
Language
en
Open access
Licence
Locations
  • Free Radical Biology and Medicine (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
NIH (GM103492, HL078825)
Topics
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
Keywords
nitric oxide, obesity, insulin resistance, energy metabolism, energy balance, adiposity, insulin sensitivity, type 2 diabetes, cardiovascular disease, diet-induced obesity, NO bioavailability, body composition
MeSH terms
Body Composition, Energy Intake, Diet, Energy Metabolism, Humans, Hunger, Insulin Resistance, Nitric Oxide, Obesity, Satiety Response, Adiposity, Nitric Oxide Synthase Type III

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.

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