Regulation of obesity and insulin resistance by nitric oxide

In the paper

“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].”

What the sources say

• Supported

  The “Current treatments of obesity” section states that caloric restriction faces a defense against a lower bound of fat content. It also says weight loss increases caloric efficiency through a reduction in basal metabolic rate, making further loss harder. (LLM, conf=0.94)

  cites [7] Tseng, 2010, Cellular bioenergetics as a target for obesity therapy, Nat. Rev. Drug Discovery source
• Not checked yetcites [31] Wells, 2009, Thrift: a guide to thrifty genes, thrifty phenotypes and thrifty norms, Int. J. Obes. source
• Supported

  The citation is attached to the body's increased caloric efficiency during dieting, not the separate claim about an evolution-engendered guard against low fat mass. The Discussion reports that caloric restriction reduced energy expenditure beyond what loss of metabolic mass could explain, calling this a metabolic adaptation that contributes to resistance to weight loss. (LLM, conf=0.89)

  cites [32] Redman, 2009, Metabolic and behavioral compensations in response to caloric restriction: implications for the maintenance of weight loss, PLoS One source
• Not checked yetcites [33] Leibel, 1995, Changes in energy expenditure resulting from altered body weight, N. Engl. J. Med. source

In the paper

“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].”

What the sources say

• Not checked yetcites [96] Rapoport, 1983, Endothelium-dependent relaxation in rat aorta may be mediated through cyclic GMP-dependent protein phosphorylation, Nature source
• Partly supported

  The Abstract and Discussion report that endothelium-dependent relaxation in rat thoracic aorta is associated with increased cGMP in smooth muscle, and propose an endothelial factor as the mediator. They do not identify that factor as NO synthesized by endothelial NOS or establish its diffusion into the vessel wall; their discussion of NO activating guanylate cyclase concerns nitrovasodilators. (LLM, conf=0.90)

  cites [97] Rapoport, 1983, Agonist-induced endothelium-dependent relaxation in rat thoracic aorta may be mediated through cGMP, Circ. Res. sourceExperimental — accuracy not yet measured
• Partly supported

  The paper’s summary (Circulation Research 58, pp. 531–538) supports the proposed sequence in which an acetylcholine-induced endothelial factor stimulates soluble guanylate cyclase, increases smooth-muscle cGMP, and accompanies vessel relaxation. Its introduction calls that factor’s chemical structure unknown; the paper does not establish that it is NO, that NOS synthesizes it, or that NO diffuses into the vessel wall. (LLM, conf=0.91)

  cites [98] Forstermann, 1986, Stimulation of soluble guanylate cyclase by an acetylcholine-induced endothelium-derived factor from rabbit and canine arteries, Circ. Res. sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion (p. 3) says endothelial nitric oxide synthase produces NO and that NO relaxes vascular smooth muscle through cyclic GMP. The results (p. 3) also link guanylate cyclase inhibition to reduced relaxation in corpus cavernosum tissue. Our copy does not describe NO diffusing from endothelium into the vessel wall or directly establish the full endothelial NO–soluble guanylate cyclase sequence in vascular smooth muscle. (LLM, conf=0.86)

  cites [99] Rajfer, 1992, Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to nonadrenergic, noncholinergic neurotransmission, N. Engl. J. Med. sourceExperimental — accuracy not yet measured
• Not checked yetcites [100] Moncada, 1986, Mechanism of action of some inhibitors of endothelium-derived relaxing factor, Proc. Natl. Acad. Sci. USA source
• Partly supported

  The ‘Release of endothelium-derived relaxing factor’ section reports that endothelial-cell-derived EDRF relaxed arterial strips, and the Discussion describes its action on tissues away from the site of release. The copy does not identify EDRF as NO, describe its synthesis by NOS, or show that EDRF raises cGMP through soluble guanylate cyclase; the Bioassay section mentions guanylate cyclase only when describing calibration with other compounds. (LLM, conf=0.88)

  cites [101] Gryglewski, 1986, Bioassay of prostacyclin and endothelium-derived relaxing factor (EDRF) from porcine aortic endothelial cells, Br. J. Pharmacol. sourceExperimental — accuracy not yet measured
• Not checked yetcites [102] Palmer, 1987, Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor, Nature source

In the paper

“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].”

What the sources say

• Not checked yetcites [7] Tseng, 2010, Cellular bioenergetics as a target for obesity therapy, Nat. Rev. Drug Discovery source

In the paper

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

In the paper

“neuropeptide Y (NPY) directly affects feeding behavior, metabolism and body composition [37, 38]”

What the sources say

• Not checked yetcites [37] Stanley, 1986, Neuropeptide Y chronically injected into the hypothalamus: a powerful neurochemical inducer of hyperphagia and obesity, Peptides source
• Not checked yetcites [38] Billington, 1994, Neuropeptide Y in hypothalamic paraventricular nucleus: a center coordinating energy metabolism, Am. J. Physiol.

In the paper

“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].”

What the sources say

• Not checked yetcites [39] Beck, 2013, Ghrelin, neuropeptide Y, and other feeding-regulatory peptides active in the hippocampus: role in learning and memory, Nutr. Rev. source

In the paper

“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].”

What the sources say

• Not checked yetcites [34] Spiegelman, 2001, Obesity and the regulation of energy balance, Cell source
• Not checked yetcites [35] Ahima, 2000, Leptin, Annu. Rev. Physiol. source
• Not checked yetcites [36] Schwartz, 2000, Central nervous system control of food intake, Nature source

In the paper

“The neurotransmitters norepinephrine, dopamine and serotonin are also important in central energy balance [34, 36]”

What the sources say

• Not checked yetcites [34] Spiegelman, 2001, Obesity and the regulation of energy balance, Cell source
• Not checked yetcites [36] Schwartz, 2000, Central nervous system control of food intake, Nature source

In the paper

“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].”

What the sources say

• Not checked yetcites [47] Cutting, 1934, Relationship between blood cholesterol and increased metabolism from dinitrophenol and thyroid, J. Clin. Invest. source
• Not checked yetcites [48] Tainter, 1934, Use of dinitrophenol in nutritional disorders: a critical survey of clinical results, Am. J. Public Health Nations Health source
• Not checked yetcites [49] Colman, 2007, Dinitrophenol and obesity: an early twentieth-century regulatory dilemma, Regul. Toxicol. Pharmacol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [45] Guerciolini, 1997, Mode of action of orlistat, Int. J. Obes. Relat. Metab. Disord

In the paper

“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].”

What the sources say

• Not checked yetcites [46] Harper, 2008, The efficiency of cellular energy transduction and its implications for obesity, Annu. Rev. Nutr. source

In the paper

“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].”

What the sources say

• Not checked yetcites [7] Tseng, 2010, Cellular bioenergetics as a target for obesity therapy, Nat. Rev. Drug Discovery source
• Not checked yetcites [46] Harper, 2008, The efficiency of cellular energy transduction and its implications for obesity, Annu. Rev. Nutr. source

In the paper

“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].”

What the sources say

• Not checked yetcites [40] Bray, 2000, Medicinal strategies in the treatment of obesity, Nature source

In the paper

“orlistat promotes weight loss; however, side effects caused discontinuation of the medication in many patients [40].”

What the sources say

• Not checked yetcites [40] Bray, 2000, Medicinal strategies in the treatment of obesity, Nature source

In the paper

“PGC-1α is a known regulator of energy metabolism and of mitochondrial biogenesis [59]”

What the sources say

• Not checked yetcites [59] Handschin, 2006, Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism, Endocr. Rev. source

In the paper

“The three isoforms of NOS generate NO at different rates [62].”

What the sources say

• Not checked yetcites [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

In the paper

“The most common route of NO production is through the action of the nitric oxide synthase (NOS) family of enzymes [62, 64].”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [64] Alderton, 2001, Nitric oxide synthases: structure, function and inhibition, Biochem. J. source

In the paper

“Such synthesis of NO depends on the availability of cofactors such as FAD, FMN, tetrahydrobiopterin (BH4), as well as the prosthetic group, heme [65].”

What the sources say

• Not checked yetcites [65] Li, 2005, Structure–function studies on nitric oxide synthases, J. Inorg. Biochem. source

In the paper

“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].”

What the sources say

• Not checked yetcites [66] Dudzinski, 2007, Life history of eNOS: partners and pathways, Cardiovasc. Res. source
• Not checked yetcites [67] Shen, 2011, Lipoamide or lipoic acid stimulates mitochondrial biogenesis in 3T3-L1 adipocytes via the endothelial NO synthase–cGMP–protein kinase G signalling pathway, Br. J. Pharmacol. source
• Not checked yetcites [68] Tedesco, 2008, Cannabinoid type 1 receptor blockade promotes mitochondrial biogenesis through endothelial nitric oxide synthase expression in white adipocytes, Diabetes source
• Not checked yetcites [69] Mei, 2011, Endothelial nitric oxide synthase is a key mediator of hepatocyte proliferation in response to partial hepatectomy in mice, Hepatology source
• Not checked yetcites [70] Vazquez-Chantada, 2009, Evidence for LKB1/AMP-activated protein kinase/endothelial nitric oxide synthase cascade regulated by hepatocyte growth factor, S-adenosylmethionine, and nitric oxide in hepatocyte proliferation, Hepatology source
• Not checked yetcites [71] Zimmermann, 1996, Decreased constitutive hepatic nitric oxide synthase expression in secondary biliary fibrosis and its changes after Roux-en-Y choledocho-jejunostomy in the rat, J. Hepatol. source

In the paper

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

What the sources say

• Not checked yetcites [60] Serra, 2013, Mitochondrial fatty acid oxidation in obesity, Antioxid. Redox Signaling source
• Not checked yetcites [61] Bostrom, 2012, A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis, Nature source

In the paper

“Nitric oxide and related nitrogen oxides have emerged as critical regulators of cell and tissue function [62].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [81] Thomas, 2001, The biological lifetime of nitric oxide: implications for the perivascular dynamics of NO and O2, Proc. Natl. Acad. Sci. USA source

In the paper

“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].”

What the sources say

• Not checked yetcites [72] Oess, 2006, Subcellular targeting and trafficking of nitric oxide synthases, Biochem. J. source
• Not checked yetcites [73] Sessa, 2004, eNOS at a glance, J. Cell Sci. source
• Not checked yetcites [74] Balligand, 2009, eNOS activation by physical forces: from short-term regulation of contraction to chronic remodeling of cardiovascular tissues, Physiol. Rev. source
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [85] Beckman, 2009, Understanding peroxynitrite biochemistry and its potential for treating human diseases, Arch. Biochem. Biophys. source
• Not checked yetcites [87] Alvarez, 2003, Peroxynitrite reactivity with amino acids and proteins, Amino Acids source
• Not checked yetcites [88] Xu, 2006, Detection of sequence-specific tyrosine nitration of manganese SOD and SERCA in cardiovascular disease and aging, Am. J. Physiol. Heart Circ. Physiol source
• Not checked yetcites [89] Koeck, 2005, Mitochondria and regulated tyrosine nitration, Biochem. Soc. Trans. source
• Not checked yetcites [90] Aulak, 2001, Proteomic method identifies proteins nitrated in vivo during inflammatory challenge, Proc. Natl. Acad. Sci. USA source
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [76] Kleinert, 2004, Regulation of the expression of inducible nitric oxide synthase, Eur. J. Pharmacol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [82] Pacher, 2007, Nitric oxide and peroxynitrite in health and disease, Physiol. Rev. source
• Not checked yetcites [83] Trujillo, 2008, Peroxynitrite detoxification and its biologic implications, Antioxid. Redox Signaling source
• Not checked yetcites [84] Szabo, 2007, Peroxynitrite: biochemistry, pathophysiology and development of therapeutics, Nat. Rev. Drug Discovery source
• Not checked yetcites [85] Beckman, 2009, Understanding peroxynitrite biochemistry and its potential for treating human diseases, Arch. Biochem. Biophys. source
• Not checked yetcites [86] McAndrew, 1997, The interplay of nitric oxide and peroxynitrite with signal transduction pathways: implications for disease, Semin. Perinatol. source

In the paper

“NOS1 activity in the medulla and hypothalamus is important for systemic regulation of blood pressure [104-107]”

What the sources say

• Not checked yetcites [104] Togashi, 1992, A central nervous system action of nitric oxide in blood pressure regulation, J. Pharmacol. Exp. Ther. source
• Not checked yetcites [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 yetcites [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 yetcites [107] Toda, 2009, Control of systemic and pulmonary blood pressure by nitric oxide formed through neuronal nitric oxide synthase, J. Hypertens. source

In the paper

“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.”

What the sources say

• Not checked yetcites [113] Kelly, 2004, Transcriptional regulatory circuits controlling mitochondrial biogenesis and function, Genes Dev. source
• Not checked yetcites [114] Nisoli, 2003, Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide, Science source
• Not checked yetcites [115] Nisoli, 2004, Mitochondrial biogenesis by NO yields functionally active mitochondria in mammals, Proc. Natl. Acad. Sci. USA source

In the paper

“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].”

What the sources say

• Not checked yetcites [82] Pacher, 2007, Nitric oxide and peroxynitrite in health and disease, Physiol. Rev. source

In the paper

“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).”

In the paper

“NOS3 and NOS1 were found to have distinct roles in regulating microvascular tone [103]”

What the sources say

• Not checked yetcites [103] Melikian, 2009, Neuronal nitric oxide synthase and human vascular regulation, Trends Cardiovasc. Med source

In the paper

“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].”

What the sources say

• Not checked yetcites [81] Thomas, 2001, The biological lifetime of nitric oxide: implications for the perivascular dynamics of NO and O2, Proc. Natl. Acad. Sci. USA source

In the paper

“tumor necrosis factor-α (TNFα), which is increased in obesity and implicated in the etiology of insulin resistance [130]”

What the sources say

• Not checked yetcites [130] Hotamisligil, 1993, Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance, Science source

In the paper

“In rodents, L-arginine was shown to increase, and NOS inhibitors to decrease, food intake [155, 251-254].”

What the sources say

• Not checked yetcites [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 yetcites [251] Morley, 1991, Evidence that nitric oxide modulates food intake in mice, Life Sci. source
• Not checked yetcites [252] Morley, 1992, Competitive antagonism of nitric oxide synthetase causes weight loss in mice, Life Sci. source
• Not checked yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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]”

What the sources say

• Not checked yetcites [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 yetcites [258] Stricker-Krongrad, 1996, Nitric oxide mediates hyperphagia of obese Zucker rats: relation to specific changes in the microstructure of feeding behavior, Life Sci.

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [268] Sugimoto, 1999, Involvement of nitric oxide in the 5-HT1A autoreceptor-mediated hyperphagia in rats, Adv. Exp. Med. Biol. source
• Not checked yetcites [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 yetcites [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

In the paper

“as well as reduce adiposity and improve insulin sensitivity in high fat-fed mouse models [259]”

What the sources say

• Not checked yetcites [259] Tsuchiya, 2007, Chronic blockade of nitric oxide synthesis reduces adiposity and improves insulin resistance in high fat-induced obese mice, Endocrinology source

In the paper

“Interestingly, intracerebroventricular administration of NG-monomethyl-L-arginine (LNMMA) was shown also to regulate insulin secretion and peripheral insulin sensitivity [260]”

What the sources say

• Not checked yetcites [260] Shankar, 1998, Central nervous system nitric oxide synthase activity regulates insulin secretion and insulin action, J. Clin. Invest. source

In the paper

“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].”

What the sources say

• Not checked yetcites [179] Kubota, 2011, Impaired insulin signaling in endothelial cells reduces insulin-induced glucose uptake by skeletal muscle, Cell Metab. source

In the paper

“Despite promoting hyperphagia, L-arginine feeding reduced white adipose tissue mass, improved insulin sensitivity, and increased energy expenditure in mice [278].”

What the sources say

• Not checked yetcites [278] Clemmensen, 2012, L-Arginine improves multiple physiological parameters in mice exposed to diet-induced metabolic disturbances, Amino Acids source

In the paper

“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].”

What the sources say

• Not checked yetcites [282] McKnight, 2010, Beneficial effects of L-arginine on reducing obesity: potential mechanisms and important implications for human health, Amino Acids source

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [279] Fu, 2005, Dietary L-arginine supplementation reduces fat mass in Zucker diabetic fatty rats, J. Nutr. source
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [283] Ayala, 2007, Chronic treatment with sildenafil improves energy balance and insulin action in high fat-fed conscious mice, Diabetes source

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“In mice, it has been reported that deletion of NOS3 causes insulin resistance, hyperlipidemia, and hypertension [326].”

What the sources say

• Not checked yetcites [326] Duplain, 2001, Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase, Circulation source

In the paper

“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].”

What the sources say

• Not checked yetcites [293] Sadri, 1999, Blockade of hepatic nitric oxide synthase causes insulin resistance, Am. J. Physiol.
• Not checked yetcites [294] Guarino, 2003, Hepatic glutathione and nitric oxide are critical for hepatic insulin-sensitizing substance action, Am. J. Physiol. Gastrointest. Liver Physiol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [335] Atochin, 2010, Endothelial nitric oxide synthase transgenic models of endothelial dysfunction, Pflugers Arch. source

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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]”

What the sources say

• Not checked yetcites [332] Le Gouill, 2007, Endothelial nitric oxide synthase (eNOS) knockout mice have defective mitochondrial beta-oxidation, Diabetes source

In the paper

“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].”

What the sources say

• Not checked yetcites [309] Broniowska, 2014, A. beta-Cell responses to nitric oxide, Vitam. Horm. source
• Not checked yetcites [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

In the paper

“Selective overexpression of NOS2 in liver is sufficient to cause hepatic insulin resistance, hyperglycemia and hyperinsulinemia [355]”

What the sources say

• Not checked yetcites [355] Handa, 2011, Reduced vascular nitric oxide–cGMP signaling contributes to adipose tissue inflammation during high-fat feeding, Arterioscler. Thromb. Vasc. Biol. source

In the paper

“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.”

In the paper

“NO derived from NOS3 appears to have both anti-obesogenic and insulin-sensitizing properties.”