712
Diabetes Volume 64, March 2015
Urmila P. Kodavanti
Air Pollution and Insulin Resistance: Do All Roads Lead to Rome?
COMMENTARY
Diabetes 2015;64:712–714 | DOI: 10.2337/db14-1682
AIR POLLUTION AND CHRONIC DISEASE SUSCEPTIBILITY
MANY MECHANISMS HAVE BEEN PROPOSED FOR SYSTEMIC EFFECTS OF AIR POLLUTION
The World Health Organization estimates that worldwide in 2012, nearly 7 million deaths occurred prematurely due to air pollution (1). In addition to respiratory and cardiovascular diseases, air pollution exposure is also linked to increased incidence of diabetes (2). Notably, the prevalence of diabetes and dyslipidemia escalated exponentially in the latter half of the 20th century coincident with the manufacture, use, and release of massive amounts of chemicals and pollution. The increase in the prevalence of these chronic conditions also coincides with an increase in sedentary lifestyles, calorie-rich diets, and human stress. Together, these factors contribute to metabolic disease. This complex tapestry suggests that many elements, including air pollution, are likely involved in an interactive manner to increase the risk of certain health conditions. Determining how air pollution might be linked to diabetes is useful not only in understanding how environmental factors contribute to the pathogenesis of this disease but also for identifying molecular targets for potential therapeutic strategies. Improved understanding of this dynamic also provides further rationale for improving air quality standards and public health. Ozone is produced in the air by photochemical reaction of components of anthropogenic emissions, and it contributes substantially to the societal burden of respiratory and cardiovascular disease. The pulmonary effects of ozone have been studied for decades (3), with recent attention turning to the metabolic and cardiovascular effects of this exposure.
A number of mechanisms have been proposed for extrapulmonary effects of inhaled pollutants. On the basis of experimental studies examining the metabolic effects of ambient particulate matter (chemically complex mixtures consisting of many components) in mouse models, Rajagopalan and Brook (4) proposed that systemic inflammation, oxidative stress, and neuronal mechanisms might be involved in adipose inflammation and tissue insulin resistance. In this issue of Diabetes, Vella et al. (5) report that although rats exposed to ozone did not show systemic inflammation associated with acute metabolic effects, they did exhibit insulin resistance in muscle tissue resulting from lipid and protein oxidation by-products.
Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, Durham, NC
© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
Corresponding author: Urmila P. Kodavanti, [email protected].
See accompanying article, p. 1011.
The research described in this article has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency and approved for publication. Approval does not signify that the contents necessarily reflect the views and the policies of the Agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use.
NEURONAL STRESS RESPONSE AS A POTENTIAL CONTRIBUTOR TO INSULIN RESISTANCE
Rats have a reversible decrease in body temperature when exposed to ozone (6,7). This is associated with impaired glucose homeostasis (8) and mobilization of energy sources during stress responses, an observation that might coincide with the adaptive insulin resistance in peripheral tissues (9) that was observed in the new work by Vella et al. (5). A growing body of evidence supports the hypothesis that ozone exposure induces a neuronal response that activates stress-sensitive centers in the nucleus tractus solitarius (10,11). Activation of catecholaminergic neurons in the nucleus tractus solitarius— central to systemic sympathetic stimulation—can mediate an immediate action (fight-or-flight response), activate a hypothalamus-pituitary-adrenal–mediated release of
diabetes.diabetesjournals.org
hormones from the adrenal cortex (12), and result in a release of glucose, free fatty acids, and branched-chain amino acids into the circulation (Fig. 1) (13). All of these responses have been implicated in insulin resistance (14). WHAT IS CHANGED IN THE CIRCULATION IN RESPONSE TO OZONE?
The lipid-rich alveolar lining fluid is known to react with ozone and produce oxidation by-products. Vella et al. (5) showed that oxidation of lipids and proteins can occur in the lung, leading to increases in oxidation by-products not only in the lung but also systemically and in muscle. They confirmed this observation by demonstrating the effectiveness of ingested N-acetyl cysteine (NAC) in reducing ozone-induced oxidation of lipids and proteins. We have recently observed that exposure to ozone is associated with marked increases in a variety of free fatty acids, branched-chain amino acids, glucose, cholesterols, and stress and metabolic hormones in the circulation (13). Many of these constituents can remain unaltered in the circulation, be taken up by liver and other peripheral tissues, or have the potential to be oxidized within the circulation and in cells. Thus, in addition to local pulmonary-derived oxidation by-products, the flux of these lipid and protein catabolism by-products in the circulation likely plays a role in acute peripheral insulin resistance (Fig. 1).
Kodavanti
713
MECHANISMS OF PERIPHERAL INSULIN RESISTANCE
Most research on insulin resistance has shown a role for circulating factors and mediators in impairing insulin signaling in different tissues. Many published studies focus on mediators that induce activation of stress kinases. These include c-Jun N-terminal kinases and tissue-specific isoforms of protein kinase C, which affect tyrosine versus serine phosphorylation of insulin receptor substrate-1. Activation of these stress kinases leads to impaired Aktmediated glucose transporter-4 translocation to the cell membrane and glucose intracellular transport (15). A variety of extracellular and intracellular biological components has been implicated in impairment of insulin signaling. These include free fatty acids (15), branched-chain amino acids (16), steroid and stress hormones (17), cytokines (18), diacylglycerol, ceramides (15), and intracellular free radicals derived from mitochondria (19). Although many studies have supported the contribution of oxidatively modified biological molecules, nonoxidized metabolites have also been implicated in insulin resistance (15,20). The intracellularly generated ceramides from fatty acyl-CoA and sphingosine have contributed to insulin resistance in muscle and liver cells (15). With regard to impairment of insulin signaling by air pollution, a key goal is to
Figure 1—Many potential mechanisms might be involved in air pollution–induced insulin resistance and diabetes. While exposure to ozone or other gas and particulate matter components of air pollution upon inhalation can oxidatively modify surfactant lining and cellular components, it can also activate a classic stress response to injury through direct sympathetic stimulation and activation of hypothalamus-pituitary-adrenal axis. A variety of systemic homeostatic metabolic and inflammatory mechanisms might be involved through neurohormone regulation, which rapidly changes the metabolic processes in multiple tissues and the circulating factors. Many of these factors are involved in tissue-selective insulin resistance, dyslipidemia, and the neuronal modulation of homeostatic mechanisms. The question that remains is how these acute changes in processes might upon chronic air pollution exposure contribute to sustained peripheral insulin resistance, dyslipidemia, diabetes, and cardiovascular disease. PM, ambient particulate matter; O3, ozone.
714
Commentary
identify systemically released metabolic by-products/ biological components and to determine their oxidation status. The most intriguing finding of Vella et al. (5) is that ozone increases lipid and protein oxidation by-products in the bronchoalveolar lavage fluid (BALF) and serum in parallel with increased muscle insulin resistance. The authors show that although the ozone-induced lung injury (protein leak) and inflammatory cell influx were not reduced in rats pretreated with NAC, the levels of thiobarbituric acid–reactive substances and protein carbonyls were decreased in BALF and in the circulation. This suggests that although NAC pretreatment was ineffective in protecting the lung from vascular leakage and inflammation, it reduced oxidation systemically and improved insulin signaling in muscle. Because incubation of myoblast cultures with BALF from ozone-exposed rats stimulated c-Jun N-terminal kinase–mediated signaling and replicated in vivo ozone effect on insulin signaling, Vella et al. (5) believe that these oxidants are involved in muscle insulin resistance. This observation is supported by detection of labeled oxygen in the blood after inhalation of labeled ozone in rats (21). However, more studies are warranted to precisely identify individual lipid oxidation by-products and their sites of generation and clearance and to determine the contribution (and possible chemical modifications) of systemically released fatty acids, amino acids, and hormones in peripheral insulin resistance. FACTORS TO CONSIDER IN FUTURE STUDIES
The outcome of NAC intervention in the study by Vella et al. (5) is interesting and it raises questions about the role of oxidation by-products and where they may be generated after ozone inhalation. However, highconcentration ozone exposure, especially during the night and in experiments of exceedingly long duration (16 h), which has been shown to cause remarkable lung injury in rats, is not likely to occur in a real-world scenario for humans. Moreover, we are still far from understanding if transient insulin resistance can be exacerbated or if adaptation is likely over extended periods, as noted with other biological end points on repeated chronic episodic ozone exposure (7,8). Considering the magnitude of the health burden of air pollution on chronic neurological and cardiovascular disease, lipidemia, ectopic lipid accumulation, nonalcoholic steatohepatitis, and diabetes in healthy and genetically compromised individuals, more studies like that by Vella et al. (5) are needed to fully understand the impact of this exposure on chronic disease. However, based on observed changes in a myriad of circulating factors (hormones, fatty acids, cholesterol, amino acids, and oxidation by-products of lipids and proteins) and alterations of peripheral metabolic homeostasis, it is quite possible that multiple mechanisms are involved in in vivo ozone-induced insulin resistance.
Diabetes Volume 64, March 2015
Acknowledgments. The author thanks Drs. Gary Hatch, Stephen Gavett, Wayne Cascio, and Ian Gilmour (U.S. Environmental Protection Agency) for their critical review of the manuscript. Duality of Interest. No potential conflicts of interest relevant to this article were reported.
References 1. World Health Organization. 7 million premature deaths annually linked to air pollution [article online], 2014. Available from http://www.who.int/mediacentre/ news/releases/2014/air-pollution/en/. Accessed 10 October 2014 2. Brook RD, Cakmak S, Turner MC, et al. Long-term fine particulate matter exposure and mortality from diabetes in Canada. Diabetes Care 2013;36:3313– 3320 3. Mauderly JL. Respiratory function responses of animals and man to oxidant gases and to pulmonary emphysema. J Toxicol Environ Health 1984;13:345–361 4. Rajagopalan S, Brook RD. Air pollution and type 2 diabetes: mechanistic insights. Diabetes 2012;61:3037–3045 5. Vella RE, Pillon NJ, Zarrouki B, et al. Ozone exposure triggers insulin resistance through muscle c-Jun N-terminal kinase activation. Diabetes 2015;64: 1011–1024 6. Watkinson WP, Campen MJ, Nolan JP, Costa DL. Cardiovascular and systemic responses to inhaled pollutants in rodents: effects of ozone and particulate matter. Environ Health Perspect 2001;109(Suppl. 4):539–546 7. Gordon CJ, Johnstone AF, Aydin C, et al. Episodic ozone exposure in adult and senescent Brown Norway rats: acute and delayed effect on heart rate, core temperature and motor activity. Inhal Toxicol 2014;26:380–390 8. Bass V, Gordon CJ, Jarema KA, et al. Ozone induces glucose intolerance and systemic metabolic effects in young and aged Brown Norway rats. Toxicol Appl Pharmacol 2013;273:551–560 9. Tsatsoulis A, Mantzaris MD, Bellou S, Andrikoula M. Insulin resistance: an adaptive mechanism becomes maladaptive in the current environment—an evolutionary perspective. Metabolism 2013;62:622–633 10. Soulage C, Perrin D, Cottet-Emard JM, Pequignot J, Dalmaz Y, Pequignot JM. Central and peripheral changes in catecholamine biosynthesis and turnover in rats after a short period of ozone exposure. Neurochem Int 2004;45:979–986 11. Gackière F, Saliba L, Baude A, Bosler O, Strube C. Ozone inhalation activates stress-responsive regions of the CNS. J Neurochem 2011;117:961–972 12. Patterson ZR, Abizaid A. Stress induced obesity: lessons from rodent models of stress. Front Neurosci 2013;7:130 13. Kodavanti UP. Emerging evidence of ozone’s metabolic effects and potential mechanisms (Abstract). The Toxicologist 2014;138:546 14. Montane J, Cadavez L, Novials A. Stress and the inflammatory process: a major cause of pancreatic cell death in type 2 diabetes. Diabetes Metab Syndr Obes 2014;7:25–34 15. Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell 2012;148:852–871 16. Lynch CJ, Adams SH. Branched-chain amino acids in metabolic signalling and insulin resistance. Nat Rev Endocrinol 2014;10:723–736 17. Park SY, Bae JH, Cho YS. Cortisone induces insulin resistance in C2C12 myotubes through activation of 11beta-hydroxysteroid dehydrogenase 1 and autocrinal regulation. Cell Biochem Funct 2014;32:249–257 18. McNelis JC, Olefsky JM. Macrophages, immunity, and metabolic disease. Immunity 2014;41:36–48 19. Coletta DK, Mandarino LJ. Mitochondrial dysfunction and insulin resistance from the outside in: extracellular matrix, the cytoskeleton, and mitochondria. Am J Physiol Endocrinol Metab 2011;301:E749–E755 20. Watt MJ, Hoy AJ. Lipid metabolism in skeletal muscle: generation of adaptive and maladaptive intracellular signals for cellular function. Am J Physiol Endocrinol Metab 2012;302:E1315–E1328 21. Hatch GE, Slade R, McKee J. Fate of pathologically bound oxygen resulting from inhalation of labeled ozone in rats. Environ Health Insights 2013;7:43–58
Diabetes Volume 64, March 2015
Urmila P. Kodavanti
Air Pollution and Insulin Resistance: Do All Roads Lead to Rome?
COMMENTARY
Diabetes 2015;64:712–714 | DOI: 10.2337/db14-1682
AIR POLLUTION AND CHRONIC DISEASE SUSCEPTIBILITY
MANY MECHANISMS HAVE BEEN PROPOSED FOR SYSTEMIC EFFECTS OF AIR POLLUTION
The World Health Organization estimates that worldwide in 2012, nearly 7 million deaths occurred prematurely due to air pollution (1). In addition to respiratory and cardiovascular diseases, air pollution exposure is also linked to increased incidence of diabetes (2). Notably, the prevalence of diabetes and dyslipidemia escalated exponentially in the latter half of the 20th century coincident with the manufacture, use, and release of massive amounts of chemicals and pollution. The increase in the prevalence of these chronic conditions also coincides with an increase in sedentary lifestyles, calorie-rich diets, and human stress. Together, these factors contribute to metabolic disease. This complex tapestry suggests that many elements, including air pollution, are likely involved in an interactive manner to increase the risk of certain health conditions. Determining how air pollution might be linked to diabetes is useful not only in understanding how environmental factors contribute to the pathogenesis of this disease but also for identifying molecular targets for potential therapeutic strategies. Improved understanding of this dynamic also provides further rationale for improving air quality standards and public health. Ozone is produced in the air by photochemical reaction of components of anthropogenic emissions, and it contributes substantially to the societal burden of respiratory and cardiovascular disease. The pulmonary effects of ozone have been studied for decades (3), with recent attention turning to the metabolic and cardiovascular effects of this exposure.
A number of mechanisms have been proposed for extrapulmonary effects of inhaled pollutants. On the basis of experimental studies examining the metabolic effects of ambient particulate matter (chemically complex mixtures consisting of many components) in mouse models, Rajagopalan and Brook (4) proposed that systemic inflammation, oxidative stress, and neuronal mechanisms might be involved in adipose inflammation and tissue insulin resistance. In this issue of Diabetes, Vella et al. (5) report that although rats exposed to ozone did not show systemic inflammation associated with acute metabolic effects, they did exhibit insulin resistance in muscle tissue resulting from lipid and protein oxidation by-products.
Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, Durham, NC
© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
Corresponding author: Urmila P. Kodavanti, [email protected].
See accompanying article, p. 1011.
The research described in this article has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency and approved for publication. Approval does not signify that the contents necessarily reflect the views and the policies of the Agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use.
NEURONAL STRESS RESPONSE AS A POTENTIAL CONTRIBUTOR TO INSULIN RESISTANCE
Rats have a reversible decrease in body temperature when exposed to ozone (6,7). This is associated with impaired glucose homeostasis (8) and mobilization of energy sources during stress responses, an observation that might coincide with the adaptive insulin resistance in peripheral tissues (9) that was observed in the new work by Vella et al. (5). A growing body of evidence supports the hypothesis that ozone exposure induces a neuronal response that activates stress-sensitive centers in the nucleus tractus solitarius (10,11). Activation of catecholaminergic neurons in the nucleus tractus solitarius— central to systemic sympathetic stimulation—can mediate an immediate action (fight-or-flight response), activate a hypothalamus-pituitary-adrenal–mediated release of
diabetes.diabetesjournals.org
hormones from the adrenal cortex (12), and result in a release of glucose, free fatty acids, and branched-chain amino acids into the circulation (Fig. 1) (13). All of these responses have been implicated in insulin resistance (14). WHAT IS CHANGED IN THE CIRCULATION IN RESPONSE TO OZONE?
The lipid-rich alveolar lining fluid is known to react with ozone and produce oxidation by-products. Vella et al. (5) showed that oxidation of lipids and proteins can occur in the lung, leading to increases in oxidation by-products not only in the lung but also systemically and in muscle. They confirmed this observation by demonstrating the effectiveness of ingested N-acetyl cysteine (NAC) in reducing ozone-induced oxidation of lipids and proteins. We have recently observed that exposure to ozone is associated with marked increases in a variety of free fatty acids, branched-chain amino acids, glucose, cholesterols, and stress and metabolic hormones in the circulation (13). Many of these constituents can remain unaltered in the circulation, be taken up by liver and other peripheral tissues, or have the potential to be oxidized within the circulation and in cells. Thus, in addition to local pulmonary-derived oxidation by-products, the flux of these lipid and protein catabolism by-products in the circulation likely plays a role in acute peripheral insulin resistance (Fig. 1).
Kodavanti
713
MECHANISMS OF PERIPHERAL INSULIN RESISTANCE
Most research on insulin resistance has shown a role for circulating factors and mediators in impairing insulin signaling in different tissues. Many published studies focus on mediators that induce activation of stress kinases. These include c-Jun N-terminal kinases and tissue-specific isoforms of protein kinase C, which affect tyrosine versus serine phosphorylation of insulin receptor substrate-1. Activation of these stress kinases leads to impaired Aktmediated glucose transporter-4 translocation to the cell membrane and glucose intracellular transport (15). A variety of extracellular and intracellular biological components has been implicated in impairment of insulin signaling. These include free fatty acids (15), branched-chain amino acids (16), steroid and stress hormones (17), cytokines (18), diacylglycerol, ceramides (15), and intracellular free radicals derived from mitochondria (19). Although many studies have supported the contribution of oxidatively modified biological molecules, nonoxidized metabolites have also been implicated in insulin resistance (15,20). The intracellularly generated ceramides from fatty acyl-CoA and sphingosine have contributed to insulin resistance in muscle and liver cells (15). With regard to impairment of insulin signaling by air pollution, a key goal is to
Figure 1—Many potential mechanisms might be involved in air pollution–induced insulin resistance and diabetes. While exposure to ozone or other gas and particulate matter components of air pollution upon inhalation can oxidatively modify surfactant lining and cellular components, it can also activate a classic stress response to injury through direct sympathetic stimulation and activation of hypothalamus-pituitary-adrenal axis. A variety of systemic homeostatic metabolic and inflammatory mechanisms might be involved through neurohormone regulation, which rapidly changes the metabolic processes in multiple tissues and the circulating factors. Many of these factors are involved in tissue-selective insulin resistance, dyslipidemia, and the neuronal modulation of homeostatic mechanisms. The question that remains is how these acute changes in processes might upon chronic air pollution exposure contribute to sustained peripheral insulin resistance, dyslipidemia, diabetes, and cardiovascular disease. PM, ambient particulate matter; O3, ozone.
714
Commentary
identify systemically released metabolic by-products/ biological components and to determine their oxidation status. The most intriguing finding of Vella et al. (5) is that ozone increases lipid and protein oxidation by-products in the bronchoalveolar lavage fluid (BALF) and serum in parallel with increased muscle insulin resistance. The authors show that although the ozone-induced lung injury (protein leak) and inflammatory cell influx were not reduced in rats pretreated with NAC, the levels of thiobarbituric acid–reactive substances and protein carbonyls were decreased in BALF and in the circulation. This suggests that although NAC pretreatment was ineffective in protecting the lung from vascular leakage and inflammation, it reduced oxidation systemically and improved insulin signaling in muscle. Because incubation of myoblast cultures with BALF from ozone-exposed rats stimulated c-Jun N-terminal kinase–mediated signaling and replicated in vivo ozone effect on insulin signaling, Vella et al. (5) believe that these oxidants are involved in muscle insulin resistance. This observation is supported by detection of labeled oxygen in the blood after inhalation of labeled ozone in rats (21). However, more studies are warranted to precisely identify individual lipid oxidation by-products and their sites of generation and clearance and to determine the contribution (and possible chemical modifications) of systemically released fatty acids, amino acids, and hormones in peripheral insulin resistance. FACTORS TO CONSIDER IN FUTURE STUDIES
The outcome of NAC intervention in the study by Vella et al. (5) is interesting and it raises questions about the role of oxidation by-products and where they may be generated after ozone inhalation. However, highconcentration ozone exposure, especially during the night and in experiments of exceedingly long duration (16 h), which has been shown to cause remarkable lung injury in rats, is not likely to occur in a real-world scenario for humans. Moreover, we are still far from understanding if transient insulin resistance can be exacerbated or if adaptation is likely over extended periods, as noted with other biological end points on repeated chronic episodic ozone exposure (7,8). Considering the magnitude of the health burden of air pollution on chronic neurological and cardiovascular disease, lipidemia, ectopic lipid accumulation, nonalcoholic steatohepatitis, and diabetes in healthy and genetically compromised individuals, more studies like that by Vella et al. (5) are needed to fully understand the impact of this exposure on chronic disease. However, based on observed changes in a myriad of circulating factors (hormones, fatty acids, cholesterol, amino acids, and oxidation by-products of lipids and proteins) and alterations of peripheral metabolic homeostasis, it is quite possible that multiple mechanisms are involved in in vivo ozone-induced insulin resistance.
Diabetes Volume 64, March 2015
Acknowledgments. The author thanks Drs. Gary Hatch, Stephen Gavett, Wayne Cascio, and Ian Gilmour (U.S. Environmental Protection Agency) for their critical review of the manuscript. Duality of Interest. No potential conflicts of interest relevant to this article were reported.
References 1. World Health Organization. 7 million premature deaths annually linked to air pollution [article online], 2014. Available from http://www.who.int/mediacentre/ news/releases/2014/air-pollution/en/. Accessed 10 October 2014 2. Brook RD, Cakmak S, Turner MC, et al. Long-term fine particulate matter exposure and mortality from diabetes in Canada. Diabetes Care 2013;36:3313– 3320 3. Mauderly JL. Respiratory function responses of animals and man to oxidant gases and to pulmonary emphysema. J Toxicol Environ Health 1984;13:345–361 4. Rajagopalan S, Brook RD. Air pollution and type 2 diabetes: mechanistic insights. Diabetes 2012;61:3037–3045 5. Vella RE, Pillon NJ, Zarrouki B, et al. Ozone exposure triggers insulin resistance through muscle c-Jun N-terminal kinase activation. Diabetes 2015;64: 1011–1024 6. Watkinson WP, Campen MJ, Nolan JP, Costa DL. Cardiovascular and systemic responses to inhaled pollutants in rodents: effects of ozone and particulate matter. Environ Health Perspect 2001;109(Suppl. 4):539–546 7. Gordon CJ, Johnstone AF, Aydin C, et al. Episodic ozone exposure in adult and senescent Brown Norway rats: acute and delayed effect on heart rate, core temperature and motor activity. Inhal Toxicol 2014;26:380–390 8. Bass V, Gordon CJ, Jarema KA, et al. Ozone induces glucose intolerance and systemic metabolic effects in young and aged Brown Norway rats. Toxicol Appl Pharmacol 2013;273:551–560 9. Tsatsoulis A, Mantzaris MD, Bellou S, Andrikoula M. Insulin resistance: an adaptive mechanism becomes maladaptive in the current environment—an evolutionary perspective. Metabolism 2013;62:622–633 10. Soulage C, Perrin D, Cottet-Emard JM, Pequignot J, Dalmaz Y, Pequignot JM. Central and peripheral changes in catecholamine biosynthesis and turnover in rats after a short period of ozone exposure. Neurochem Int 2004;45:979–986 11. Gackière F, Saliba L, Baude A, Bosler O, Strube C. Ozone inhalation activates stress-responsive regions of the CNS. J Neurochem 2011;117:961–972 12. Patterson ZR, Abizaid A. Stress induced obesity: lessons from rodent models of stress. Front Neurosci 2013;7:130 13. Kodavanti UP. Emerging evidence of ozone’s metabolic effects and potential mechanisms (Abstract). The Toxicologist 2014;138:546 14. Montane J, Cadavez L, Novials A. Stress and the inflammatory process: a major cause of pancreatic cell death in type 2 diabetes. Diabetes Metab Syndr Obes 2014;7:25–34 15. Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell 2012;148:852–871 16. Lynch CJ, Adams SH. Branched-chain amino acids in metabolic signalling and insulin resistance. Nat Rev Endocrinol 2014;10:723–736 17. Park SY, Bae JH, Cho YS. Cortisone induces insulin resistance in C2C12 myotubes through activation of 11beta-hydroxysteroid dehydrogenase 1 and autocrinal regulation. Cell Biochem Funct 2014;32:249–257 18. McNelis JC, Olefsky JM. Macrophages, immunity, and metabolic disease. Immunity 2014;41:36–48 19. Coletta DK, Mandarino LJ. Mitochondrial dysfunction and insulin resistance from the outside in: extracellular matrix, the cytoskeleton, and mitochondria. Am J Physiol Endocrinol Metab 2011;301:E749–E755 20. Watt MJ, Hoy AJ. Lipid metabolism in skeletal muscle: generation of adaptive and maladaptive intracellular signals for cellular function. Am J Physiol Endocrinol Metab 2012;302:E1315–E1328 21. Hatch GE, Slade R, McKee J. Fate of pathologically bound oxygen resulting from inhalation of labeled ozone in rats. Environ Health Insights 2013;7:43–58
