Acta Physiol 2015, 214, 291–294
ExActa The metabolic syndrome: the future is now Just in the beginning of the last century, infectious diseases and malnutrition were most life threatening for the world0 s population. Today, we are threatened by a slower killing enemy: dysfunction in metabolic processes caused by the Western lifestyle and food (Swinburn et al. 2011). Our sedentary way of life in combination with unhealthy food, rich in fat and sugar, brought us obesity and the metabolic syndrome (Symonds et al. 2009). The worldwide prevalence of obesity rises dramatically among children, adolescents and adults, not only in the Western countries but also in other countries (Seidell 2000). The WHO expects about 300 million people worldwide suffering from metabolic syndrome and associated disorders in the year 2025 (Seidell 2000, Schmerbach & Patzak 2014). The metabolic syndrome also called syndrome X is defined by obesity and several cardiovascular risk factors such as lipid abnormalities, high blood pressure and impaired glucose tolerance as well as a proinflammatory and prothrombotic state (Alberti et al. 2006, Morrow 2014). This cluster of symptoms predisposes for the development of several complications such as cardiovascular disease, non-alcoholic fatty liver disease and type 2 diabetes leading to enormous financial burdens for societies all over the world (Berrington de Gonzalez et al. 2010, King 2011, Swinburn et al. 2011, Persson & Bondke Persson 2013, Xiong et al. 2014). Excessive caloric intake is facilitated by eating strongly processed, industrially produced food (Mozaffarian et al. 2011, Swinburn et al. 2011). There were a number of recent efforts to understand the pathophysiology in more detail. For example, Heinonen et al. recently showed that a Western diet (high fat, high carbohydrate content) as well as a high-fat diet induced whole-body oxidative stress and increased body adiposity in mice (Heinonen et al. 2014). Interestingly, the diet fat content is decisive for the increasing body weight, rather than the equal-caloric Western diet. The short-time high-caloric diet intervention did not induce remarkable changes in glucose metabolism, but impairments in resistance artery endothelial function, which supports the idea that these microvascular impairments represent early signs of metabolic syndrome (Wang & Widlansky 2009, Heinonen et al. 2014). Endothelial dysfunction seems to result from disturbed secretion of adipokines and inflammatory factors from visceral adipose tissue. The study by Heinonen furthermore revealed an effect also
seen in humans where enhanced total body, visceral and liver adiposity occur without a change in total body weight, highlighting the role of visceral body fat, not only in obese but also in normal weight people (Smith & Adams 2011). Consequently, body fat content should be considered an additional risk factor for the development of metabolic syndrome-associated cardiovascular and organ complications. Adipose tissue (AT) is no longer considered as a simple and passive energy depot, but as the central node in a multi-directional organ crosstalk by secreting bioactive factors, the so-called adipokines, reviewed in detail by Romacho et al. (2014). Adipokines are a heterogenous group of molecules displaying local effects in the AT itself, but they also reach distant organs and tissues through the circulation and influence central metabolic processes such as the regulation of food intake, appetite regulation, insulin sensitivity, coagulation and vascular function. Imbalances in adipokine expression and secretion, especially of pro-inflammatory adipokines, were suggested to play a role in metabolic dysfunction and the development of insulin resistance and nevertheless represent signs of impaired adipocyte development (Kahn & Flier 2000). Several adipokines have protective effects on adipocyte development and metabolic processes, but they are often downregulated in obesity such as leptin and adiponectin. Leptin, the adipokine discovered first, is secreted under high glucose, insulin and pyruvate (Zhang et al. 1994) and together with adiponectin improves insulin sensitivity (Zhang et al. 1994). Exacerbating factors such as TNF-a, IL-6, chemerin and dipeptidyl peptidase 4 were elevated in obese patients and their serum levels correlate with adipocyte hypertrophy or represent markers of metabolic dysfunction (Lamers et al. 2011). The complex organ AT crosstalk builds the link between metabolic dysfunctions and organspecific complications. The microvascular network plays an important role in the development of cardiovascular disease. Musa et al. reviewed the microvascular dysfunctions present in individuals with type 2 diabetes, metabolic syndrome and obese or overweight people (Musa et al. 2014). The early stages of cardiovascular disease in humans are associated with a reduction in capillary numbers and diameters in the skin and retinal microcirculation. This reduction in skeletal muscle microvascular network length and
© 2015 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12530
291
ExActa
· S Reuter and R Mrowka
surface area is also found in obese and diabetic mice such as the db/db mice (leptin receptor deficiency). Circulating increased levels of pro-inflammatory cytokines, free fatty acids and glucose oxidation during hyperglycaemic states enhance the release of reactive oxygen species and impair the availability of endogenous vasodilators (Goodwill & Frisbee 2012). Despite the strong correlation between low birthweight and cardiovascular disease, the mechanisms underlying foetal ‘reprogramming’ of the microvasculature remain a field of ongoing investigation. Nevertheless, subclinical changes in the microvasculature due to an unfavourable lifestyle could be easily detected by clinicians and offer the chance for lifestyle intervention before the onset of cardiovascular disease. Despite strong efforts to promote a healthier lifestyle and weight loss, the prevalence of the metabolic syndrome is still increasing. Several studies emphasize the early developmental environment as an additional factor in the aetiology of the metabolic syndrome (Pruis et al. 2014). Mother–child studies revealed that the enormous rise of cardiometabolic disease is not only caused by lifestyle and diet, but also by the pre- and perinatal environment of each individual (Gluckman et al. 2008, Kirk et al. 2009, Schmerbach & Patzak 2014). After Hales and Barker reported low birthweight as a strong risk factor for metabolic dysfunction, several studies afterwards found evidence that the maternal body composition could lead to permanent metabolic and physiological alterations during the perinatal development, resulting in increased risk for type 2 diabetes and metabolic syndrome in the offspring (Hales & Barker 2001). The growing number of obese women is especially worrisome as Reynolds et al. reported an increased all-cause mortality in adult offspring of obese mothers, especially from cardiovascular disease (Reynolds et al. 2013). During rapid cell proliferation in the foetus, environmental and nutritional influences may lead to permanent changes in the phenotype and are therefore considered as programming steps during ontogenesis (Brenseke et al. 2013). Several studies on nutritional programming during gestation in mice were recently published (Khanal et al. 2014, Kjaergaard et al. 2014, Ong & Muhlhausler 2014, Schmerbach & Patzak 2014). Maternal body mass index (BMI), excessive gestational weight gain (GWG) and maternal gestational diabetes are related to higher body fat mass in older children, higher childhood blood pressure and plasma cardiovascular biomarkers (Poston 2011, West et al. 2011, 2013). Taylor and colleagues discuss the quite different role of leptin in the programming of hypertension (Taylor et al. 2014). Interestingly, pre-pregnancy BMI 292
Acta Physiol 2015, 214, 291–294
and excessive GWG are independent factors related to higher childhood blood pressure. With the help of rodent models, they showed that obesity in pregnant mice leads to alterations in cardiovascular and metabolic function including hypertension, resistance arterial endothelial dysfunction and increased visceral adiposity. Hyperleptinaemia was suggested to lead to obesity-related hypertension. Leptin plays a critical role during brain development, especially during development of the neural circuitry of the hypothalamus that is important for appetite and blood pressure control (Kirk et al. 2009). The early post-natal leptin surge in rat pups is a critical step in hypothalamic neural outgrowth, where pups are resistant to the anorectic effect of leptin. Both maternal under- and overnutrition during pregnancy modulate the leptin surge and were found relevant in different models of developmental programming of metabolic dysfunction (Delahaye et al. 2008). Mature adipocytes seem to build the leptin source, and adipocyte maturation is accelerated by insulin. Indeed, a neonatal plasma insulin peak is observed in OffOb (offspring of obese) rats several days before the leptin peak. Hyperinsulinaemia during pregnancy of obese rats may indirectly lead to hyperleptinaemia in the neonates. The biological mechanisms underlying developmental programming of adult health are extensively studied especially using rodent models of high-fat diets during gestation and the early perinatal phase. Hepatic hypertrophy, hepatic fat accumulation and mitochondrial abnormalities were found in different models of overnutrition. Systematic changes in insulin and adiponectin levels and alterations in genes of carbohydrate metabolism, fatty acid catabolism and lipid biosynthesis are induced by maternal overweight (Bruce et al. 2009, Pruis et al. 2014). Sterol regulatory element binding protein 1 (SREBP1) is a common regulator of such genes and was identified in a rat model of in utero programming of offspring metabolism by maternal overweight (Shankar et al. 2010). It became evident that in addition to genetic and environmental factors, epigenetic effects play a role in the pathogenesis of metabolic syndrome (Sebert et al. 2014). Studies in the liver epigenom revealed changes in methylation and transcription of key factors such as the glucocorticoid receptor, peroxisome proliferator-activated receptor alpha (Ppar), liver X receptor alpha and several other loci. The fat mass- and obesity-associated gene FTO is a further candidate gene for early 0 programming0 of metabolism and weight gain recently reviewed by Sebert et al. (2014). FTO is ubiquitously expressed in every screened tissue and seems to build the missing link between energy metabolism and DNA methylation as a site for nucleic acid demethylation was discovered in the FTO protein
© 2015 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12530
Acta Physiol 2015, 214, 291–294
(Gerken et al. 2007). The promoting region of FTO contains a response element of forkhead member Foxa2, an important transcription factor for genes associated with glucose and lipid metabolism. FTOKO mice are severely growth retarded and ‘obese resistant’ whereas transgenic mice with FTO overexpression become obese and show greater food intake and white AT hypertrophy (Church et al. 2010). In a sheep and rat model of early nutritional programming, an organ-specific change in FTO expression correlates with malnutrition in sheep or high-fat diet in rats (Caruso et al. 2011, Sebert et al. 2014). However, further studies in humans and mammals are necessary to understand the role of FTO in foetal metabolism. Facing the nutritional 0 programming0 during foetal development, it becomes clear that the fight for the next generations0 health starts now by supporting overweight and obese pregnant women. The prevention and therapy of obesity and metabolic syndrome is a big challenge for the global health system as lifestyle interventions from the early childhood on are most useful today to reduce weight and to decrease the development of metabolic syndrome and obesity (WHO | Obesity, n.d.). These interventions include nutritional changes from energy-dense food to highquality food with low energy density, changes from a sedentary to a more active lifestyle, low alcohol and drug consume and comorbidity management. As there will not exist a simple pill to cure obesity, governments, physicians, the media, the food industry as well as health and education systems have to develop new concepts and to cooperate in this field to stop this avoidable enemy.
Conflict of interest None.
S. Reuter and R. Mrowka Klinik f€ ur Innere Medizin III, AG Experimentelle Nephrologie, Universit€ atsklinikum Jena, Jena, Germany E-mail: [email protected] References Alberti, K.G.M.M., Zimmet, P. & Shaw, J. 2006. Metabolic syndrome–a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med 23, 469–480. Berrington de Gonzalez, A., Hartge, P., Cerhan, J.R., Flint, A.J., Hannan, L., MacInnis, R.J., Moore, S.C., Tobias, G.S., Anton-Culver, H., Freeman, L.B. et al. 2010. Body-
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· ExActa
mass index and mortality among 1.46 million white adults. N Engl J Med 363, 2211–2219. Brenseke, B., Prater, M.R., Bahamonde, J. & Gutierrez, J.C. 2013. Current thoughts on maternal nutrition and fetal programming of the metabolic syndrome. J Pregnancy 2013, 368461. Bruce, K.D., Cagampang, F.R., Argenton, M., Zhang, J., Ethirajan, P.L., Burdge, G.C., Bateman, A.C., Clough, G.F., Poston, L., Hanson, M.A., McConnell, J.M. & Byrne, C.D. 2009. Maternal high-fat feeding primes steatohepatitis in adult mice offspring, involving mitochondrial dysfunction and altered lipogenesis gene expression. Hepatology 50, 1796–1808. Caruso, V., Chen, H. & Morris, M.J. 2011. Early hypothalamic FTO overexpression in response to maternal obesity– potential contribution to postweaning hyperphagia. PLoS ONE 6, e25261. Church, C., Moir, L., McMurray, F., Girard, C., Banks, G.T., Teboul, L., Wells, S., Br€ uning, J.C., Nolan, P.M., Ashcroft, F.M. & Cox, R.D. 2010. Overexpression of Fto leads to increased food intake and results in obesity. Nat Genet 42, 1086–1092. Delahaye, F., Breton, C., Risold, P.-Y., Enache, M., DutriezCasteloot, I., Laborie, C., Lesage, J. & Vieau, D. 2008. Maternal perinatal undernutrition drastically reduces postnatal leptin surge and affects the development of arcuate nucleus proopiomelanocortin neurons in neonatal male rat pups. Endocrinology 149, 470–475. Gerken, T., Girard, C.A., Tung, Y.-C.L., Webby, C.J., Saudek, V., Hewitson, K.S., Yeo, G.S.H., McDonough, M.A., Cunliffe, S., McNeill, L.A. et al. 2007. The obesityassociated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science 318, 1469–1472. Gluckman, P.D., Hanson, M.A., Cooper, C. & Thornburg, K.L. 2008. Effect of in utero and early-life conditions on adult health and disease. N Engl J Med 359, 61–73. Goodwill, A.G. & Frisbee, J.C. 2012. Oxidant stress and skeletal muscle microvasculopathy in the metabolic syndrome. Vascul Pharmacol 57, 150–159. Hales, C.N. & Barker, D.J. 2001. The thrifty phenotype hypothesis. Br Med Bull 60, 5–20. Heinonen, I., Rinne, P., Ruohonen, S.T., Ruohonen, S., Ahotupa, M. & Savontaus, E. 2014. The effects of equal caloric high fat and western diet on metabolic syndrome, oxidative stress and vascular endothelial function in mice. Acta Physiol 211, 515–527. Kahn, B.B. & Flier, J.S. 2000. Obesity and insulin resistance. J Clin Invest 106, 473–481. Khanal, P., Husted, S.V., Axel, A.M.D., Johnsen, L., Pedersen, K.L., Mortensen, M.S., Kongsted, A.H. & Nielsen, M.O. 2014. Late gestation over- and undernutrition predispose for visceral adiposity in response to a post-natal obesogenic diet, but with differential impacts on glucoseinsulin adaptations during fasting in lambs. Acta Physiol (Oxf) 210, 110–126. King, D. 2011. The future challenge of obesity. Lancet 378, 743–744. Kirk, S.L., Samuelsson, A.-M., Argenton, M., Dhonye, H., Kalamatianos, T., Poston, L., Taylor, P.D. & Coen, C.W.
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2009. Maternal obesity induced by diet in rats permanently influences central processes regulating food intake in offspring. PLoS ONE 4, e5870. Kjaergaard, M., Nilsson, C., Rosendal, A., Nielsen, M.O. & Raun, K. 2014. Maternal chocolate and sucrose soft drink intake induces hepatic steatosis in rat offspring associated with altered lipid gene expression profile. Acta Physiol (Oxf) 210, 142–153. Lamers, D., Famulla, S., Wronkowitz, N., Hartwig, S., Lehr, S., Ouwens, D.M., Eckardt, K., Kaufman, J.M., Ryden, M., M€ uller, S., Hanisch, F.-G., Ruige, J., Arner, P., Sell, H. & Eckel, J. 2011. Dipeptidyl peptidase 4 is a novel adipokine potentially linking obesity to the metabolic syndrome. Diabetes 60, 1917–1925. Morrow, J.P. 2014. High-fat diet, obesity and sudden cardiac death. Acta Physiol (Oxf) 211, 13–16. Mozaffarian, D., Hao, T., Rimm, E.B., Willett, W.C. & Hu, F.B. 2011. Changes in diet and lifestyle and long-term weight gain in women and men. N Engl J Med 364, 2392– 2404. Musa, M.G., Torrens, C. & Clough, G.F. 2014. The microvasculature: a target for nutritional programming and later risk of cardio-metabolic disease. Acta Physiol 210, 31– 45. Ong, Z.Y. & Muhlhausler, B.S. 2014. Consuming a low-fat diet from weaning to adulthood reverses the programming of food preferences in male, but not in female, offspring of “junk food”-fed rat dams. Acta Physiol (Oxf) 210, 127– 141. Persson, P.B. & Bondke Persson, A. 2013. Obesity: the BIG issue. Acta Physiol 207, 1–4. Poston, L. 2011. Influence of maternal nutritional status on vascular function in the offspring. Microcirculation 18, 256–262. Pruis, M.G.M., van Ewijk, P.A., Schrauwen-Hinderling, V.B. & Pl€ osch, T. 2014. Lipotoxicity and the role of maternal nutrition. Acta Physiol 210, 296–306. Reynolds, R.M., Allan, K.M., Raja, E.A., Bhattacharya, S., McNeill, G., Hannaford, P.C., Sarwar, N., Lee, A.J., Bhattacharya, S. & Norman, J.E. 2013. Maternal obesity during pregnancy and premature mortality from cardiovascular event in adult offspring: follow-up of 1 323 275 person years. BMJ 347, f4539. Romacho, T., Elsen, M., R€ ohrborn, D. & Eckel, J. 2014. Adipose tissue and its role in organ crosstalk. Acta Physiol 210, 733–753.
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Acta Physiol 2015, 214, 291–294 Schmerbach, K. & Patzak, A. 2014. The metabolic syndrome: is it the mother’s fault?. Acta Physiol (Oxf) 210, 702–704. Sebert, S., Salonurmi, T., Kein€ anen-Kiukaanniemi, S., Savolainen, M., Herzig, K.-H., Symonds, M.E. & J€ arvelin, M.R. 2014. Programming effects of FTO in the development of obesity. Acta Physiol (Oxf) 210, 58–69. Seidell, J.C. 2000. Obesity, insulin resistance and diabetes–a worldwide epidemic. Br J Nutr 83(Suppl 1), S5–S8. Shankar, K., Kang, P., Harrell, A., Zhong, Y., Marecki, J.C., Ronis, M.J.J. & Badger, T.M. 2010. Maternal overweight programs insulin and adiponectin signaling in the offspring. Endocrinology 151, 2577–2589. Smith, B.W. & Adams, L.A. 2011. Nonalcoholic fatty liver disease and diabetes mellitus: pathogenesis and treatment. Nat Rev Endocrinol 7, 456–465. Swinburn, B.A., Sacks, G., Hall, K.D., McPherson, K., Finegood, D.T., Moodie, M.L. & Gortmaker, S.L. 2011. The global obesity pandemic: shaped by global drivers and local environments. Lancet 378, 804–814. Symonds, M.E., Sebert, S.P., Hyatt, M.A. & Budge, H. 2009. Nutritional programming of the metabolic syndrome. Nat Rev Endocrinol 5, 604–610. Taylor, P.D., Samuelsson, A.-M. & Poston, L. 2014. Maternal obesity and the developmental programming of hypertension: a role for leptin. Acta Physiol 210, 508–523. Wang, J. & Widlansky, M.E. 2009. Lifestyle choices and endothelial function: risk and relevance. Curr Vasc Pharmacol 7, 209–224. West, N.A., Crume, T.L., Maligie, M.A. & Dabelea, D. 2011. Cardiovascular risk factors in children exposed to maternal diabetes in utero. Diabetologia 54, 504–507. West, N.A., Kechris, K. & Dabelea, D. 2013. Exposure to maternal diabetes in utero and DNA methylation patterns in the offspring. Immunometabolism 1, 1–9. WHO | Obesity: Preventing and managing the global epidemic [WWW Document], n.d. WHO. URL http:// www.who.int/nutrition/publications/obesity/ WHO_TRS_894/en/ (accessed 29 April 2015). Xiong, X.-Q., Chen, W.-W. & Zhu, G.-Q. 2014. Adipose afferent reflex: sympathetic activation and obesity hypertension. Acta Physiol (Oxf) 210, 468–478. Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L. & Friedman, J.M. 1994. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432.
© 2015 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12530
ExActa The metabolic syndrome: the future is now Just in the beginning of the last century, infectious diseases and malnutrition were most life threatening for the world0 s population. Today, we are threatened by a slower killing enemy: dysfunction in metabolic processes caused by the Western lifestyle and food (Swinburn et al. 2011). Our sedentary way of life in combination with unhealthy food, rich in fat and sugar, brought us obesity and the metabolic syndrome (Symonds et al. 2009). The worldwide prevalence of obesity rises dramatically among children, adolescents and adults, not only in the Western countries but also in other countries (Seidell 2000). The WHO expects about 300 million people worldwide suffering from metabolic syndrome and associated disorders in the year 2025 (Seidell 2000, Schmerbach & Patzak 2014). The metabolic syndrome also called syndrome X is defined by obesity and several cardiovascular risk factors such as lipid abnormalities, high blood pressure and impaired glucose tolerance as well as a proinflammatory and prothrombotic state (Alberti et al. 2006, Morrow 2014). This cluster of symptoms predisposes for the development of several complications such as cardiovascular disease, non-alcoholic fatty liver disease and type 2 diabetes leading to enormous financial burdens for societies all over the world (Berrington de Gonzalez et al. 2010, King 2011, Swinburn et al. 2011, Persson & Bondke Persson 2013, Xiong et al. 2014). Excessive caloric intake is facilitated by eating strongly processed, industrially produced food (Mozaffarian et al. 2011, Swinburn et al. 2011). There were a number of recent efforts to understand the pathophysiology in more detail. For example, Heinonen et al. recently showed that a Western diet (high fat, high carbohydrate content) as well as a high-fat diet induced whole-body oxidative stress and increased body adiposity in mice (Heinonen et al. 2014). Interestingly, the diet fat content is decisive for the increasing body weight, rather than the equal-caloric Western diet. The short-time high-caloric diet intervention did not induce remarkable changes in glucose metabolism, but impairments in resistance artery endothelial function, which supports the idea that these microvascular impairments represent early signs of metabolic syndrome (Wang & Widlansky 2009, Heinonen et al. 2014). Endothelial dysfunction seems to result from disturbed secretion of adipokines and inflammatory factors from visceral adipose tissue. The study by Heinonen furthermore revealed an effect also
seen in humans where enhanced total body, visceral and liver adiposity occur without a change in total body weight, highlighting the role of visceral body fat, not only in obese but also in normal weight people (Smith & Adams 2011). Consequently, body fat content should be considered an additional risk factor for the development of metabolic syndrome-associated cardiovascular and organ complications. Adipose tissue (AT) is no longer considered as a simple and passive energy depot, but as the central node in a multi-directional organ crosstalk by secreting bioactive factors, the so-called adipokines, reviewed in detail by Romacho et al. (2014). Adipokines are a heterogenous group of molecules displaying local effects in the AT itself, but they also reach distant organs and tissues through the circulation and influence central metabolic processes such as the regulation of food intake, appetite regulation, insulin sensitivity, coagulation and vascular function. Imbalances in adipokine expression and secretion, especially of pro-inflammatory adipokines, were suggested to play a role in metabolic dysfunction and the development of insulin resistance and nevertheless represent signs of impaired adipocyte development (Kahn & Flier 2000). Several adipokines have protective effects on adipocyte development and metabolic processes, but they are often downregulated in obesity such as leptin and adiponectin. Leptin, the adipokine discovered first, is secreted under high glucose, insulin and pyruvate (Zhang et al. 1994) and together with adiponectin improves insulin sensitivity (Zhang et al. 1994). Exacerbating factors such as TNF-a, IL-6, chemerin and dipeptidyl peptidase 4 were elevated in obese patients and their serum levels correlate with adipocyte hypertrophy or represent markers of metabolic dysfunction (Lamers et al. 2011). The complex organ AT crosstalk builds the link between metabolic dysfunctions and organspecific complications. The microvascular network plays an important role in the development of cardiovascular disease. Musa et al. reviewed the microvascular dysfunctions present in individuals with type 2 diabetes, metabolic syndrome and obese or overweight people (Musa et al. 2014). The early stages of cardiovascular disease in humans are associated with a reduction in capillary numbers and diameters in the skin and retinal microcirculation. This reduction in skeletal muscle microvascular network length and
© 2015 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12530
291
ExActa
· S Reuter and R Mrowka
surface area is also found in obese and diabetic mice such as the db/db mice (leptin receptor deficiency). Circulating increased levels of pro-inflammatory cytokines, free fatty acids and glucose oxidation during hyperglycaemic states enhance the release of reactive oxygen species and impair the availability of endogenous vasodilators (Goodwill & Frisbee 2012). Despite the strong correlation between low birthweight and cardiovascular disease, the mechanisms underlying foetal ‘reprogramming’ of the microvasculature remain a field of ongoing investigation. Nevertheless, subclinical changes in the microvasculature due to an unfavourable lifestyle could be easily detected by clinicians and offer the chance for lifestyle intervention before the onset of cardiovascular disease. Despite strong efforts to promote a healthier lifestyle and weight loss, the prevalence of the metabolic syndrome is still increasing. Several studies emphasize the early developmental environment as an additional factor in the aetiology of the metabolic syndrome (Pruis et al. 2014). Mother–child studies revealed that the enormous rise of cardiometabolic disease is not only caused by lifestyle and diet, but also by the pre- and perinatal environment of each individual (Gluckman et al. 2008, Kirk et al. 2009, Schmerbach & Patzak 2014). After Hales and Barker reported low birthweight as a strong risk factor for metabolic dysfunction, several studies afterwards found evidence that the maternal body composition could lead to permanent metabolic and physiological alterations during the perinatal development, resulting in increased risk for type 2 diabetes and metabolic syndrome in the offspring (Hales & Barker 2001). The growing number of obese women is especially worrisome as Reynolds et al. reported an increased all-cause mortality in adult offspring of obese mothers, especially from cardiovascular disease (Reynolds et al. 2013). During rapid cell proliferation in the foetus, environmental and nutritional influences may lead to permanent changes in the phenotype and are therefore considered as programming steps during ontogenesis (Brenseke et al. 2013). Several studies on nutritional programming during gestation in mice were recently published (Khanal et al. 2014, Kjaergaard et al. 2014, Ong & Muhlhausler 2014, Schmerbach & Patzak 2014). Maternal body mass index (BMI), excessive gestational weight gain (GWG) and maternal gestational diabetes are related to higher body fat mass in older children, higher childhood blood pressure and plasma cardiovascular biomarkers (Poston 2011, West et al. 2011, 2013). Taylor and colleagues discuss the quite different role of leptin in the programming of hypertension (Taylor et al. 2014). Interestingly, pre-pregnancy BMI 292
Acta Physiol 2015, 214, 291–294
and excessive GWG are independent factors related to higher childhood blood pressure. With the help of rodent models, they showed that obesity in pregnant mice leads to alterations in cardiovascular and metabolic function including hypertension, resistance arterial endothelial dysfunction and increased visceral adiposity. Hyperleptinaemia was suggested to lead to obesity-related hypertension. Leptin plays a critical role during brain development, especially during development of the neural circuitry of the hypothalamus that is important for appetite and blood pressure control (Kirk et al. 2009). The early post-natal leptin surge in rat pups is a critical step in hypothalamic neural outgrowth, where pups are resistant to the anorectic effect of leptin. Both maternal under- and overnutrition during pregnancy modulate the leptin surge and were found relevant in different models of developmental programming of metabolic dysfunction (Delahaye et al. 2008). Mature adipocytes seem to build the leptin source, and adipocyte maturation is accelerated by insulin. Indeed, a neonatal plasma insulin peak is observed in OffOb (offspring of obese) rats several days before the leptin peak. Hyperinsulinaemia during pregnancy of obese rats may indirectly lead to hyperleptinaemia in the neonates. The biological mechanisms underlying developmental programming of adult health are extensively studied especially using rodent models of high-fat diets during gestation and the early perinatal phase. Hepatic hypertrophy, hepatic fat accumulation and mitochondrial abnormalities were found in different models of overnutrition. Systematic changes in insulin and adiponectin levels and alterations in genes of carbohydrate metabolism, fatty acid catabolism and lipid biosynthesis are induced by maternal overweight (Bruce et al. 2009, Pruis et al. 2014). Sterol regulatory element binding protein 1 (SREBP1) is a common regulator of such genes and was identified in a rat model of in utero programming of offspring metabolism by maternal overweight (Shankar et al. 2010). It became evident that in addition to genetic and environmental factors, epigenetic effects play a role in the pathogenesis of metabolic syndrome (Sebert et al. 2014). Studies in the liver epigenom revealed changes in methylation and transcription of key factors such as the glucocorticoid receptor, peroxisome proliferator-activated receptor alpha (Ppar), liver X receptor alpha and several other loci. The fat mass- and obesity-associated gene FTO is a further candidate gene for early 0 programming0 of metabolism and weight gain recently reviewed by Sebert et al. (2014). FTO is ubiquitously expressed in every screened tissue and seems to build the missing link between energy metabolism and DNA methylation as a site for nucleic acid demethylation was discovered in the FTO protein
© 2015 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12530
Acta Physiol 2015, 214, 291–294
(Gerken et al. 2007). The promoting region of FTO contains a response element of forkhead member Foxa2, an important transcription factor for genes associated with glucose and lipid metabolism. FTOKO mice are severely growth retarded and ‘obese resistant’ whereas transgenic mice with FTO overexpression become obese and show greater food intake and white AT hypertrophy (Church et al. 2010). In a sheep and rat model of early nutritional programming, an organ-specific change in FTO expression correlates with malnutrition in sheep or high-fat diet in rats (Caruso et al. 2011, Sebert et al. 2014). However, further studies in humans and mammals are necessary to understand the role of FTO in foetal metabolism. Facing the nutritional 0 programming0 during foetal development, it becomes clear that the fight for the next generations0 health starts now by supporting overweight and obese pregnant women. The prevention and therapy of obesity and metabolic syndrome is a big challenge for the global health system as lifestyle interventions from the early childhood on are most useful today to reduce weight and to decrease the development of metabolic syndrome and obesity (WHO | Obesity, n.d.). These interventions include nutritional changes from energy-dense food to highquality food with low energy density, changes from a sedentary to a more active lifestyle, low alcohol and drug consume and comorbidity management. As there will not exist a simple pill to cure obesity, governments, physicians, the media, the food industry as well as health and education systems have to develop new concepts and to cooperate in this field to stop this avoidable enemy.
Conflict of interest None.
S. Reuter and R. Mrowka Klinik f€ ur Innere Medizin III, AG Experimentelle Nephrologie, Universit€ atsklinikum Jena, Jena, Germany E-mail: [email protected] References Alberti, K.G.M.M., Zimmet, P. & Shaw, J. 2006. Metabolic syndrome–a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med 23, 469–480. Berrington de Gonzalez, A., Hartge, P., Cerhan, J.R., Flint, A.J., Hannan, L., MacInnis, R.J., Moore, S.C., Tobias, G.S., Anton-Culver, H., Freeman, L.B. et al. 2010. Body-
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· ExActa
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