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DOI: 10.1055/s-0029-1233448
© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York
Obesity: A Complex Growing Challenge
Publication History
received 27.01.2009
first decision 13.05.2009
accepted 22.06.2009
Publication Date:
23 October 2009 (online)
Abstract
The prevalence of overweight and obesity is increasing worldwide. The physiological mechanisms involved in body weight regulation are complex and incompletely understood. Increasing evidence suggests that obesity is a multifactorial disease where many, if not all, organs of the body are involved. The adipose tissue was considered as a simple fat accumulation for a long period of time. However, nowadays it is fascinating to progressively discover its involvement in hormonal, inflammatory or immune system dysregulation. Adipokines and cytokines are involved in control and regulation of appetite and energy balance, glucose and lipid metabolism, neuroendocrine function, reproduction, immunity, and cardiovascular function. The inflammatory background associated with obesity is closely related to insulin resistance. Moreover, the inhibitory effect of endocannabinoids on the expression of adiponectin could be involved in insulin resistance. Gut microbiota related factor may be responsible for the development of diet-induced obesity and diabetes through metabolic endotoxemia which triggers the inflammatory tone. Based on recent research, several physiopathological mechanisms involved in the development of obesity are reviewed.
Key words
Obesity - Adipocytokines < - Obesity - Leptin < - Obesity
References
- 1 Allison DB, Fontaine KR, Manson JE. et al . Annual deaths attributable to obesity in the United States. JAMA. 1999; 282 1530-1538
- 2 Asakawa A, Inui A, Kaga T. et al . Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin. Gastroenterology. 2001; 120 337-345
- 3 Backhed F, Ding H, Wang T. et al . The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A. 2004; 101 15718-15723
- 4 Basham P, Luik J. Is the obesity epidemic exaggerated? Yes. BMJ. 2008; 336 244
- 5 Batterham RL, Cohen MA, Ellis SM. et al . Inhibition of food intake in obese subjects by peptide YY3-36. N Engl J Med. 2003; 349 941-948
- 6 Beltowski J. Leptin and atherosclerosis. Atherosclerosis. 2006; 189 47-60
- 7 Bermudez-Siva FJ, Serrano A, Diaz-Molina FJ. et al . Activation of cannabinoid CB1 receptors induces glucose intolerance in rats. Eur J Pharmacol. 2006; 531 282-284
- 8 Bluher M, Bullen Jr JW, Lee JH. et al . Circulating adiponectin and expression of adiponectin receptors in human skeletal muscle: associations with metabolic parameters and insulin resistance and regulation by physical training. J Clin Endocrinol Metab. 2006; 91 2310-2316
- 9 Burdyga G, Lal S, Varro A. et al . Expression of cannabinoid CB1 receptors by vagal afferent neurons is inhibited by cholecystokinin. J Neurosci. 2004; 24 2708-2715
- 10 Cani PD, Amar J, Iglesias MA. et al . Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007; 56 1761-1772
- 11 Cassoni P, Ghe C, Marrocco T. et al . Expression of ghrelin and biological activity of specific receptors for ghrelin and des-acyl ghrelin in human prostate neoplasms and related cell lines. Eur J Endocrinol. 2004; 150 173-184
- 12 Cottam DR, Mattar SG, Barinas-Mitchell E. et al . The chronic inflammatory hypothesis for the morbidity associated with morbid obesity: implications and effects of weight loss. Obes Surg. 2004; 14 589-600
- 13 Coutts AA, Izzo AA. The gastrointestinal pharmacology of cannabinoids: an update. Curr Opin Pharmacol. 2004; 4 572-579
- 14 Das UN. Metabolic syndrome X: an inflammatory condition?. Curr Hypertens Rep. 2004; 6 66-73
- 15 Di Marzo V, Goparaju SK, Wang L. et al . Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature. 2001; 410 822-825
- 16 Di Marzo V, Matias I. Endocannabinoid control of food intake and energy balance. Nat Neurosci. 2005; 8 585-589
- 17 Dina C, Meyre D, Gallina S. et al . Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet. 2007; 39 724-726
- 18 Fain JN, Madan AK, Hiler ML. et al . Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology. 2004; 145 2273-2282
- 19 Farooqi IS, Matarese G, Lord GM. et al . Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest. 2002; 110 1093-1103
- 20 Fontana L, Eagon JC, Trujillo ME. et al . Visceral fat adipokine secretion is associated with systemic inflammation in obese humans. Diabetes. 2007; 56 1010-1013
- 21 Frayling TM, Timpson NJ, Weedon MN. et al . A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007; 316 889-894
- 22 Fried SK, Bunkin DA, Greenberg AS. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab. 1998; 83 847-850
- 23 Fruhbeck G, Gomez-Ambrosi J, Muruzabal FJ. et al . The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation. Am J Physiol Endocrinol Metab. 2001; 280 E827-847
- 24 Gamber KM, Macarthur H, Westfall TC. Cannabinoids augment the release of neuropeptide Y in the rat hypothalamus. Neuropharmacology. 2005; 49 646-652
- 25 Gomez R, Navarro M, Ferrer B. et al . A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding. J Neurosci. 2002; 22 9612-9617
- 26 Gonzalez S, Manzanares J, Berrendero F. et al . Identification of endocannabinoids and cannabinoid CB(1) receptor mRNA in the pituitary gland. Neuroendocrinology. 1999; 70 137-145
- 27 Griffin ME, Marcucci MJ, Cline GW. et al . Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes. 1999; 48 1270-1274
- 28 Harris RB. Leptin – much more than a satiety signal. Annu Rev Nutr. 2000; 20 45-75
- 29 Haslam DW, James WP. Obesity. Lancet. 2005; 366 1197-1209
- 30 Hauner H. Secretory factors from human adipose tissue and their functional role. Proc Nutr Soc. 2005; 64 163-169
- 31 Helge JW, Watt PW, Richter EA. et al . Fat utilization during exercise: adaptation to a fat-rich diet increases utilization of plasma fatty acids and very low density lipoprotein-triacylglycerol in humans. J Physiol. 2001; 537 1009-1020
- 32 Hopkins TA, Ouchi N, Shibata R. et al . Adiponectin actions in the cardiovascular system. Cardiovasc Res. 2007; 74 11-18
- 33 Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006; 444 860-867
- 34 Hotamisligil GS, Murray DL, Choy LN. et al . Tumor necrosis factor alpha inhibits signaling from the insulin receptor. Proc Natl Acad Sci U S A. 1994; 91 4854-4858
- 35 Huda MS, Wilding JP, Pinkney JH. Gut peptides and the regulation of appetite. Obes Rev. 2006; 7 163-182
- 36 Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors. Endocr Rev. 2005; 26 439-451
- 37 Klein TW. Cannabinoid-based drugs as anti-inflammatory therapeutics. Nat Rev Immunol. 2005; 5 400-411
- 38 Korbonits M, Goldstone AP, Gueorguiev M. et al . Ghrelin – a hormone with multiple functions. Front Neuroendocrinol. 2004; 25 27-68
- 39 Lago F, Dieguez C, Gomez-Reino J, Gualillo O. The emerging role of adipokines as mediators of inflammation and immune responses. Cytokine Growth Factor Rev. 2007; 18 313-325
- 40 Li H, Wu Y, Loos RJ. et al . Variants in the fat mass- and obesity-associated (FTO) gene are not associated with obesity in a Chinese Han population. Diabetes. 2008; 57 264-268
- 41 Li S, Loos RJ. Progress in the genetics of common obesity: size matters. Curr Opin Lipidol. 2008; 19 113-121
- 42 Maes HH, Neale MC, Eaves LJ. Genetic and environmental factors in relative body weight and human adiposity. Behav Genet. 1997; 27 325-351
- 43 Matias I, Gonthier MP, Orlando P. et al . Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia. J Clin Endocrinol Metab. 2006; 91 3171-3180
- 44 Mazurek T, Zhang L, Zalewski A. et al . Human epicardial adipose tissue is a source of inflammatory mediators. Circulation. 2003; 108 2460-2466
- 45 Mooney RA, Senn J, Cameron S. et al . Suppressors of cytokine signaling-1 and -6 associate with and inhibit the insulin receptor. A potential mechanism for cytokine-mediated insulin resistance. J Biol Chem. 2001; 276 25889-25893
- 46 Niswender KD, Baskin DG, Schwartz MW. Insulin and its evolving partnership with leptin in the hypothalamic control of energy homeostasis. Trends Endocrinol Metab. 2004; 15 362-369
- 47 O’Rahilly S, Farooqi IS. Genetics of obesity. Philos Trans R Soc Lond B Biol Sci. 2006; 361 1095-1105
- 48 Ordovas JM, Tai ES. Why study gene-environment interactions?. Curr Opin Lipidol. 2008; 19 158-167
- 49 Osei-Hyiaman D, DePetrillo M, Pacher P. et al . Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest. 2005; 115 1298-1305
- 50 Pagotto U, Marsicano G, Cota D. et al . The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev. 2006; 27 73-100
- 51 Peeters A, Barendregt JJ, Willekens F. et al . Obesity in adulthood and its consequences for life expectancy: a life-table analysis. Ann Intern Med. 2003; 138 24-32
- 52 Perreault M, Marette A. Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle. Nat Med. 2001; 7 1138-1143
- 53 Pertwee RG. Pharmacological actions of cannabinoids. Handb Exp Pharmacol. 2005; 168 1-51
- 54 Perwitz N, Fasshauer M, Klein J. Cannabinoid receptor signaling directly inhibits thermogenesis and alters expression of adiponectin and visfatin. Horm Metab Res. 2006; 38 356-358
- 55 Petersen KF, Befroy D, Dufour S. et al . Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science. 2003; 300 1140-1142
- 56 Petersen KF, Dufour S, Befroy D. et al . Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med. 2004; 350 664-671
- 57 Piche ME, Lemieux S, Weisnagel SJ. et al . Relation of high-sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-alpha, and fibrinogen to abdominal adipose tissue, blood pressure, and cholesterol and triglyceride levels in healthy postmenopausal women. Am J Cardiol. 2005; 96 92-97
- 58 Rajala MW, Scherer PE. Minireview: The adipocyte – at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology. 2003; 144 3765-3773
- 59 Rankinen T, Zuberi A, Chagnon YC. et al . The human obesity gene map: the 2005 update. Obesity (Silver Spring). 2006; 14 529-644
- 60 Rayner DV, Trayhurn P. Regulation of leptin production: sympathetic nervous system interactions. J Mol Med. 2001; 79 8-20
- 61 Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988; 37 1595-1607
- 62 Ridker PM, Buring JE, Cook NR. et al . C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation. 2003; 107 391-397
- 63 Robbe D, Kopf M, Remaury A. et al . Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens. Proc Natl Acad Sci U S A. 2002; 99 8384-8388
- 64 Roche R, Hoareau L, Bes-Houtmann S. et al . Presence of the cannabinoid receptors, CB1 and CB2, in human omental and subcutaneous adipocytes. Histochem Cell Biol. 2006; 126 177-187
- 65 Sattar N, Gaw A, Scherbakova O. et al . Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and diabetes in the West of Scotland Coronary Prevention Study. Circulation. 2003; 108 414-419
- 66 Shanik MH, Xu Y, Skrha J. et al . Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse?. Diabetes Care. 2008; 31 ((Suppl 2)) S262-268
- 67 Shulman GI. Cellular mechanisms of insulin resistance. J Clin Invest. 2000; 106 171-176
- 68 Teoh H, Verma S. C-reactive protein, metabolic syndrome, and end organ damage. Metabolism. 2007; 56 1620-1622
- 69 Thompson NM, Gill DA, Davies R. et al . Ghrelin and des-octanoyl ghrelin promote adipogenesis directly in vivo by a mechanism independent of the type 1a growth hormone secretagogue receptor. Endocrinology. 2004; 145 234-242
- 70 Trayhurn P, Beattie JH. Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. Proc Nutr Soc. 2001; 60 329-339
- 71 Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr. 2004; 92 347-355
- 72 Trujillo ME, Scherer PE. Adipose tissue-derived factors: impact on health and disease. Endocr Rev. 2006; 27 762-778
- 73 Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature. 2000; 407 908-913
- 74 Verdich C, Toubro S, Buemann B. et al . The role of postprandial releases of insulin and incretin hormones in meal-induced satiety – effect of obesity and weight reduction. Int J Obes Relat Metab Disord. 2001; 25 1206-1214
- 75 Verma S, Devaraj S, Jialal I. Is C-reactive protein an innocent bystander or proatherogenic culprit? C-reactive protein promotes atherothrombosis. Circulation. 2006; 113 2135-2150 ; discussion 2150.
- 76 Wang B, Trayhurn P. Acute and prolonged effects of TNF-alpha on the expression and secretion of inflammation-related adipokines by human adipocytes differentiated in culture. Pflugers Arch. 2006; 452 418-427
- 77 Wang PY, Caspi L, Lam CK. et al . Upper intestinal lipids trigger a gut-brain-liver axis to regulate glucose production. Nature. 2008; 1012-1016
- 78 Wang Z, Nicholls SJ, Rodriguez ER. et al . Protein carbamylation links inflammation, smoking, uremia and atherogenesis. Nat Med. 2007; 13 1176-1184
- 79 Weisberg SP, McCann D, Desai M. et al . Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003; 112 1796-1808
- 80 Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest. 2005; 115 1111-1119
- 81 Xu H, Barnes GT, Yang Q. et al . Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003; 112 1821-1830
- 82 Yang Q, Graham TE, Mody N. et al . Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature. 2005; 436 356-362
- 83 Yang W, Kelly T, He J. Genetic epidemiology of obesity. Epidemiol Rev. 2007; 29 49-61
- 84 Yoon MJ, Lee GY, Chung JJ. et al . Adiponectin increases fatty acid oxidation in skeletal muscle cells by sequential activation of AMP-activated protein kinase, p38 mitogen-activated protein kinase, and peroxisome proliferator-activated receptor alpha. Diabetes. 2006; 55 2562-2570
- 85 Yudkin JS. Inflammation, obesity, and the metabolic syndrome. Horm Metab Res. 2007; 39 707-709
- 86 Zderic TW, Davidson CJ, Schenk S. et al . High-fat diet elevates resting intramuscular triglyceride concentration and whole body lipolysis during exercise. Am J Physiol Endocrinol Metab. 2004; 286 E217-225
- 87 Zhang Y, Proenca R, Maffei M. et al . Positional cloning of the mouse obese gene and its human homologue. Nature. 1994; 372 425-432
- 88 Zhao Z, Nie H, He H. et al . High-sensitivity C-reactive protein predicts target organ damage in Chinese patients with metabolic syndrome. Metabolism. 2007; 56 1612-1619
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Z. PatakyMD
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