- Email: [email protected]
NAFLD, Obesity, and Bariatric Surgery
GASTROENTEROLOGY 2006;130:1848 –1852
NEW CONCEPTS IN GASTROENTEROLOGY NAFLD, Obesity, and Bariatric Surgery PAUL ANGULO Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota
he health consequences of obesity are many and varied, ranging from an increased risk of premature death to several nonfatal but debilitating complaints that adversely impact quality of life. Obesity is a major risk factor for type 2 diabetes mellitus, cardiovascular diseases, and a variety of cancers, and it is associated with various psychosocial consequences. Central obesity is a particular area of concern, as it is associated with elevated risks to health in comparison with a more peripheral fat distribution. Central obesity often clusters with several abnormalities related to insulin resistance including raised blood pressure, increased triglyceride levels, hyperglycemia, decreased HDL-cholesterol, and nonalcoholic fatty liver disease (NAFLD). Insulin resistance is almost a universal finding in patients with NAFLD.
T
NAFLD and Obesity-Related Insulin Resistance: A Chronic Inflammatory State Visceral fat, and to a lesser degree, subcutaneous fat produce a multitude of secretions implicated in initiating and perpetuating a chronic inflammatory state seen in obesity. These secretions include several hormones, cytokines, neurohumoral mediators, and clotting cascade regulators that have marked detrimental effects on diabetes, dyslipidemia, hypertension, infectious diseases, and several types of cancer.1 Excessive adiposity contributes to the tissue damage occurring in patients with obesity because fat-derived factors regulate the inflammatory and immune response. Obesity alters the adipose tissue by changing both the cellular composition and function of fat.2,3 Macrophages infiltration of adipose tissue is characteristic of both human obesity and obese mouse models, and the extent of macrophage infiltration of adipose tissue correlates with both body mass index and adipocyte size. Macrophages in fat are mostly derived from bone marrow. Macrophages and adipocytes colocalize in adipose tissue in obesity, and the functional capability of these 2 cells overlaps. In addition, preadipocytes exhibit phagocytic and antimicrobial properties under some conditions and have the potential to transdifferen-
tiate into macrophages. Macrophages in adipose tissue either alone or in combination with adipocytes and preadipocytes contribute significantly to the whole host of cytokines, hormones, and growth factors seen in patients with obesity promoting a chronic inflammatory state and insulin resistance (Figure 1). In the liver, at least 3 of the fat-derived factors, adiponectin, free fatty acids (FFA), and tumor necrosis factor-␣ (TNF-␣) promote NAFLD by modulating the hepatic inflammatory response. Adiponectin through the interaction with its receptor in liver cells inhibits FFA uptake while stimulating FFA oxidation and lipid export. These actions of adiponectin inhibit fat accumulation in hepatocytes and enhance hepatic insulin sensitivity.3 Thus, adiponectin has a protective effect in the liver against NAFLD development. Conversely, TNF-␣ is a proapoptotic cytokine with a key role in recruiting inflammatory cells to injured tissues. TNF-␣ induces activation of the nuclear transcription factor-B (NF-B) in the liver, increasing hepatic expression of several proinflammatory cytokines including TNF-␣, interleukin-6 (IL-6) and IL-1, and activation of Kupffer cells.4,5 In addition, TNF-␣ down-regulates proteins mediating the effects of insulin, such as the insulin-responsive glucose transporter 4 and peroxisome proliferator-activated factor ␥ promoting insulin resistance. Adiponectin and TNF-␣ are mutually antagonistic, inhibiting each other’s production and activity. As opposed to other adipocyte-derived proteins, circulating levels of adiponectin are found to be reduced in subjects with obesity correlating inversely with measures of insulin sensitivity and the amount of visceral adiposity, as well as circulating levels of TNF-␣ and IL-6. Both TNF-␣ and IL-6 inhibit human adiponectin messenger RNA levels in adipose tissue. In humans, circulating levels of adiponectin and adiponectin messenger RNA levels in subcutaneous adipose tissue increase after weight loss in obese and insu© 2006 by the American Gastroenterological Association Institute
0016-5085/06/$32.00 doi:10.1053/j.gastro.2006.03.041
May 2006
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Figure 1. The most abundant cellular element in adipose tissue of lean subjects is mature adipocytes. Less numerous are stromal cells including isolated macrophages, lymphocytes, and preadipocytes (ie, immature adipocytes). Obesity alters both the cellular composition and function of adipose tissue. Adipose tissue of obese individuals contains an increased number of macrophages, which seem to originate mostly from the bone marrow and possibly also from transdifferentiation of preadipocytes. Macrophages, endothelial cells, and to a lesser degree, adipocytes, and other cellular components of adipose tissue produce numerous circulating inflammatory markers including pro- and anti-inflammatory factors, chemokines, growth factors, and proteases that induce a systemic low-grade inflammatory state and insulin resistance. This obesity-induced chronic inflammatory state and insulin resistance seen in individuals with increased body mass index, and in particular in those with increased visceral adipose tissue, has a systemic effect inducing several metabolic complications and increased cardiovascular risk profile. The liver component of this metabolic disarray is NAFLD, which includes a spectrum of liver pathology ranging from bland steatosis to cirrhosis, with steatohepatitis being an intermediate stage between those 2 extreme lesions. Successful lifestyle intervention, antiobesity medications, and bariatric surgery induce weight loss and decrease in the amount of visceral fat. Weight loss achieved by these antiobesity modalities is accompanied by normalization of the several inflammatory mediator levels and improvement or resolution of insulin resistance and the obesity-related metabolic complications. Abbreviations: TNF-␣, tumor necrosis factor ␣; IL-6, interleukin 6; IL-1, interleukin 1; TGF-, transforming growth factor ; MCP, monocyte chemoattractant protein 1; FFA, free fatty acids; CRP, C-reactive protein; VEGF, vascular endothelial growth factor; PAI-1, plasminogen activator inhibitor 1. Steatosis, hematoxylin-eosin stain, magnification 100⫻. Steatohepatitis, hematoxylin-eosin stain, magnification 100⫻. Fibrosis, trichrome stain, magnification 400⫻. Cirrhosis, trichrome stain, magnification 100⫻. Illustration by Jerry Schoendorf, MAMS.
lin-resistant subjects, as well as after treatment with the insulin sensitizers, thiazolidinediones. Different fat depots in the body have dissimilar metabolic activities that may relate to their differential effects on insulin sensitivity. The central obesity phenotype is associated with increased truncal fat, consisting of both subcutaneous and visceral (intra-abdominal) fat. Visceral adipose tissue is more resistant to insulin, exhibits greater lipolysis, and provides an important source of FFA for the liver. The resulting high rate of FFA turnover in the visceral fat depot has an important physiological consequence because of the direct link between the visceral fat depot and the liver through the portal vein. Conversely, FFA flux and concentrations in individuals with predominantly lower-body obesity tend to be normal, regardless of body mass index. Further, adiponectin is produced mostly by subcutaneous fat rather than visceral fat. Therefore, patients with central obesity characteristically are insulin-resistant and more commonly present with increased aminotransferase levels as a
result of NAFLD compared with patients with lowerbody obesity.6 The severity of steatosis is most strongly correlated with the amount of visceral adipose tissue as compared with body mass index or total fat mass and is only weakly correlated with subcutaneous adiposity.7 Consistent with the notion that visceral rather than subcutaneous adipose tissue may be the major force behind obesity-related insulin resistance and the chronic inflammatory state is the observation that removing subcutaneous abdominal fat by liposuction is essentially a cosmetic maneuver with minimal, if any, effects on the underlying metabolic abnormalities. This observation has been replicated in women with central obesity undergoing liposuction of both superficial and deep subcutaneous abdominal fat.8 Ten to 12 weeks after liposuction, the subcutaneous abdominal adipose tissue volume decreased significantly with a minimal nonsignificant change in visceral adipose tissue volume. In that study,8 the degree of insulin sensitivity of liver, muscle, and adipose tissue remained essentially unchanged as did
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circulating levels of adiponectin, TNF-␣, IL-6, C-reactive protein, insulin, glucose, and lipids. Conversely, a similar amount of weight loss achieved by other treatment modalities such as lifestyle intervention, anti-obesity medications, and bariatric surgery, is associated with decrease of both subcutaneous and visceral fat mass. Weight loss achieved by these other treatment modalities is associated with a significant improvement in insulin sensitivity9 and obesity-related chronic inflammatory state.10 These other treatment modalities for obesity induce a negative daily net energy balance between dietary energy intake and energy expenditure, which is not affected by suction or excision of subcutaneous fat. Thus, the location rather than the amount of adipose tissue removed may be the key factor to attain metabolic improvement of obesity-related chronic inflammatory state and insulin resistance, as well as its clinical manifestations. The association between abdominal fat and insulin resistance, however, does not prove causality. The precise relationship between specific abdominal fat depots and insulin resistance is not yet totally clear, and some conflicting results have been reported.
Steatosis, Steatohepatitis, and Liver Fibrosis Steatosis (excessive hepatic lipid accumulation) is often seen in obese patients, and both presence and severity of steatosis correlate positively with adiposity. Increased hepatic FFA oxidation that occurs in steatotic livers increases the generation of reactive oxygen species. Increased hepatocyte exposure to reactive oxygen species generates a state of oxidant stress and mitochondrial dysfunction, inducing hepatocellular injury and activation of hepatic stellate cells (HSC). Fatty livers clear intestinally derived endotoxin lipopolysaccharide poorly, permitting this potent cytokine-inducing substance to escape the liver. Increased exposure of peripheral fat tissue to lipopolysaccharide stimulates release of TNF␣.11 Increased levels of glucose and insulin— characteristic of states of insulin resistance— up-regulate the synthesis of connective tissue growth factor by HSC.12 In addition, HSC produce transforming growth factor-, angiotensin II, leptin, adiponectin, and norepinephrine,13–15 which may participate in the activation process of HSC and development of liver fibrosis. Thus, along with steatosis, hepatocellular injury (ie, steatohepatitis) with or without increased fibrosis may be seen on liver biopsy specimens taken from obese patients. In some patients, the disease progresses to advanced fibrosis and cirrhosis and, as in other types of cirrhosis, cirrhotic-
GASTROENTEROLOGY Vol. 130, No. 6
stage NAFLD may be complicated by hepatocellular carcinoma.
Weight Control and Obesity-Related Metabolic Abnormalities Achieving and maintaining appropriate weight control results in improvement or resolution of the obesity-related chronic inflammatory state, insulin resistance, and obesity-associated complications. There are several different types of effective treatment options to manage weight, including dietary therapy, physical activity, behavior therapy, drug therapy, and surgery. Bariatric surgery is medically necessary because it is the only proven method of achieving long-term weight control for the morbidly obese patient. Bariatric surgical procedures do not remove adipose tissue by suction or excision, but by reducing the size of the gastric reservoir with or without a degree of associated malabsorption. Many series16,17 had documented that after bariatric surgery, most patients lost weight rapidly and continued to do so for 18 to 24 months. Patients may lose up to 50% of their excess weight in the first 6 months and 77% of excess weight in 1 year. Two recent meta-analyses16,17 evaluating the effects of bariatric surgery in several thousands of patients found that diabetes mellitus, hypertension, sleep apnea, and dyslipidemia either resolve or improve in a substantial proportion of patients within the first 2 years. Although data beyond 2 years after surgery are sparse, a recent report18 of 1268 patients demonstrates that many patients are able to maintain weight control after 10 years of bariatric surgery. In that study,18 the benefits in terms of improving/resolving or preventing development of associated metabolic abnormalities persisted at 10 years. Bariatric surgery is currently the most successful approach to resolve and/or prevent the development of several obesity-related comorbidities in severely obese patients.
Bariatric Surgery and NAFLD Although it seems intuitive that the marked improvement of the underlying metabolic abnormalities and insulin resistance achieved with successful bariatric surgery in morbidly obese patients will lead to improvement or resolution of NAFLD, the effect of bariatric surgery on the disease remains poorly defined. The reported series comparing liver biopsy pre- and postbariatric surgery had included small numbers of highly selected patients. Liver biopsies had not been performed in a prospective and carefully designed systematic way to draw firm conclusions. Two articles in this issue of GASTROENTEROLOGY illustrate some of the effects of
May 2006
bariatric surgery on NAFLD.19,20 Mathurin et al19 report on 121 patients evaluated 1 year after an average 27 kg of weight loss induced by biliointestinal bypass or gastric banding. A significant improvement occurred in liver enzymes and severity of steatosis. The proportion of patients with steatohepatitis was unusually low, and the vast majority of patients had absence of or only minimal fibrosis, whereas patients with cirrhosis were excluded. The proportion of patients showing features of steatohepatitis did not change significantly, but there was a significant increase in the mean fibrosis score at 1 year. Klein et al20 studied 7 extremely obese patients 1 year after an average weight loss of 45 kg (29% of baseline) induced by gastric bypass surgery. A number of unique and well-conducted metabolic studies performed on these patients showed a marked improvement in systemic and hepatic insulin sensitivity and in several metabolic abnormalities seen in obesity-induced NAFLD. Furthermore, weight loss led to a marked improvement in several factors involved in the regulation of inflammation and fibrogenesis in patients with NAFLD.
Is the Cure of NAFLD in the Operating Room? Both studies19,20 confirm prior observations of the marked improvement or resolution of steatosis achieved after 1 year of weight loss induced by bariatric surgery. Klein et al took us a step further by demonstrating the beneficial effect of surgery-induced weight loss on molecular aspects of liver inflammation and fibrosis. None of these studies, however, demonstrate a benefit on the severity of steatohepatitis or liver fibrosis on liver biopsy. Several explanations may arise. First, the relatively mild hepatocellular injury and liver fibrosis before surgery in patients in both studies makes it difficult to determine the effect of surgery on these histological features. Second, the well-known sampling variability of liver histological features makes it difficult to interpret liver biopsy findings in a small series. Third, the effect of weight loss on hepatocellular injury and fibrosis may be related to the amount of weight that was lost, how rapid weight loss was achieved, and how long after surgery the liver biopsy is repeated. As most weight loss induced by bariatric surgery occurs in the first year, liver biopsy repeated at 1 year after surgery would be expected to show no improvement or even worsening of hepatocellular injury and fibrosis, particularly in cases of massive weight loss. Liver biopsy repeated several months or years after body weight stabilization may show improvement or resolution of histological features, however. Although both studies19,20 and several other series16 –18
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reported to date show clear beneficial effects of surgeryinduced weight loss on health, it is not known whether these benefits translate into reduced rates of liver-related morbidity and mortality. Successful bariatric surgery seems to cure the obesity-induced metabolic abnormalities, but keep in mind that this is not the first time we think a surgical procedure cures a disease. Some decades ago, we thought surgery was the cure for “peptic ulcer disease,” but the identification of Helicobacter pylori proved how wrong our thoughts were! In terms of the effect of bariatric surgery on NAFLD, larger appropriately designed studies with long follow-up are necessary.
References 1. Lafontan M. Fat cells: afferent and efferent messages define new approaches to treat obesity. Annu Rev Pharmacol Toxicol 2005; 45:119 –146. 2. Bouloumie A, Curat CA, Sengenes C, Lolmede K, Miranville A, Busse R. Role of macrophage tissue infiltration in metabolic diseases. Curr Opin Clin Nutr Metab Care 2005;8:347–354. 3. Caspar-Bauguil S, Cousin B, Galinier A, Segafredo C, Nibbelink M, Andre M, Casteilla L, Penicaud L. Adipose tissues as an ancestral immune organ: site-specific change in obesity. FEBS Lett 2005; 579:3487–3492. 4. Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappa B. Nat Med 2005; 11:183–190. 5. Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw-Boris A, Poli G, Olefsky J, Karin M. IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 2005; 11:191–198. 6. Stranges S, Dorn JM, Muti P, Freudenheim JL, Farinaro E, Russell M, Nochajski TH, Trevisan M. Body fat distribution, relative weight, and liver enzyme levels: a population based study. Hepatology 2004;39:754 –763. 7. Kelley DE, McKolanis TM, Hegazi RAF, Kuller LH, Kalhan SC. Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance. Am J Physiol Endocrinol Metabol 2003;285:E906 –E916. 8. Klein S, Fontana L, Young L, Coggan AR, Kilo C, Patterson BW, Mohammed BS. Absence of an effect of liposuction on insulin action and risk factors for coronary artery disease. N Engl J Med 2004;350:2549 –2557. 9. Uusitupa M, Lindi V, Louheranta A, Salopuro T, Lindstrom J, Tuomilehto J. Long-term improvement in insulin sensitivity by changing lifestyles of people with impaired glucose tolerance: 4-year results from the Finnish Diabetes Prevention Study. Diabetes 2003;52:2532–2538. 10. Ziccardi P, Nappo F, Giugliano G, Esposito K, Marfella R, Cioffi M, D’Andrea F, Molinari AM, Giugliano D. Reduction of inflammatory cytokines concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation 2002;105:804 – 809. 11. Yang SQ, Lin HZ, Lane MD, Clements M, Diehl AM. Obesity increases sensitivity to endotoxin liver injury: implications for the pathogenesis of steatohepatitis. Proc Natl Acad Sci U S A 1997; 94:2557–2562. 12. Paradis V, Perlemuter G, Bonvoust F, Dargere D, Parfait B, Vidaud M, Conti M, Huet S, Ba N, Buffet C, Bedossa P. High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis. Hepatology 2001;34:738 –744.
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13. Bataller R, Sancho-Bru P, Gines P, Brenner DA. Liver fibrogenesis: a new role for the renin-angiotensin system. Antioxid Redox Signal 2005;7:1346 –1355. 14. Ding X, Saxena NK, Lin S, Xu A, Srinivasan S, Anania FA. The roles of leptin and adiponectin: a novel paradigm in adipocytokine regulation of liver fibrosis and stellate cell biology. Am J Pathol 2005;166:1655–1669. 15. Oben JA, Roskams T, Yang S, Lin H, Sinelli N, Torbenson M, Smedh U, Moran TH, Li Z, Huang J, Thomas SA, Diehl AM. Hepatic fibrogenesis requires sympathetic neurotransmitters. Gut 2004;53:438 – 445. 16. Buchwald H, Avidor Y, Braunwald E, Jensen MD, Pories W, Fahrbach K, Schoelles K. Bariatric surgery: a systematic review and meta-analysis. JAMA 2004;292:1724 –1737. Erratum in: JAMA 2005;293:1728. 17. Maggard MA, Shugarman LR, Suttorp M, Maglione M, Sugerman HJ, Livingston EH, Nguyen NT, Li Z, Mojica WA, Hilton L, Rhodes S, Morton SC, Shekelle PG. Meta-analysis: surgical treatment of obesity. Ann Intern Med 2005;142:547–559. 18. Sjostrom L, Lindroos AK, Peltonen M, Torgerson J, Bouchard C, Carlsson B, Dahlgren S, Larsson B, Narbro K, Sjostrom CD,
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Sullivan M, Wedel H. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004;351:2683–2693. 19. Mathurin P, Gonzalez F, Kerdraon O, Leteurtre E, Arnalsteen L, Hollebecque A, Louvet A, Dharancy S, Cocq P, Jany T, Boitard J, Deltenre P, Romon M, Pattou F. The evolution of severe steatosis after bariatric surgery is related to insulin resistance. Gastroenterology 2006;130. 20. Klein S, Mittendorfer B, Eagon C, Patterson B, Grant L, Feirt N, Seki E, Brenner D, Korenblat K, McCrea J. Gastric bypass surgery improves metabolic and hepatic abnormalities associated with nonalcoholic fatty liver disease. Gastroenterology 2006; 130:1564 –1572.
Address requests for reprints to: Paul Angulo, MD, Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905. e-mail: [email protected]; fax: (507) 266-4531.
NEW CONCEPTS IN GASTROENTEROLOGY NAFLD, Obesity, and Bariatric Surgery PAUL ANGULO Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota
he health consequences of obesity are many and varied, ranging from an increased risk of premature death to several nonfatal but debilitating complaints that adversely impact quality of life. Obesity is a major risk factor for type 2 diabetes mellitus, cardiovascular diseases, and a variety of cancers, and it is associated with various psychosocial consequences. Central obesity is a particular area of concern, as it is associated with elevated risks to health in comparison with a more peripheral fat distribution. Central obesity often clusters with several abnormalities related to insulin resistance including raised blood pressure, increased triglyceride levels, hyperglycemia, decreased HDL-cholesterol, and nonalcoholic fatty liver disease (NAFLD). Insulin resistance is almost a universal finding in patients with NAFLD.
T
NAFLD and Obesity-Related Insulin Resistance: A Chronic Inflammatory State Visceral fat, and to a lesser degree, subcutaneous fat produce a multitude of secretions implicated in initiating and perpetuating a chronic inflammatory state seen in obesity. These secretions include several hormones, cytokines, neurohumoral mediators, and clotting cascade regulators that have marked detrimental effects on diabetes, dyslipidemia, hypertension, infectious diseases, and several types of cancer.1 Excessive adiposity contributes to the tissue damage occurring in patients with obesity because fat-derived factors regulate the inflammatory and immune response. Obesity alters the adipose tissue by changing both the cellular composition and function of fat.2,3 Macrophages infiltration of adipose tissue is characteristic of both human obesity and obese mouse models, and the extent of macrophage infiltration of adipose tissue correlates with both body mass index and adipocyte size. Macrophages in fat are mostly derived from bone marrow. Macrophages and adipocytes colocalize in adipose tissue in obesity, and the functional capability of these 2 cells overlaps. In addition, preadipocytes exhibit phagocytic and antimicrobial properties under some conditions and have the potential to transdifferen-
tiate into macrophages. Macrophages in adipose tissue either alone or in combination with adipocytes and preadipocytes contribute significantly to the whole host of cytokines, hormones, and growth factors seen in patients with obesity promoting a chronic inflammatory state and insulin resistance (Figure 1). In the liver, at least 3 of the fat-derived factors, adiponectin, free fatty acids (FFA), and tumor necrosis factor-␣ (TNF-␣) promote NAFLD by modulating the hepatic inflammatory response. Adiponectin through the interaction with its receptor in liver cells inhibits FFA uptake while stimulating FFA oxidation and lipid export. These actions of adiponectin inhibit fat accumulation in hepatocytes and enhance hepatic insulin sensitivity.3 Thus, adiponectin has a protective effect in the liver against NAFLD development. Conversely, TNF-␣ is a proapoptotic cytokine with a key role in recruiting inflammatory cells to injured tissues. TNF-␣ induces activation of the nuclear transcription factor-B (NF-B) in the liver, increasing hepatic expression of several proinflammatory cytokines including TNF-␣, interleukin-6 (IL-6) and IL-1, and activation of Kupffer cells.4,5 In addition, TNF-␣ down-regulates proteins mediating the effects of insulin, such as the insulin-responsive glucose transporter 4 and peroxisome proliferator-activated factor ␥ promoting insulin resistance. Adiponectin and TNF-␣ are mutually antagonistic, inhibiting each other’s production and activity. As opposed to other adipocyte-derived proteins, circulating levels of adiponectin are found to be reduced in subjects with obesity correlating inversely with measures of insulin sensitivity and the amount of visceral adiposity, as well as circulating levels of TNF-␣ and IL-6. Both TNF-␣ and IL-6 inhibit human adiponectin messenger RNA levels in adipose tissue. In humans, circulating levels of adiponectin and adiponectin messenger RNA levels in subcutaneous adipose tissue increase after weight loss in obese and insu© 2006 by the American Gastroenterological Association Institute
0016-5085/06/$32.00 doi:10.1053/j.gastro.2006.03.041
May 2006
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Figure 1. The most abundant cellular element in adipose tissue of lean subjects is mature adipocytes. Less numerous are stromal cells including isolated macrophages, lymphocytes, and preadipocytes (ie, immature adipocytes). Obesity alters both the cellular composition and function of adipose tissue. Adipose tissue of obese individuals contains an increased number of macrophages, which seem to originate mostly from the bone marrow and possibly also from transdifferentiation of preadipocytes. Macrophages, endothelial cells, and to a lesser degree, adipocytes, and other cellular components of adipose tissue produce numerous circulating inflammatory markers including pro- and anti-inflammatory factors, chemokines, growth factors, and proteases that induce a systemic low-grade inflammatory state and insulin resistance. This obesity-induced chronic inflammatory state and insulin resistance seen in individuals with increased body mass index, and in particular in those with increased visceral adipose tissue, has a systemic effect inducing several metabolic complications and increased cardiovascular risk profile. The liver component of this metabolic disarray is NAFLD, which includes a spectrum of liver pathology ranging from bland steatosis to cirrhosis, with steatohepatitis being an intermediate stage between those 2 extreme lesions. Successful lifestyle intervention, antiobesity medications, and bariatric surgery induce weight loss and decrease in the amount of visceral fat. Weight loss achieved by these antiobesity modalities is accompanied by normalization of the several inflammatory mediator levels and improvement or resolution of insulin resistance and the obesity-related metabolic complications. Abbreviations: TNF-␣, tumor necrosis factor ␣; IL-6, interleukin 6; IL-1, interleukin 1; TGF-, transforming growth factor ; MCP, monocyte chemoattractant protein 1; FFA, free fatty acids; CRP, C-reactive protein; VEGF, vascular endothelial growth factor; PAI-1, plasminogen activator inhibitor 1. Steatosis, hematoxylin-eosin stain, magnification 100⫻. Steatohepatitis, hematoxylin-eosin stain, magnification 100⫻. Fibrosis, trichrome stain, magnification 400⫻. Cirrhosis, trichrome stain, magnification 100⫻. Illustration by Jerry Schoendorf, MAMS.
lin-resistant subjects, as well as after treatment with the insulin sensitizers, thiazolidinediones. Different fat depots in the body have dissimilar metabolic activities that may relate to their differential effects on insulin sensitivity. The central obesity phenotype is associated with increased truncal fat, consisting of both subcutaneous and visceral (intra-abdominal) fat. Visceral adipose tissue is more resistant to insulin, exhibits greater lipolysis, and provides an important source of FFA for the liver. The resulting high rate of FFA turnover in the visceral fat depot has an important physiological consequence because of the direct link between the visceral fat depot and the liver through the portal vein. Conversely, FFA flux and concentrations in individuals with predominantly lower-body obesity tend to be normal, regardless of body mass index. Further, adiponectin is produced mostly by subcutaneous fat rather than visceral fat. Therefore, patients with central obesity characteristically are insulin-resistant and more commonly present with increased aminotransferase levels as a
result of NAFLD compared with patients with lowerbody obesity.6 The severity of steatosis is most strongly correlated with the amount of visceral adipose tissue as compared with body mass index or total fat mass and is only weakly correlated with subcutaneous adiposity.7 Consistent with the notion that visceral rather than subcutaneous adipose tissue may be the major force behind obesity-related insulin resistance and the chronic inflammatory state is the observation that removing subcutaneous abdominal fat by liposuction is essentially a cosmetic maneuver with minimal, if any, effects on the underlying metabolic abnormalities. This observation has been replicated in women with central obesity undergoing liposuction of both superficial and deep subcutaneous abdominal fat.8 Ten to 12 weeks after liposuction, the subcutaneous abdominal adipose tissue volume decreased significantly with a minimal nonsignificant change in visceral adipose tissue volume. In that study,8 the degree of insulin sensitivity of liver, muscle, and adipose tissue remained essentially unchanged as did
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circulating levels of adiponectin, TNF-␣, IL-6, C-reactive protein, insulin, glucose, and lipids. Conversely, a similar amount of weight loss achieved by other treatment modalities such as lifestyle intervention, anti-obesity medications, and bariatric surgery, is associated with decrease of both subcutaneous and visceral fat mass. Weight loss achieved by these other treatment modalities is associated with a significant improvement in insulin sensitivity9 and obesity-related chronic inflammatory state.10 These other treatment modalities for obesity induce a negative daily net energy balance between dietary energy intake and energy expenditure, which is not affected by suction or excision of subcutaneous fat. Thus, the location rather than the amount of adipose tissue removed may be the key factor to attain metabolic improvement of obesity-related chronic inflammatory state and insulin resistance, as well as its clinical manifestations. The association between abdominal fat and insulin resistance, however, does not prove causality. The precise relationship between specific abdominal fat depots and insulin resistance is not yet totally clear, and some conflicting results have been reported.
Steatosis, Steatohepatitis, and Liver Fibrosis Steatosis (excessive hepatic lipid accumulation) is often seen in obese patients, and both presence and severity of steatosis correlate positively with adiposity. Increased hepatic FFA oxidation that occurs in steatotic livers increases the generation of reactive oxygen species. Increased hepatocyte exposure to reactive oxygen species generates a state of oxidant stress and mitochondrial dysfunction, inducing hepatocellular injury and activation of hepatic stellate cells (HSC). Fatty livers clear intestinally derived endotoxin lipopolysaccharide poorly, permitting this potent cytokine-inducing substance to escape the liver. Increased exposure of peripheral fat tissue to lipopolysaccharide stimulates release of TNF␣.11 Increased levels of glucose and insulin— characteristic of states of insulin resistance— up-regulate the synthesis of connective tissue growth factor by HSC.12 In addition, HSC produce transforming growth factor-, angiotensin II, leptin, adiponectin, and norepinephrine,13–15 which may participate in the activation process of HSC and development of liver fibrosis. Thus, along with steatosis, hepatocellular injury (ie, steatohepatitis) with or without increased fibrosis may be seen on liver biopsy specimens taken from obese patients. In some patients, the disease progresses to advanced fibrosis and cirrhosis and, as in other types of cirrhosis, cirrhotic-
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stage NAFLD may be complicated by hepatocellular carcinoma.
Weight Control and Obesity-Related Metabolic Abnormalities Achieving and maintaining appropriate weight control results in improvement or resolution of the obesity-related chronic inflammatory state, insulin resistance, and obesity-associated complications. There are several different types of effective treatment options to manage weight, including dietary therapy, physical activity, behavior therapy, drug therapy, and surgery. Bariatric surgery is medically necessary because it is the only proven method of achieving long-term weight control for the morbidly obese patient. Bariatric surgical procedures do not remove adipose tissue by suction or excision, but by reducing the size of the gastric reservoir with or without a degree of associated malabsorption. Many series16,17 had documented that after bariatric surgery, most patients lost weight rapidly and continued to do so for 18 to 24 months. Patients may lose up to 50% of their excess weight in the first 6 months and 77% of excess weight in 1 year. Two recent meta-analyses16,17 evaluating the effects of bariatric surgery in several thousands of patients found that diabetes mellitus, hypertension, sleep apnea, and dyslipidemia either resolve or improve in a substantial proportion of patients within the first 2 years. Although data beyond 2 years after surgery are sparse, a recent report18 of 1268 patients demonstrates that many patients are able to maintain weight control after 10 years of bariatric surgery. In that study,18 the benefits in terms of improving/resolving or preventing development of associated metabolic abnormalities persisted at 10 years. Bariatric surgery is currently the most successful approach to resolve and/or prevent the development of several obesity-related comorbidities in severely obese patients.
Bariatric Surgery and NAFLD Although it seems intuitive that the marked improvement of the underlying metabolic abnormalities and insulin resistance achieved with successful bariatric surgery in morbidly obese patients will lead to improvement or resolution of NAFLD, the effect of bariatric surgery on the disease remains poorly defined. The reported series comparing liver biopsy pre- and postbariatric surgery had included small numbers of highly selected patients. Liver biopsies had not been performed in a prospective and carefully designed systematic way to draw firm conclusions. Two articles in this issue of GASTROENTEROLOGY illustrate some of the effects of
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bariatric surgery on NAFLD.19,20 Mathurin et al19 report on 121 patients evaluated 1 year after an average 27 kg of weight loss induced by biliointestinal bypass or gastric banding. A significant improvement occurred in liver enzymes and severity of steatosis. The proportion of patients with steatohepatitis was unusually low, and the vast majority of patients had absence of or only minimal fibrosis, whereas patients with cirrhosis were excluded. The proportion of patients showing features of steatohepatitis did not change significantly, but there was a significant increase in the mean fibrosis score at 1 year. Klein et al20 studied 7 extremely obese patients 1 year after an average weight loss of 45 kg (29% of baseline) induced by gastric bypass surgery. A number of unique and well-conducted metabolic studies performed on these patients showed a marked improvement in systemic and hepatic insulin sensitivity and in several metabolic abnormalities seen in obesity-induced NAFLD. Furthermore, weight loss led to a marked improvement in several factors involved in the regulation of inflammation and fibrogenesis in patients with NAFLD.
Is the Cure of NAFLD in the Operating Room? Both studies19,20 confirm prior observations of the marked improvement or resolution of steatosis achieved after 1 year of weight loss induced by bariatric surgery. Klein et al took us a step further by demonstrating the beneficial effect of surgery-induced weight loss on molecular aspects of liver inflammation and fibrosis. None of these studies, however, demonstrate a benefit on the severity of steatohepatitis or liver fibrosis on liver biopsy. Several explanations may arise. First, the relatively mild hepatocellular injury and liver fibrosis before surgery in patients in both studies makes it difficult to determine the effect of surgery on these histological features. Second, the well-known sampling variability of liver histological features makes it difficult to interpret liver biopsy findings in a small series. Third, the effect of weight loss on hepatocellular injury and fibrosis may be related to the amount of weight that was lost, how rapid weight loss was achieved, and how long after surgery the liver biopsy is repeated. As most weight loss induced by bariatric surgery occurs in the first year, liver biopsy repeated at 1 year after surgery would be expected to show no improvement or even worsening of hepatocellular injury and fibrosis, particularly in cases of massive weight loss. Liver biopsy repeated several months or years after body weight stabilization may show improvement or resolution of histological features, however. Although both studies19,20 and several other series16 –18
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reported to date show clear beneficial effects of surgeryinduced weight loss on health, it is not known whether these benefits translate into reduced rates of liver-related morbidity and mortality. Successful bariatric surgery seems to cure the obesity-induced metabolic abnormalities, but keep in mind that this is not the first time we think a surgical procedure cures a disease. Some decades ago, we thought surgery was the cure for “peptic ulcer disease,” but the identification of Helicobacter pylori proved how wrong our thoughts were! In terms of the effect of bariatric surgery on NAFLD, larger appropriately designed studies with long follow-up are necessary.
References 1. Lafontan M. Fat cells: afferent and efferent messages define new approaches to treat obesity. Annu Rev Pharmacol Toxicol 2005; 45:119 –146. 2. Bouloumie A, Curat CA, Sengenes C, Lolmede K, Miranville A, Busse R. Role of macrophage tissue infiltration in metabolic diseases. Curr Opin Clin Nutr Metab Care 2005;8:347–354. 3. Caspar-Bauguil S, Cousin B, Galinier A, Segafredo C, Nibbelink M, Andre M, Casteilla L, Penicaud L. Adipose tissues as an ancestral immune organ: site-specific change in obesity. FEBS Lett 2005; 579:3487–3492. 4. Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappa B. Nat Med 2005; 11:183–190. 5. Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw-Boris A, Poli G, Olefsky J, Karin M. IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 2005; 11:191–198. 6. Stranges S, Dorn JM, Muti P, Freudenheim JL, Farinaro E, Russell M, Nochajski TH, Trevisan M. Body fat distribution, relative weight, and liver enzyme levels: a population based study. Hepatology 2004;39:754 –763. 7. Kelley DE, McKolanis TM, Hegazi RAF, Kuller LH, Kalhan SC. Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance. Am J Physiol Endocrinol Metabol 2003;285:E906 –E916. 8. Klein S, Fontana L, Young L, Coggan AR, Kilo C, Patterson BW, Mohammed BS. Absence of an effect of liposuction on insulin action and risk factors for coronary artery disease. N Engl J Med 2004;350:2549 –2557. 9. Uusitupa M, Lindi V, Louheranta A, Salopuro T, Lindstrom J, Tuomilehto J. Long-term improvement in insulin sensitivity by changing lifestyles of people with impaired glucose tolerance: 4-year results from the Finnish Diabetes Prevention Study. Diabetes 2003;52:2532–2538. 10. Ziccardi P, Nappo F, Giugliano G, Esposito K, Marfella R, Cioffi M, D’Andrea F, Molinari AM, Giugliano D. Reduction of inflammatory cytokines concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation 2002;105:804 – 809. 11. Yang SQ, Lin HZ, Lane MD, Clements M, Diehl AM. Obesity increases sensitivity to endotoxin liver injury: implications for the pathogenesis of steatohepatitis. Proc Natl Acad Sci U S A 1997; 94:2557–2562. 12. Paradis V, Perlemuter G, Bonvoust F, Dargere D, Parfait B, Vidaud M, Conti M, Huet S, Ba N, Buffet C, Bedossa P. High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis. Hepatology 2001;34:738 –744.
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13. Bataller R, Sancho-Bru P, Gines P, Brenner DA. Liver fibrogenesis: a new role for the renin-angiotensin system. Antioxid Redox Signal 2005;7:1346 –1355. 14. Ding X, Saxena NK, Lin S, Xu A, Srinivasan S, Anania FA. The roles of leptin and adiponectin: a novel paradigm in adipocytokine regulation of liver fibrosis and stellate cell biology. Am J Pathol 2005;166:1655–1669. 15. Oben JA, Roskams T, Yang S, Lin H, Sinelli N, Torbenson M, Smedh U, Moran TH, Li Z, Huang J, Thomas SA, Diehl AM. Hepatic fibrogenesis requires sympathetic neurotransmitters. Gut 2004;53:438 – 445. 16. Buchwald H, Avidor Y, Braunwald E, Jensen MD, Pories W, Fahrbach K, Schoelles K. Bariatric surgery: a systematic review and meta-analysis. JAMA 2004;292:1724 –1737. Erratum in: JAMA 2005;293:1728. 17. Maggard MA, Shugarman LR, Suttorp M, Maglione M, Sugerman HJ, Livingston EH, Nguyen NT, Li Z, Mojica WA, Hilton L, Rhodes S, Morton SC, Shekelle PG. Meta-analysis: surgical treatment of obesity. Ann Intern Med 2005;142:547–559. 18. Sjostrom L, Lindroos AK, Peltonen M, Torgerson J, Bouchard C, Carlsson B, Dahlgren S, Larsson B, Narbro K, Sjostrom CD,
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Sullivan M, Wedel H. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004;351:2683–2693. 19. Mathurin P, Gonzalez F, Kerdraon O, Leteurtre E, Arnalsteen L, Hollebecque A, Louvet A, Dharancy S, Cocq P, Jany T, Boitard J, Deltenre P, Romon M, Pattou F. The evolution of severe steatosis after bariatric surgery is related to insulin resistance. Gastroenterology 2006;130. 20. Klein S, Mittendorfer B, Eagon C, Patterson B, Grant L, Feirt N, Seki E, Brenner D, Korenblat K, McCrea J. Gastric bypass surgery improves metabolic and hepatic abnormalities associated with nonalcoholic fatty liver disease. Gastroenterology 2006; 130:1564 –1572.
Address requests for reprints to: Paul Angulo, MD, Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905. e-mail: [email protected]; fax: (507) 266-4531.