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Metabolic correlates of nonalcoholic fatty liver in women and men: insulin resistance, body changes cause liver fat
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lipodystrophy and insulin resistance associated with liver fat
Hepatology Aug 2007
Gloria Lena Vega 1 2 3 4 *, Manisha Chandalia 1 2 3, Lidia S. Szczepaniak 2 3, Scott M. Grundy 1 2 3 4 *
1The Center for Human Nutrition of the University of Texas Southwestern Medical Center at Dallas, Texas
2Donald W. Reynolds Cardiovascular Research Center of the University of Texas Southwestern Medical Center at Dallas, Texas
3Departments of Clinical Nutrition and Internal Medicine of the University of Texas Southwestern Medical Center at Dallas, Texas
4The Veterans Affairs Medical Center, Dallas, TX
Abstract
Nonalcoholic hepatic steatosis associates with a clustering of metabolic risk factors and steatohepatitis. One risk factor for hepatic steatosis is obesity, but other factors likely play a role. We examined metabolic concomitants of hepatic steatosis in nonobese and obese men and women. Sixty-one obese women and 35 obese men were studied; both those with and without hepatic steatosis were compared against each other and against nonobese controls (17 women and 32 men) without hepatic steatosis. Obesity (defined as 25% body fat in men and 35% in women), was identified by x-ray absorptiometry, whereas hepatic steatosis (5.5% liver fat) was detected by magnetic resonance spectroscopy. The primary endpoint was a difference in insulin sensitivity. Obese groups with and without steatosis had similar body fat percentages. Compared with obese women without hepatic steatosis, those with steatosis were more insulin resistant; the same was true for men, although differences were less striking. Obese subjects with hepatic steatosis had higher ratios of truncal-to-lower body fat and other indicators of adipose tissue dysfunction compared with obese subjects without steatosis.
Conclusion: These results support the concept that obesity predisposes to hepatic steatosis; but in addition, insulin resistance beyond that induced by obesity alone and a relatively high ratio of truncal-to-lower body fat usually combined with obesity to produce an elevated liver fat content.
Article Text
An increased hepatic triglyceride content (HTGC) associates commonly in the metabolic syndrome and can predispose to liver disease.[1] Obesity is well recognized as 1 underlying cause.[1][2] Several mechanisms may play a role: high plasma nonesterified fatty acids (NEFA),[3][4] reduced adiponectin levels,[5][6] and increased fatty acid synthesis in the liver.[7]
A recent report[1] on a representative population from Dallas Country [the Dallas Heart Study (DHS)] showed a high prevalence of hepatic steatosis. In DHS, HTGC correlated with body mass index, confirming a contribution from obesity. However, DHS findings also indicated that other yet-to-be-identified factors can raise HTGC. One factor may be insulin resistance,[8][9] but because obesity itself is accompanied by increased insulin resistance, the pathophysiological significance of the relationship between insulin resistance and hepatic steatosis is not clear. We therefore addressed whether systemic metabolic abnormalities in obese women and men with hepatic steatosis, compared with obese persons without steatosis at a similar percentage of total body fat, can be identified. The primary focus of the study was on insulin sensitivity differences; however, differences in adipose tissue metabolism were also examined.
By multiple regression analysis for the whole groups of men and women, percent total body fat alone explained 13.4% of the variance in liver fat content in women and 33.5% in men. In men, the combination percent body fat + body fat ratios (truncal to lower body fat ratios) explained 35.4% of variance, and by adding OGIS, 36.8%. In all women, adding body fat ratios to percent body fat accounted for 28.7% of variance, and with addition of OGIS, 34.9%. Within the obese category, percent total body fat alone explained only 3.7% of the variance in liver fat content in women and 14.9% in men. In obese men, the combination percent body fat + body fat ratios explained 21% of variance, and by adding OGIS, 28.6%. In obese women, adding body fat ratios to percent body fat accounted for 28.2% of variance, and by addition of OGIS, 38.8%.
Discussion
Almost one-third of the whole adult population in the DHS had hepatic steatosis.[1] DHS data further suggested that obesity is virtually a requisite for development of hepatic steatosis (Fig. 1); yet, metabolic differences presumably exist among obese subjects that lead to steatosis in some but not others. In this study we addressed whether systemic metabolic differences can be detected between obese persons with and without hepatic steatosis. Among white and black men and women, within a given body-fat category, no ethnic differences were observed for metabolic correlates. The metabolic focus of our study was on insulin sensitivity. The major finding was that those obese persons with hepatic steatosis are less insulin sensitive than obese persons with normal liver fat content even when both groups had a similar percent total body fat. This finding suggests a dual defect underlying hepatic steatosis, namely, obesity plus a second metabolic defect. The latter appears to be linked in some way to a greater insulin resistance than occurs with obesity alone.
Insulin Resistance and Hepatic Steatosis.
That persons with hepatic steatosis commonly are insulin resistant is known.[8][9][13] However, a given degree of obesity individuals with hepatic steatosis are more insulin resistant than are those without. Our study shows that obese subjects with steatosis in fact are more insulin resistant than those without. It further suggests that this greater insulin resistance originates in adipose tissue. Subjects with hepatic steatosis had either higher NEFA levels or AUCs of NEFA during OGTT; higher NEFA, which should raise liver fat content, impairs insulin signaling in muscle and liver.[14-16] Moreover, obese women with steatosis had lower adiponectin levels than those without; these lower levels could reduce fatty acid oxidation and raise liver-fat content.[6] Furthermore, hyperinsulinemia, secondary to insulin resistance and high NEFA levels, could enhance fatty acid synthesis and inhibit fatty acid oxidation in the liver[15][16]; both should increase HTGC and exacerbate insulin resistance.[17][18] Finally, inflammatory cytokines released by adipose tissue may further accentuate insulin resistance.[19] Whether obese subjects with hepatic steatosis had higher levels of circulating cytokines was not examined in this study. No differences were observed between CRP levels between obese individuals with and without steatosis, but CRP levels may not be sensitive enough to identify differences in cytokine levels. All told, obese subjects with steatosis had several abnormalities suggestive of a dysfunctional adipose tissue that can explain higher insulin resistance and increased liver fat content. Increased insulin resistance itself likely signifies the presence of multiple metabolic abnormalities that can affect hepatic fat content.
Obesity Plus Adipose Tissue Disorders as Cause of Hepatic Steatosis.
If dysfunctional adipose tissue combines with obesity to produce hepatic steatosis, what might be the disorder? Two readily identified disorders are adipose tissue deficiencies (lipodystrophies) and body-fat misdistribution characterized by upper body fat. Lipodystrophies commonly manifest fatty liver.[20] Upper body obesity may in fact represent a form of adipose-tissue deficiency in which there is an inadequate reservoir of lower body adipose tissue.[10] When lower body adipose tissue is deficient, overloading with upper body fat may lead to ectopic fat accumulation. Upper body obesity, particularly of the visceral type, appears to be more commonly associated with fatty liver than is lower body obesity.[21] A third type of disorder is a reduced adipose-tissue sensitivity to insulin.[22] Although obesity per se induces insulin resistance of adipose tissue, other defects may enhance resistance beyond that observed with obesity alone. Insulin-resistant South Asians appear to have a dysfunctional adipose tissue in that they have the metabolic characteristics of obesity even in the absence of obesity, i.e., elevated NEFA, elevated CRP, and reduced adiponectin levels.[23][24] Current findings point to several defects in adipose tissue distribution or function in obese patients with hepatic steatosis compared with obese without steatosis. In obese women with steatosis, waist circumferences and percent truncal fat were higher than in obese women without steatosis, whereas percent lower body fat was lower. Consequently, the ratio of truncal-to-lower body fat was highest in obese women with steatosis. Furthermore, in this group, fasting NEFA levels were highest, and the AUC of NEFA during OGTT remained highest; conversely, adiponectin levels were significantly lower. In men with hepatic steatosis, the ratio of truncal-to-lower body fat was significantly higher than that of the other groups, and the AUC of NEFA during OGTT likewise was higher.
Protective Effect of Lower Body Fat Against Hepatic Steatosis.
Previous studies show that women with predominant upper body (truncal) obesity are more prone to insulin resistance and to type 2 diabetes than those with lower body obesity[25][26]; we observed that they are more prone to hepatic steatosis and readily demonstrable metabolic differences. Thus a pattern of lower body fat seems protective. Men typically have a predominance of truncal fat even when not obese (Table 2); in fact, even nonobese men of the current study had the same ratios of truncal-to-lower body fat as obese women with hepatic steatosis. For this reason, the metabolic difference between obese men with and without steatosis likely was less distinct than that observed in women. Presumably men in general are prone to hepatic steatosis when they become obese because they generally are restricted to fat accumulation in the upper body.[1]
In summary, only a portion of obese persons develop hepatic steatosis. Therefore, a second abnormality must combine with obesity to promote triglyceride accumulation inliver. We attempted to uncover evidence for a systemic abnormality in persons with hepatic steatosis. Our primary evidence for this systemic abnormality was greater insulin resistance. Both obese women and men with steatosis were more insulin resistant than obese counterparts without steatosis. Both sexes who developed hepatic steatosis with obesity had evidence of a greater maldistribution of excess fat, which was best characterized by higher truncal-to-lower body fat ratios. However, the metabolic consequences of maldistribution were more readily detected in women than in men. Because men commonly have predominant upper body fat when obesity develops, the metabolic abnormalities responsible for hepatic steatosis are more subtle and more difficult to detect. Nonetheless, as shown in this study, their presence is revealed by a greater insulin resistance in those with hepatic steatosis.
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