In the present study, the relationship between metabolic factors (total/regional adiposity, insulin resistance, hypertriglyceridemia) and HTGC was examined in a large multiethnic population-based sample (n=2,170) containing the three major U.S. ethnic groups: African-Americans, Hispanics, and Caucasians (2
). This is the largest study to date to examine the relationships between HTGC, total adiposity, and body fat distribution, inclusive of the abdominal compartments (intraperitoneal and subcutaneous) in any population. A major finding of this study was that controlling for intraperitoneal fat content almost entirely eliminated ethnic differences in levels of HTGC and prevalence of hepatic steatosis. This was not the case with insulin resistance, total adiposity, or other fat depots. Despite the lower levels of intraperitoneal adipose tissue and liver fat in African-Americans, their prevalence of insulin resistance was similar to Hispanics, the group with the highest levels of intraperitoneal and liver fat. Furthermore, insulin levels and HOMAIR
values were higher and serum triglyceride levels were lower among African-Americans, even after adjusting for intraperitoneal adiposity and HTGC. Thus, the metabolic response to obesity and insulin resistance differs in African-Americans when compared to either Hispanics or Caucasians: African-Americans appear to be more resistant to both the accretion of triglyceride in the abdominal visceral compartment (adipose tissue and liver) and hypertriglyceridemia associated with insulin resistance.
Controlling for differences in total body fat, abdominal subcutaneous fat, and lower extremity fat failed to account for the observed variability in HTGC between the ethnic groups. Only after adjusting for intraperitoneal fat content, were the ethnic differences in HTGC between the groups nearly abolished (). Thus, visceral adiposity appears to be more closely linked to HTGC than other parameters of body fat content or distribution. These findings extend previous work in this area (25
) by suggesting that the factors responsible for reduced visceral adiposity in African-Americans are causally linked to the reduced propensity for this group to deposit triglycerides in hepatocytes. Whether visceral fat is causative in the development of hepatic steatosis or is simply a marker of an underlying metabolic derangement that is contributing to excess liver fat could not be determined by this study.
Visceral fat has been postulated to play a role in the development of hepatic steatosis/insulin resistance via the release of free fatty acids and adipokines directly into the portal circulation. Indeed, the surgical removal of visceral fat, but not subcutaneous abdominal fat, improves peripheral and hepatic insulin sensitivity (28
). However, only 5–20% of the fatty acids entering the portal circulation originate from visceral adipose tissue (31
): the remainder is derived from upper and lower body subcutaneous fat. Furthermore, only ~60% of triglycerides within steatotic livers originate from adipose tissue derived fatty acids (i.e., lipolysis) (24
). Taken together, these data suggest that the contribution of fatty acids derived from visceral fat lipolysis to HTGC is relatively small. Though it appears that visceral fat and hepatic fat are metabolically connected, this connection is unlikely to be mediated via fatty acid delivery and uptake alone.
Interestingly, although several studies have indicated a link between visceral/liver fat content and insulin resistance, the relationship between these two variables differs in African-Americans, as compared to Hispanics and Caucasians. Insulin levels and HOMAIR
values were significantly higher in African-Americans after adjusting for both intraperitoneal and liver fat. Similar results were found in the Insulin Resistance Atherosclerosis Study, where African-Americans had more insulin resistance than Hispanics or Caucasians after controlling for obesity, body fat distribution, and environmental factors (32
). In addition, several studies comparing African-Americans to Caucasian have failed to account for the differences in insulin resistance between these two groups based upon adiposity alone (33
), with one study indicating that a genetic basis for these differences was likely (36
The multiple phenotypic changes in carbohydrate and lipid metabolism that occur in association with insulin resistance has been referred to as the metabolic syndrome (37
). Hepatic steatosis is also considered by many to be a feature of this syndrome (9
). Our data, as well as the others (11
), is consistent with insulin resistance being phenotypically different in African-Americans. African-Americans have less visceral adiposity, lower levels of plasma triglycerides, higher levels of HDL-c, and lower levels of liver triglyceride than either Hispanics or Caucasians with similar levels of insulin resistance. African-Americans also appear to be protected from the accumulation of intramyocellular triglyceride (13
), another feature of insulin resistance (39
). Taken together, these data imply that the term “insulin resistance” equates to a different, but overlapping, set of metabolic derangements in African-Americans.
Heterogeneity in the contribution of liver, muscle, and adipose tissue to the insulin resistant state may account for the different complexion of the metabolic syndrome in African-Americans. Selective inactivation of the insulin receptor in each of these tissues has dramatically different effects on carbohydrate and lipid metabolism. For example, genetic ablation of the insulin receptor in liver leads to hyperinsulinemia, hyperglycemia, and peripheral insulin resistance without the development of hypertriglyceridemia or hepatic steatosis (42
). Conversely, isolated loss of the insulin receptor in muscle leads to increased visceral fat mass, free fatty acids, and serum triglycerides, all of which are characteristics of metabolic syndrome; however, hyperinsulinemia and hyperglycemia develop only after insulin resistance is present in additional organs (43
). It is possible that the observed differences in the clinical manifestation of insulin resistance between the ethnic groups may be due to tissue-specific differences in insulin signaling.
The relative “health” of adipose tissue in African-Americans may also be a factor in the observed phenotypic differences in this group. Compared to Hispanics, African-Americans tended to have larger subcutaneous depots of adipose tissue, especially with regard to the lower extremities (). This was also the case when comparing the genders: as a group, women had more subcutaneous adiposity and less visceral adiposity than men. Work in an animal model (transgenic ob/ob mice over-expressing adiponectin) has demonstrated that the expansion of subcutaneous, but not visceral, adipose tissue ameliorates hepatic steatosis and insulin resistance (44
). Thus, the ability to expand subcutaneous adipose tissue in the setting of excessive caloric intake may prevent the accumulation of fat in the visceral compartment (adipose and liver). This may be an adaptive response to increasing adiposity that has different limits in these ethnic and gender groups. Indeed, women tended to have lower levels of liver triglycerides despite a greater degree adiposity than men (). Such differences in the ability to expand the subcutaneous fat depot may explain, in part, the observed differences in HTGC between these groups. Further support for this idea can be found in the significant negative correlation between lower extremity fat and liver fat content in all subjects ().
Dietary carbohydrate intake has been postulated to play a role in the development of hepatic steatosis. Indeed, several observational studies support the notion that diets high in carbohydrates relative to the other macronutrients are associated with higher degrees of hepatic steatosis and inflammation (45
). We did not obtain structured dietary information in the current study and therefore, could not examine its association with the ethnic-specific differences observed in hepatic steaotsis. However, prior studies examining such ethnic variation would suggest that environmental factors are not solely responsible for the differences in insulin sensitivity between these groups (32
In conclusion, HTGC is closely linked to visceral adiposity in African-Americans, Hispanics, and Caucasians. Ethnic differences in the propensity to accumulate visceral fat explains, in part, the observed differences in levels of HTGC and prevalence of hepatic steatosis among these ethnic groups. The relative protection from visceral fat accumulation with increasing adiposity experienced by African-Americans is associated with a similar protection from hepatic steatosis but not insulin resistance. Indeed, many of the derangements in lipid metabolism typically associated with insulin resistance were not present in African-Americans. A possible explanation for these findings is that the insulin resistance phenotype is: 1) a function of the organ contributing primarily to reduced insulin sensitivity; and/or 2) a function of the ability to expand subcutaneous adipose tissue in response to overnutrition. Further study is needed to establish the basis for this insulin resistance paradox.