Low Liver Fat Content Research Articles

Steatosis in South African women: How much and why?

BackgroundGlobally, steatosis is the commonest type of liver pathology and is closely associated with obesity and the metabolic syndrome. Obesity is common in urban African females but no data is available on hepatic fat content in this population group when compared to other ethnic groups. The aim of this study was therefore to compare hepatic fat content in woman from different ethnic groups in South Africa and to characterise the principle determinants of liver fat.Materials and methodsA convenience sample of 106 (48 Indian, 29 African and 29 Caucasian) female volunteers aged 20–60 years and having no history of cardiometabolic disorders were recruited. Hepatic fat was determined from CT scans using the liver-spleen attenuation ratio (LAR), which decreases with increasing levels of hepatic fat. Anthropometric and cardiometabolic parameters were measured with insulin resistance determined using the HOMA index and dysglycaemia defined as fasting glucose ≥5.60 mmol/L.ResultsThe African subjects had significantly lower hepatic fat content (LAR as median [interquartile range]: 1.35 [1.28, 1.41]) than the Indian (1.22 [1.10, 1.35]; p<0.005) and Caucasian (1.27 [1.16, 1.33]; p<0.05) females even though they had significantly higher BMIs than both groups (p<0.0005 and p<0.05, respectively). Linear regression showed that: subcutaneous abdominal fat was a significant (unstandardised β = 0.007; p = 0.03) negative, whilst insulin resistance (β = -0.97; p = 0.01) and dysglycaemia (β = -3.58; p = 0.01) were significant positive determinants of liver fat; higher hepatic fat levels in subjects with the metabolic syndrome were explained by insulin resistance and dysglycaemia.DiscussionAfrican ethnicity is associated with low liver fat content. Subcutaneous abdominal fat protects against steatosis, possibly by acting as a triglyceride reservoir. Insulin resistance and dysglycaemia lead to greater hepatic fat deposition and explain higher liver fat levels in subjects with the metabolic syndrome. These observations must be further investigated in longitudinal surveys.

Relationship of Serum Betatrophin with Nonalcoholic Fatty Liver in a Chinese Population.

ObjectiveThis study aimed to investigate the association of serum betatrophin with the status and progression of nonalcoholic fatty liver disease (NAFLD).MethodsA total of 249 subjects who received ultrasonic examination of liver fat content (LFC) were recruited. Anthropometric and biochemical examinations were performed. Serum betatrophin was measured by ELISA.ResultsCompared with control group, serum betatrophin significantly increased in NAFLD group (P < 0.05). There was significant difference in serum betatrophin among control, low liver fat content (LLFC), and high liver fat content (HLFC) groups (P < 0.01). After adjustment for gender, age, BMI, FPG and HbA1c, the betatrophin positively correlated with LFC (r = 0.185, P < 0.01) and TG (r = 0.195, P < 0.01). Stepwise multiple regression analysis indicated serum betatrophin was independently related to LFC (P < 0.05). Multivariate logistic regression analysis revealed subjects in the highest tertile of serum betatrophin had higher odds of having NAFLD after adjustment for traditional NAFLD risk factors (OR = 2.88, 95%CI: 1.15–7.19) (P<0.05).ConclusionSerum betatrophin is an independent risk factor for NAFLD and potential non-invasive marker for its progression. Serum betatrophin may be helpful for the early diagnosis of NAFLD and improvement of its prognosis.

Effects of acute glucocorticoid blockade on metabolic dysfunction in patients with Type 2 diabetes with and without fatty liver.

To investigate the potential of therapies which reduce glucocorticoid action in patients with Type 2 diabetes we performed a randomized, double-blinded, placebo-controlled crossover study of acute glucocorticoid blockade, using the glucocorticoid receptor antagonist RU38486 (mifepristone) and cortisol biosynthesis inhibitor (metyrapone), in 14 men with Type 2 diabetes. Stable isotope dilution methodologies were used to measure the rates of appearance of glucose, glycerol, and free fatty acids (FFAs), including during a low-dose (10 mU·m −2·min−1) hyperinsulinemic clamp, and subgroup analysis was conducted in patients with high or low liver fat content measured by magnetic resonance spectroscopy (n = 7/group). Glucocorticoid blockade lowered fasting glucose and insulin levels and improved insulin sensitivity of FFA and glycerol turnover and hepatic glucose production. Among this population with Type 2 diabetes high liver fat was associated with hyperinsulinemia, higher fasting glucose levels, peripheral and hepatic insulin resistance, and impaired suppression of FFA oxidation and FFA and glycerol turnover during hyperinsulinemia. Glucocorticoid blockade had similar effects in those with and without high liver fat. Longer term treatments targeting glucocorticoid action may be useful in Type 2 diabetes with and without fatty liver.

Predisposition - obesity phenotype

Obesity belongs to the five most important health burdens in modern societies and reaches with ~20 % prevalence in Germany epidemic proportions. Obesity significantly increases the risk of developing metabolic (e. g. type 2 diabetes), cardiovascular, orthopaedic, psychologic and other disorders. Despite the well established epidemiologic relationship between obesity and these co-morbidities, there is a subgroup of metabolically healthy obese patients, which seems to be protected against metabolic and cardiovascular obesity related disorders. Compared to metabolically unhealthy or high risk obese patients, metabolically healthy obese individuals are characterized by preserved insulin sensitivity, lower liver fat content, lower visceral fat mass, as well as normal adipose tissue function. Noteworthy, metabolically healthy obese individuals do not significantly improve their obesity-associated risk for the development of type 2 diabetes and vascular diseases. Therefore, distinction between metabolically healthy from high-risk obese phenotypes will facilitate the identification of the obese person who will benefit the most from early lifestyle, pharmacological or bariatric surgery interventions. A stratified treatment approach considering these different obesity phenotypes should be introduced into clinical management of obese patients.

Plasma ghrelin is positively associated with body fat, liver fat and milk fat content but not with feed intake of dairy cows after parturition

Ghrelin is a gastrointestinal peptide hormone that is present in blood mostly in a non-posttranslationally modified form, with a minor proportion acylated at Ser(3). Both ghrelin forms were initially assigned a role in the control of food intake but there is accumulating evidence for their involvement in fat allocation and utilization. We investigated changes in the ghrelin system in dairy cows, exhibiting differences in body fat mobilization and fatty liver, from late pregnancy to early lactation. Sixteen dairy cows underwent liver biopsy and were retrospectively grouped based on high (H) or low (L) liver fat content post-partum. Both groups had a comparable feed intake in week -6 (before parturition) and week 2 (after parturition). Only before parturition was preprandial total ghrelin concentration higher in L than in H cows and only after parturition was the basal plasma concentration of non-esterified fatty acids higher in H than in L cows. Both before and after parturition, H cows had higher preprandial plasma concentrations of acyl ghrelin, a higher acyl:total ghrelin ratio, lower plasma triacylglyceride concentrations and a lower respiratory quotient compared with L cows. These group differences could not be attributed to an allelic variant of the acyl ghrelin receptor. Rather, the ratio of acyl:total ghrelin correlated with several aspects of fat metabolism and with respiratory quotient but not with feed intake. These results show that endogenous ghrelin forms are associated with fat allocation, fatty liver, and utilization of fat during the periparturient period.

Increased Anaplerosis, TCA Cycling, and Oxidative Phosphorylation in the Liver of Dairy Cows with Intensive Body Fat Mobilization during Early Lactation

The onset of milk production lets mammals experience an enormous energy and nutrient demand. To meet these requirements, high-yielding dairy cows mobilize body fat resulting in an augmented hepatic oxidative metabolism, which has been suggested to signal for depressing hunger after calving. To examine how the extent of fat mobilization influences hepatic oxidative metabolism and thus potentially feed intake, blood and liver samples of 19 Holstein cows were taken throughout the periparturient period. Retrospectively grouped according to high (H) and low (L) liver fat content, H cows showed higher fatty acid but lower amino acid plasma concentrations and lower feed intake than L cows. The hepatic phospho-AMPK/total AMP ratio was not different between groups but decreased after parturition. A 2-DE coupled MALDI-TOF-TOF analysis and qRT-PCR studies revealed H cows having lower expressions of major enzymes involved in mitochondrial β-oxidation, urea cycling, and the pentose phosphate pathway but higher expressions of enzymes participating in peroxisomal and endoplasmic fatty acid degradation, pyruvate and TCA cycling, amino acid catabolism, oxidative phosphorylation, and oxidative stress defense. These data indicate that increasing lipolysis leads to augmenting nutrient catabolism for anaplerosis and mitochondrial respiration, providing a molecular link between hepatic oxidative processes and feed intake.

High Hepatic SCD1 Activity Is Associated with Low Liver Fat Content in Healthy Subjects under a Lipogenic Diet

Increased hepatic de novo lipogenesis (DNL) in response to dietary sugar is implicated in the pathophysiology of fatty liver. Saturated fatty acids are the product of DNL and exert lipotoxic effects that promote liver fat accumulation. Desaturation of fatty acids by stearoyl-CoA desaturase 1 (SCD1) can prevent these deleterious effects. Here we investigated whether DNL and SCD1 are activated in parallel by dietary sugar and influence liver fat accumulation. In 20 healthy subjects (eight females and 12 males, aged 30.5 ± 2.0 yr, body mass index 25.9 ± 0.5 kg/m(2)) who received a 4-wk lipogenic diet supplemented with 150 g/d of monosaccharides, hepatic SCD1 activity and DNL were determined using validated fatty acid ratios (16:1n-7/16:0; 16:0/18:2n-6) in very low-density lipoprotein triglycerides. Liver fat content was measured by localized (1)H-magnetic resonance spectroscopy. At baseline, liver fat content was positively associated with the DNL (r = 0.54, P = 0.01) but not the SCD1 activity index (r = 0.16, P = 0.49). Dietary sugar supplementation increased liver fat content and DNL and SCD1 activity indices (+33, +19, and +8%, respectively). The increase of the DNL index was strongly related to the changes in liver fat content during the sugar supplementation (r = 0.75, P = 0.0001) but showed no association with changes in the SCD1 activity (P > 0.35). After the monosaccharide supplementation, the DNL index was still positively associated with liver fat content (r = 0.52, P = 0.02), whereas SCD1 activity showed a strong negative correlation with liver fat content (r = -0.63, P = 0.002). DNL is closely linked with hepatic steatosis under dietary conditions rich in monosaccharides. Our data suggest that the individual hepatic SCD1 activity is a determinant of liver fat accumulation under lipogenic dietary conditions.

Increased erythrocytes n-3 and n-6 polyunsaturated fatty acids is significantly associated with a lower prevalence of steatosis in patients with type 2 diabetes

Non-alcoholic fatty liver disease (NAFLD) is commonly associated with obesity, metabolic syndrome and type 2 diabetes. Although dietary fat contributes substantially to the accumulation of liver fat, the role of individual fatty acids in this accumulation is unclear. In this study, we set out to determine whether liver fat content (LFC), was associated with red blood cell fatty acid (RBC-FA) composition in people with type 2 diabetes. One hundred and sixty-two type 2 diabetic patients were included in this study. LFC was measured using (1)H-MR Spectroscopy. RBC-FA composition was measured by gas chromatography. One hundred and nine (67.2%) patients had steatosis. Patients with steatosis had a higher BMI (p = 0.0005), and higher plasma triglyceride levels (p = 0.009) than did patients without steatosis. We report a significant association between palmitic acid (16:0), palmitoleic acid (16:1n-7) concentrations and ratio of monounsaturated to saturated fatty acid (palmitoleic acid to palmitic acid) and higher liver fat content. Total polyunsaturated fatty acid (PUFA), homo-gamma-linolenic acid (20:3n-6), docosahexaenoic acid (22:6n-3), and arachidonic acid (20:4 n-6) were associated with lower LFC. Our data showed that an increased erythrocytes long-chain n-3 and n-6 fatty acids was associated with a lower prevalence of steatosis in patients with type 2 diabetes. These results suggest that n-3 and n-6 fatty acids supplementation could be a promising treatment for NAFLD in patients with type 2 diabetes.

Increased Liver Fat Content and Unfavorable Glucose Profiles in Subjects Without Diabetes

Liver fat content (LFC) in subjects without diabetes may be correlated with adverse glucose profiles. LFC was measured by (1)H magnetic resonance spectroscopy in 47 healthy subjects, 35 of whom also completed continuous glucose monitoring (CGM) studies. Subjects were divided into two groups according to LFC, and between-group comparisons of glucose profiles were made. The median LFC value was 3.8% (interquartile range, 2.4-7.6%), and 29.8% of the subjects had LFC values ≥ 5.5%. LFC was positively correlated with triglyceride, aspartate aminotransferase, γ-glutamyltransferase, fasting C-peptide, fasting insulin, insulin concentration at 120 min, area under the time-concentration curve for insulin, and change in insulin from 0 to 30 min, homeostatic model assessment of insulin resistance, fasting plasma glucose, nocturnal mean blood glucose concentration (MBG) (all P < 0.05). The 35 CGM profiles revealed that nocturnal MBG was higher in subjects with LFC ≥ 3.8% (P < 0.05). In subjects with LFC ≥ 5.5%, both diurnal and nocturnal MBG values were elevated compared with subjects with lower LFC (P < 0.05). LFC was the strongest predictive factor of nocturnal MBG. Even modestly elevated LFC was associated with unfavorable glucose profiles in subjects without diabetes.

C-reactive protein mediates the association of liver fat and carotid intima–media thickness in healthy men and men with the metabolic syndrome and/or uncomplicated type 2 diabetes

We investigated whether the relation between liver fat and subclinical atherosclerosis is mediated by low-grade systemic inflammation in type 2 diabetes (T2DM) and the metabolic syndrome (MetS). In 16 T2DM, 36 MetS, and 21 age-matched healthy men, liver fat was quantified by 1H-MRS. Carotid intima–media thickness (cIMT) was measured by ultrasound. Differences between controls, MetS and T2DM or between high versus low liver fat content were calculated. Furthermore, the association of liver fat content, cIMT and CRP was assessed. Liver fat percentage was highest in T2DM, as compared to MetS and controls [17.5% (8.0–27.6), 8.2% (4.2–14.2) and 5.3% (2.3–7.4), respectively; P < 0.001]. Subjects with high-liver fat content had increased cIMT and CRP (all P < 0.02). Liver fat content was positively associated with cIMT ( r = 0.37; P = 0.003). The association of liver fat content and cIMT disappeared after adjustment for CRP. The association between liver fat content and subclinical atherosclerosis seems mediated by low-grade inflammation, possibly due to increased hepatic production. Lowering of liver fat content may decrease CVD risk by concomitantly reducing the pro-inflammatory state in high-risk populations.

Metabolically healthy but obese individuals: relationship with hepatic enzymes

The purpose of this study was to investigate the level of plasma hepatic enzymes in obese women displaying the metabolically healthy but obese (MHO) phenotype. We studied 104 obese, sedentary, postmenopausal women. Subjects were classified as MHO or at risk based on insulin sensitivity as assessed with the oral glucose tolerance test–derived Matsuda index. Subjects were divided into quartiles according to insulin sensitivity values. Subjects in the upper quartile were categorized as MHO, whereas subjects in the lower 3 quartiles represented at-risk subjects. Outcome measures were hepatic enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase, and γ-glutamyltransferase [GGT]], high-density lipoprotein cholesterol, triglycerides, triglycerides to high-density lipoprotein cholesterol ratio, apolipoprotein B, fatty liver index, body composition (dual-energy x-ray absorptiometry), and visceral adipose tissue (computed tomography). The MHO individuals had significantly lower concentrations of ALT, AST, and GGT as well as a lower fatty liver index compared with at-risk subjects ( P < .05). In addition, lean body mass index and visceral adipose tissue were significantly lower in MHO individuals ( P < .05). Moreover, stepwise regression analysis showed that ALT explained 17.9% of the variation in insulin sensitivity in our cohort, which accounted for the greatest source of unique variance. Results of the present study indicate that postmenopausal women displaying the MHO phenotype present favorable levels of ALT, AST, and GGT. Lower concentrations of hepatic enzymes, in particular, lower circulating ALT levels, in MHO individuals may reflect lower hepatic insulin resistance and lower liver fat content; and this could be involved, at least in part, in the protective profile of MHO individuals.

Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis

Metabolic dyslipidemia is characterized by high circulating triglyceride (TG) and low HDL cholesterol levels and is frequently accompanied by hepatic steatosis. Increased hepatic lipogenesis contributes to both of these problems. Because insulin fails to suppress gluconeogenesis but continues to stimulate lipogenesis in both obese and lipodystrophic insulin-resistant mice, it has been proposed that a selective postreceptor defect in hepatic insulin action is central to the pathogenesis of fatty liver and hypertriglyceridemia in these mice. Here we show that humans with generalized insulin resistance caused by either mutations in the insulin receptor gene or inhibitory antibodies specific for the insulin receptor uniformly exhibited low serum TG and normal HDL cholesterol levels. This was due at least in part to surprisingly low rates of de novo lipogenesis and was associated with low liver fat content and the production of TG-depleted VLDL cholesterol particles. In contrast, humans with a selective postreceptor defect in AKT2 manifest increased lipogenesis, elevated liver fat content, TG-enriched VLDL, hypertriglyceridemia, and low HDL cholesterol levels. People with lipodystrophy, a disorder characterized by particularly severe insulin resistance and dyslipidemia, demonstrated similar abnormalities. Collectively these data from humans with molecularly characterized forms of insulin resistance suggest that partial postreceptor hepatic insulin resistance is a key element in the development of metabolic dyslipidemia and hepatic steatosis.

Gene expression in human NAFLD

Despite the high prevalence of nonalcoholic fatty liver disease (NAFLD), little is known of its pathogenesis based on study of human liver samples. By the use of Affymetrix GeneChips (17,601 genes), we investigated gene expression in the human liver of subjects with extreme steatosis due to NAFLD without histological signs of inflammation (liver fat 66.0 +/- 6.8%) and in subjects with low liver fat content (6.4 +/- 2.7%). The data were analyzed by using sequence-based reannotation of Affymetrix probes and a robust model-based normalization method. We identified genes involved in hepatic glucose and lipid metabolism, insulin signaling, inflammation, coagulation, and cell adhesion to be significantly associated with liver fat content. In addition, genes involved in ceramide signaling (MAP2K4) and metabolism (UGCG) were found to be positively associated with liver fat content. Genes involved in lipid metabolism (PLIN, ACADM), fatty acid transport (FABP4, CD36), amino acid catabolism (BCAT1), and inflammation (CCL2) were validated by real-time PCR and were found to be upregulated in subjects with high liver fat content. The data show that multiple changes in gene expression characterize simple steatosis.

“Buffalo” hump in nonalcoholic fatty liver disease

I read with interest the recent article by Cheung et al.1 regarding the impact of fat distribution, as estimated by several anthropometric parameters, on the severity of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome in obese NAFLD patients. Notably, they found that dorsocervical lipohypertrophy (“buffalo” hump) was the single greatest predictor of the histological severity of NAFLD, whereas waist circumference was the greatest predictor of the severity of metabolic syndrome.1 Dorsocervical lipohypertrophy (DCL) was diagnosed only clinically but no quantitative measure (for example, ultrasound imaging) was used for diagnosing the “hump” at the base of the neck. Obviously, this is a major limitation of the study. Additionally, it is conceivable that the differential impact of DCL and waist circumference on the severity of NAFLD histology and metabolic syndrome is simply due to the fact that they are only indirect and crude indices of abdominal visceral fat distribution.2 A direct and more accurate measure of abdominal visceral fat, obtained by computed tomography or magnetic resonance imaging,2 would be useful to explore this issue adequately. However, the authors have interestingly shown that DCL, which is commonly seen in Cushing's syndrome, is a highly prevalent condition (28.5%) in obese NAFLD patients,1 thus suggesting an underlying subclinical hypercortisolism in NAFLD. Regarding this, recent studies have consistently shown a subclinical hypothalamo-pituitary-adrenal (HPA) axis dysfunction in NAFLD. Westerbacka et al.3 reported that obese men with higher liver fat content (as evaluated by magnetic resonance imaging spectroscopy) have a selective increase in 24-hour urinary excretion of 5-beta-reduced cortisol metabolites and a lower ratio of urinary cortisol/cortisone metabolites than men with lower liver fat content. Saruc et al.4 found that postmenopausal women with NAFLD, as assessed by ultrasound, have higher plasma dehydroepiandrosterone levels than controls. Others have shown that obese individuals5 and overweight type 2 diabetic patients6 with ultrasonographically diagnosed NAFLD have higher 24-hour urinary free cortisol excretion and postdexamethasone suppression cortisol concentrations than nonsteatotic controls. More importantly, we have recently demonstrated that overweight patients with biopsy-proven NAFLD have a subclinical, chronic HPA axis activation (as reflected by the increased, albeit still normal, 24-hour urinary free cortisol values and the blunted suppression of cortisol levels by 1.0 mg-dexamethasone with normal serum corticosteroid-binding globulin concentrations) that is correlated to the histopathological severity of NAFLD (that is, necro-inflammatory grade and fibrosis stage) independently of multiple potential confounders, including insulin resistance and metabolic syndrome components.7 Overall, therefore, the evidence from these studies,3-7 although only correlative in nature, suggests the hypothesis that overweight/obese NAFLD patients have a subtle HPA axis dysfunction that is strongly correlated with the severity of NAFLD histology, leading to subclinical cortisol overproduction that might be implicated in the development/progression of NAFLD. Future prospective and interventional (by using a cortisol inhibitor or specific 11beta-hydroxysteroid dehydrogenase-type 1 inhibitors) studies are obviously needed to validate this hypothesis and to better understand the underlying biological mechanisms linking HPA axis dysfunction to the development of NAFLD. Giovanni Targher M.D.*, * Section of Endocrinology, Department of Biomedical and Surgical Sciences, University Hospital, Verona, Italy.

Liver steatosis coexists with myocardial insulin resistance and coronary dysfunction in patients with type 2 diabetes

Nonalcoholic fatty liver (NAFL) is a common comorbidity in patients with type 2 diabetes and links to the risk of coronary syndromes. The aim was to determine the manifestations of metabolic syndrome in different organs in patients with liver steatosis. We studied 55 type 2 diabetic patients with coronary artery disease using positron emission tomography. Myocardial perfusion was measured with [15O]H2O and myocardial and skeletal muscle glucose uptake with 2-deoxy-2-[18F]fluoro-D-glucose during hyperinsulinemic euglycemia. Liver fat content was determined by magnetic resonance proton spectroscopy. Patients were divided on the basis of their median (8%) into two groups with low (4.6 +/- 2.0%) and high (17.4 +/- 8.0%) liver fat content. The groups were well matched for age, BMI, and fasting plasma glucose. In addition to insulin resistance at the whole body level (P = 0.012) and muscle (P = 0.002), the high liver fat group had lower insulin-stimulated myocardial glucose uptake (P = 0.040) and glucose extraction rate (P = 0.0006) compared with the low liver fat group. In multiple regression analysis, liver fat content was the most significant explanatory variable for myocardial insulin resistance. In addition, the high liver fat group had increased concentrations of high sensitivity C-reactive protein, soluble forms of E-selectin, vascular adhesion protein-1, and intercellular adhesion molecule-1 (P < 0.05) and lower coronary flow reserve (P = 0.02) compared with the low liver fat group. In conclusion, in patients with type 2 diabetes and coronary artery disease, liver fat content is a novel independent indicator of myocardial insulin resistance and reduced coronary functional capacity. Further studies will reveal the effect of hepatic fat reduction on myocardial metabolism and coronary function.

Effects of identical weight loss on body composition and features of insulin resistance in obese women with high and low liver fat content.

Our objective was to determine how 8% weight loss influences subcutaneous, intra-abdominal, and liver fat (LFAT), as well as features of insulin resistance, in obese women with high versus low LFAT. A total of 23 women with previous gestational diabetes were divided into groups of high (9.4 +/- 1.4%) and low (3.3 +/- 0.4%) LFAT based on their median LFAT (5%) measured with proton spectroscopy. Both groups were similar with respect to age, BMI, and intra-abdominal and subcutaneous fat. Before weight loss, women with high LFAT had higher fasting serum insulin and triglyceride concentrations than women with low LFAT. At baseline, LFAT correlated with the percent of fat (r = 0.44, P < 0.05) and saturated fat (r = 0.45, P < 0.05) of total caloric intake but not intra-abdominal or subcutaneous fat or fasting serum free fatty acids. Weight loss was similar between the groups (high LFAT -7.4 +/- 0.2 vs. low LFAT -7.7 +/- 0.3 kg). LFAT decreased from 9.4 +/- 1.4 to 4.8 +/- 0.7% (P < 0.001) in women with high LFAT and from 3.3 +/- 0.4 to 2.0 +/- 0.2% (P < 0.001) in women with low LFAT. The absolute decrease in LFAT was significantly higher in women with high than low LFAT (-4.6 +/- 1.0 vs. -1.3 +/- 0.3%, P < 0.005). The decrease in LFAT was closely correlated with baseline LFAT (r = -0.85, P < 0.001) but not with changes in the volumes of intra-abdominal or subcutaneous fat depots, which decreased similarly in both groups. LFAT appears to be related to the amount of fat in the diet rather than the size of endogenous fat depots in obese women. Women with initially high LFAT lost more LFAT by similar weight loss than those with low LFAT, although both groups lost similar amounts of subcutaneous and intra-abdominal fat. These data suggest that LFAT is regulated by factors other than intra-abdominal and subcutaneous fat. Therefore, LFAT does not appear to simply reflect the size of endogenous fat stores.

Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men.

We determined whether interindividual variation in hepatic insulin sensitivity could be attributed to variation in liver fat content (LFAT) independent of obesity. We recruited 30 healthy nondiabetic men whose LFAT (determined by proton spectroscopy); intraabdominal, sc, and total (determined by magnetic resonance imaging) fat; and insulin sensitivity of endogenous glucose rate of production (R(a)) and suppression of serum FFA [euglycemic insulin clamp combined with [3-(3)H]glucose (0-300 min); insulin infusion rate, 0.3 mU/kg.min, 120-300 min] were measured. The men were divided into groups of low (mean +/- SD, 1.7 +/- 0.2%) and high (10.5 +/- 2.0%) LFAT based on their median fat content. The low and high LFAT groups were comparable with respect to age (44 +/- 2 vs. 42 +/- 2 yr), body mass index (25 +/- 1 vs. 26 +/- 1 kg/m(2) ), waist to hip ratio (0.953 +/- 0.013 vs. 0.953 +/- 0.013), maximal oxygen uptake (35.6 +/- 1.5 vs. 33.5 +/- 1.5 ml/kg.min), and intraabdominal, sc, and total fat. The high compared with the low LFAT group had several features of insulin resistance, including fasting hyperinsulinemia (7.3 +/- 0.6 vs. 5.3 +/- 0.6 mU/liter; P < 0.02, high vs. low LFAT) hypertriglyceridemia (1.4 +/- 0.2 vs. 0.9 +/- 0.1 mmol/liter; P < 0.02), a low high density lipoprotein (HDL) cholesterol concentration (1.4 +/- 0.1 vs. 1.6 +/- 0.1 mmol/liter; P < 0.05), and a higher ambulatory 24-h systolic blood pressure (130 +/- 3 vs. 122 +/- 3 mm Hg; P < 0.05). Basal glucose R(a) and serum FFA were comparable between the groups, whereas insulin suppression of glucose R(a) [51 +/- 8 vs. 20 +/- 12 mg/m(2).min during 240-300 min (P < 0.05) or -55 +/- 7 vs. -85 +/- 12% below basal (P < 0.05, high vs. low LFAT)] and of serum FFA (299 +/- 33 vs. 212 +/- 13 micromol/liter; 240-300 min; P < 0.02) were impaired in the high compared with the low LFAT group. Insulin stimulation of glucose Rd were comparable in the men with high LFAT (141 +/- 12 mg/m(2).min) and those with low LFAT (156 +/- 14 mg/m(2).min; P = NS). Fat accumulation in the liver is, independent of body mass index and intraabdominal and overall obesity, characterized by several features of insulin resistance in normal weight and moderately overweight subjects.

Influence of Diet Composition on Hepatic Lipid Deposition in Two Lines of Australorps Selected for Liver Fat Differences

This investigation was conducted to determine if the level of liver fat in Black Australorp laying hens, which had been selected over several generations for high or low liver fat content, would respond to changes in diet composition similar to the response of commercial strains of White Leghorns. In the first experiment, the two selected lines were fed either a corn-soybean diet (CS) or an tsonitrogenous and isoenergetic diet containing 4.89% each of fish meal, alfalfa meal, and torula yeast (FAY) for 6 weeks. Liver lipid was significantly higher for the high (19.4%) than for the low line (10.8%), but the FAY diet did not significantly affect this parameter. In a second 6-week experiment, the high and low lines of Black Australorps and unselected commercial White Leghorn hens were fed either the CS diet or one containing 14.67% distillers dried grains with solubles (DDGS). The DDGS significantly reduced both liver lipid and relative liver weight in Leghorns but not in the low and high liver fat Black Australorp lines. These results indicate that the mechanism of hepatic lipid accumulation in the genetically selected birds is different from that caused by feeding Leghorn hens a simplified CS diet and that the high liver fat line would not be useful in delineating nutritional effects on hepatic lipid accumulation.