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Ceruloplasmin (Cp) is a ferroxidase that plays a role in cellular iron homeostasis and is mainly expressed in the liver and secreted into the blood. Cp is also produced by adipose tissue, which releases it as an adipokine. Although a dysfunctional interaction of iron with the metabolism of lipids has been associated with several metabolic diseases, the role of Cp in adipose tissue metabolism and in the interplay between hepatocytes and adipocytes has been poorly investigated. We previously found that Cp-deficient (CpKO) mice become overweight and demonstrate adipose tissue accumulation together with liver steatosis during aging, suggestive of lipid dysmetabolism. In the present study, we investigated the lipid alterations which occur during aging in adipose tissue and liver of CpKO and wild-type mice both in vivo and ex vivo. During aging of CpKO mice, we observed adipose tissue accumulation and liver lipid deposition, both of which are associated with macrophage infiltration. Liver lipid deposition was characterized by accumulation of triglycerides, fatty acids and ω-3 fatty acids, as well as by a switch from unsaturated to saturated fatty acids, which is characteristic of lipid storage. Liver steatosis was preceded by iron deposition and macrophage infiltration, and this was observed to be already occurring in younger CpKO mice. The accumulation of ω-3 fatty acids, which can only be acquired through diet, was associated with body weight increase in CpKO mice despite food intake being equal to that of wild-type mice, thus underlining the alterations in lipid metabolism/catabolism in Cp-deficient animals., (© 2023 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Fatty liver is characterized by metabolic abnormalities at the liver, but also at skeletal muscle and adipose tissue sites. It is hypothesized that the heart may be suffering metabolic alterations, and this study was undertaken to ascertain whether individuals with fatty liver have left ventricular (LV) alterations of energy metabolism, structure, and function and abnormal amounts of epicardial fat as a specific marker of visceral fat accumulation. To this end we studied young, nondiabetic men matched for anthropometric features with (n = 21) or without (n = 21) fatty liver by means of (1) cardiac magnetic resonance imaging (MRI); (2) cardiac (31)P-MR spectroscopy (MRS); and (3) hepatic (1)H-MRS to assess quantitatively the intrahepatic fat (IHF) content. Insulin sensitivity was determined by the updated HOMA-2 computer model. Individuals with fatty liver showed reduced insulin sensitivity, increased serum free fatty acid (FFA), and E-selectin, abnormal adipokine concentrations, and higher blood pressure. LV morphology and systolic and diastolic functions were not different; however, in the scanned intrathoracic region, the intrapericardial (7.8 +/- 3.1 versus 5.9 +/- 2.5 cm(2); P < 0.05) and extrapericardial (11.7 +/- 6.1 versus 7.8 +/- 3.2 cm(2); P < 0.03) fat was increased in men with fatty liver compared with those without fatty liver. The phosphocreatine (PCr)/adenosine triphosphate (ATP) ratio, a recognized in vivo marker of myocardial energy metabolism, was reduced in men with fatty liver in comparison with normals (1.85 +/- 0.35 versus 2.11 +/- 0.31; P < 0.016). In conclusion, in newly found individuals with fatty liver, fat was accumulated in the epicardial area and despite normal LV morphological features and systolic and diastolic functions, they had abnormal LV energy metabolism.

Objective: Fatty liver may be involved in the pathogenesis of type 2 diabetes. Physical exercise is a tool to improve insulin sensitivity, but little is known about its effect on intrahepatic fat (IHF) content. The purpose of this study was to examine the association of habitual physical activity, insulin resistance, and adiponectin with IHF content., Research Design and Methods: Participants were 191 (77 female and 114 male) apparently healthy, nonalcoholic individuals (aged 19-62 years; BMI 17.0-35.5 kg/m2). IHF content was assessed in a quantitative fashion and noninvasively as a continuous variable by means of 1H magnetic resonance spectroscopy (MRS), and habitual physical activity was assessed by means of a questionnaire. Fatty liver was defined as IHF content of >5% wet weight, and insulin sensitivity was estimated using the computer homeostasis model assessment (HOMA)-2 indexes., Results: A reduced prevalence of fatty liver in the quartile of the most physically active individuals (25, 11, 25, and 2% in quartile 1, 2, 3, and 4, respectively; chi2 = 15.63; P = 0.001) was found along with an inverse correlation between the physical activity index and the IHF content when plotted as continuous variables (Pearson's r = -0.27; P < 0.000). This association was not attenuated when adjusted for age, sex, BMI, HOMA-2, and adiponectin (partial correlation r = -0.25; P < 0.001)., Conclusions: This study demonstrated that a higher level of habitual physical activity is associated with a lower IHF content and suggested that this relationship may be due to the effect of exercise per se.

Obese adolescents are at risk of developing NAFLD and type 2 diabetes. We measured noninvasively the IHF content of obese adolescents to ascertain whether it is associated with insulin resistance and abnormal energy homeostasis. IHF content, whole body energy homeostasis, insulin sensitivity, and body composition were measured using localized hepatic (1)H-MRS, indirect calorimetry, fasting-derived and 3-h-OGTT-derived surrogate indexes (HOMA2 and WBISI), and DEXA, respectively, in 54 obese adolescents (24 female and 30 male, age 13 +/- 2 yr, BMI >99th percentile for their age and sex). NAFLD (defined as IHF content >5% wet weight) was found in 16 individuals (30%) in association with higher ALT (P < 0.006), Hb A(1c) (P = 0.021), trunk fat content (P < 0.03), and lower HDL cholesterol (P < 0.05). Individuals with NAFLD had higher fasting plasma glucose (89 +/- 8 vs. 83 +/- 9 mg/dl, P = 0.01) and impaired insulin sensitivity (HOMA2 and WBISI, P < 0.05). Meanwhile, parameters of insulin secretion were unaffected. Their reliance on fat oxidation in the fasting state was lower (RQ 0.83 +/- 0.08 vs. 0.77 +/- 0.05, P < 0.01), and their ability to suppress it during the oral glucose challenge was impaired (P < 0.05) vs. those with normal IHF content. When controlling for trunk fat content, the correlation between IHF content and insulin sensitivity was weakened, whereas the correlation with fasting lipid oxidation was maintained. In conclusion, NAFLD is common in childhood obesity, and insulin resistance is present in association with increased trunk fat content. In contrast, the rearrangement of whole body substrate oxidation in these youngsters appeared to be an independent feature.

Studies have pointed to insulin resistance as pathogenic factor in fatty liver; the role of beta-cell function, even if generally accepted, is unexplored. This study was undertaken to test whether fasting indexes of beta-cell function were related to the intra-hepatic fat (IHF) content in non-diabetic humans. IHF content was measured by means of ¹H-Magnetic Resonance Spectroscopy (MRS), and insulin sensitivity and beta-cell function were estimated based on fasting plasma glucose, insulin and C-peptide in 31 patients with fatty liver and 62 individuals with matched anthropometric features (age: 36±8 vs. 36±7 years, BMI: 27.4±3.8 vs. 26.7±3.2 kg/m²). Patients with fatty liver had higher fasting glucose (P<0.05), insulin (P<0.01), c-peptide (P<0.005) and insulin resistance (HOMA2-%S: 56±24% vs. 77±38%; P=0.008). Fasting insulin secretion (383±168 vs. 284±107 pmol/L; P=0.007) and the beta-cell insulin sensitivity (HOMA2-%B: 171 ± 41% vs. 152±43%; P=0.04) were also increased in patients with fatty liver. A subgroup analysis, performed matching also for HOMA2-%S (including only those <70%; n=25 and n=30 in subjects with and without fatty liver: 47±12% vs. 49±12; P=0.56), confirmed increased insulin secretion (408±178 vs. 266±107 pmol/L; P=0.002) and HOMA2-%B (174±62% ys. 136±56%; P=0.02) in the individuals with fatty liver. In univariate analysis including the entire population fasting insulin explained 14% of the IHF content variability (P<0.000); in multivariate analysis the inclusion of fasting C-peptide increased it more than two-fold (to 32%; P<0.000); inclusion of age, sex, BMI and glucose in this model was not useful. Logistic regression showed that the insulin*C-peptide product was associated with the likelihood of having fatty liver (P<0.001). In conclusion, nondiabetic individuals with fatty liver are characterized not only by reduced insulin sensitivity but also by features of enhanced fasting beta-cell function, which is an independent meaningful factor. [ABSTRACT FROM AUTHOR]