Obesity characterized by adiposity and ectopic fat accumulation is associated with the development of non-alcoholic fatty liver disease (NAFLD). Treatments that stimulate lipid utilization may prevent the development of obesity and comorbidities. This study evaluated the potential anti-obesogenic hepatoprotective effects of combined treatment with L-carnitine and nicotinamide riboside, i.e., components that can enhance fatty acid transfer across the inner mitochondrial membrane and increase nicotinamide adenine nucleotide (NAD+) levels, which are necessary for β-oxidation and the TCA cycle, respectively. Ldlr −/−.Leiden mice were treated with high-fat diet (HFD) supplemented with L-carnitine (LC; 0.4% w/w), nicotinamide riboside (NR; 0.3% w/w) or both (COMBI) for 21 weeks. L-carnitine plasma levels were reduced by HFD and normalized by LC. NR supplementation raised its plasma metabolite levels demonstrating effective delivery. Although food intake and ambulatory activity were comparable in all groups, COMBI treatment significantly attenuated HFD-induced body weight gain, fat mass gain (−17%) and hepatic steatosis (−22%). Also, NR and COMBI reduced hepatic 4-hydroxynonenal adducts. Upstream-regulator gene analysis demonstrated that COMBI reversed detrimental effects of HFD on liver metabolism pathways and associated regulators, e.g., ACOX, SCAP, SREBF, PPARGC1B, and INSR. Combination treatment with LC and NR exerts protective effects on metabolic pathways and constitutes a new approach to attenuate HFD-induced obesity and NAFLD.

Objective To investigate the relationship between abdominal ultrasound (US) findings and demographic, historical and clinical features in children with CF. Study design Children age 3-12 years with CF without known cirrhosis, were enrolled in a prospective, multi-center study of US to predict hepatic fibrosis. Consensus US patterns were assigned by 3 radiologists as normal, heterogeneous, homogeneous, or cirrhosis. Data were derived from direct collection and U.S. or Toronto CF registries. Chi-square or ANOVA were used to compare variables among US groups and between normal and abnormal. Logistic regression was used to study risk factors for having abnormal US. Results Findings in 719 subjects were normal (n=590, 82.1%), heterogeneous (64, 8.9%), homogeneous (41, 5.7%), and cirrhosis (24, 3.3%). Cirrhosis (p=0.0004), homogeneous (p<0.0001) and heterogeneous (p=0.03) were older than normal. More males were heterogeneous (p=0.001). More heterogeneous (15.0%, p=0.009) and cirrhosis (25.0%, p=0.005) had CF-related diabetes or impaired glucose tolerance versus normal (5.4%). Early infection with Pseudomonas aeruginosa (<2 years old) was associated with a lower risk (OR 0.42, p=0.0007) of abnormal. Ursodeoxycholic acid use (OR 3.69, p <0.0001) and CF-related diabetes (OR 2.21, p=0.019) were associated with increased risk of abnormal. Conclusions Unsuspected cirrhosis is seen in 3.3% of young patients with CF, heterogeneous in 8.9%. abnormal US is associated with CF-related diabetes, and early P aeruginosa is associated with normal US. Prospective assessment of these risk factors may identify potential interventional targets.

Background: Chronic inflammation is an important driver in the progression of non-alcoholic steatohepatitis (NASH) and atherosclerosis. The complement system, one of the first lines of defense in innate immunity, has been implicated in both diseases. However, the potential therapeutic value of complement inhibition in the ongoing disease remains unclear. Methods: After 20 weeks of high-fat diet (HFD) feeding, obese Ldlr-/-.Leiden mice were treated twice a week with an established anti-C5 antibody (BB5.1) or vehicle control. A separate group of mice was kept on a chow diet as a healthy reference. After 12 weeks of treatment, NASH was analyzed histopathologically, and genome-wide hepatic gene expression was analyzed by next-generation sequencing and pathway analysis. Atherosclerotic lesion area and severity were quantified histopathologically in the aortic roots. Results: Anti-C5 treatment considerably reduced complement system activity in plasma and MAC deposition in the liver but did not affect NASH. Anti-C5 did, however, reduce the development of atherosclerosis, limiting the total lesion size and severity independently of an effect on plasma cholesterol but with reductions in oxidized LDL (oxLDL) and macrophage migration inhibitory factor (MIF). Conclusion: We show, for the first time, that treatment with an anti-C5 antibody in advanced stages of NASH is not sufficient to reduce the disease, while therapeutic intervention against established atherosclerosis is beneficial to limit further progression.

Introduction:While underlying pathophysiology linking obesity to brain health is not completely understood, white adipose tissue (WAT) is considered a key player. In obesity, WAT becomes dysregulated, showing hyperplasia, hypertrophy and eventually inflammation. This disbalance leads to dysregulated secretion of adipokines influencing both (cardio)vascular and brain health. Within this study we investigated the association between omental (oWAT) and subcutaneous WAT (scWAT) with brain structure, perfusion and cognition in adults with severe obesity.Methods:Within the cross-sectional BARICO study, brain structure, perfusion and cognitive function were measured before bariatric surgery (BS) using MRI and cognitive assessments. During BS, oWAT and scWAT depots were collected and analyzed by histopathology. Number and diameter of adipocytes were quantified together with amount of crown-like structures (CLS) as indication of inflammation. Blood samples were collected to analyze adipokines and inflammatory markers. Neuroimaging outcomes included brain volumes, cortical thickness, white matter (WM) integrity, WM hyperintensities, cerebral blood flow using arterial spin labeling (ASL) and the ASL spatial coefficient of variation (sCoV), reflecting cerebrovascular health.Results:71 patients were included (mean age 45.1±5.8 years; 83.1% women; mean BMI 40.8±3.8). scWAT showed more CLS (Z=-2.72, p<0.01, r=-0.24) and hypertrophy compared to oWAT (F(1,64)=3.99, p<0.05, η2=0.06). Adiponectin levels were inversely associated with the average diameter of scWAT (β=-0.31, 95%CI -0.54 to -0.08) and oWAT (β=-0.33, 95%CI -0.55 to -0.09). Furthermore, the adipocyte diameter in oWAT was positively associated with the sCoV in the parietal cortex (β=0.33, 95%CI 0.10 to 0.60) and the number of adipocytes (per mm2) was positively associated with sCoV in the nucleus accumbens (NAcc) (β=0.34, 95%CI 0.09 to 0.61). Cognitive function did not correlate with any WAT parameter nor plasma marker. These associations were highly influenced by age and sex. sCoV in the NAcc was positively associated with fasting plasma glucose (β=0.35, 95%CI 0.10 to 0.56).Conclusion:scWAT and oWAT are different in morphology and in their relationship with plasma markers and cerebrovascular health. Although scWAT showed more CLS and hypertrophy, scWAT was not associated with brain readouts. This study showed however important relations between oWAT morphology and cerebrovascular health in obesity.