Therapeutic intervention with anti-complement component 5 antibody does not reduce nash but does attenuate atherosclerosis and mif concentrations in ldlr-/-.Leiden mice

Background: Chronic inflammation is an important driver in the progression of nonalcoholic 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

Lipid profiling analyses from mouse models and human infants.

This protocol outlines a translational lipidomic approach to discover lipid biomarkers that could predict morphometric body and histological organ measurements (e.g., weight and adiposity gains) during specific stages of life (e.g., early life). We describe procedures ranging from animal experimentation and histological analyses to downstream analytical steps through lipid profiling, both in mice and humans. This protocol represents a reliable and versatile approach to translate and validate candidate lipid biomarkers from animal models to a human cohort. For complete details on the use and execution of this protocol, please refer to Olga et al. (2021)

Combined Treatment with L-Carnitine and Nicotinamide Riboside Improves Hepatic Metabolism and Attenuates Obesity and Liver Steatosis

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.</p

Impact of White Adipose Tissue on Brain Structure, Perfusion, and Cognitive Function in Patients with Severe Obesity

Background and Objective 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 WAT (oWAT) and subcutaneous WAT (scWAT) with brain structure and perfusion and cognition in adults with severe obesity. Methods Within the cross-sectional BARICO study, brain structure and 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. The number and diameter of adipocytes were quantified together with the amount of crown-like structures (CLS) as an 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 Seventy-one patients were included (mean age 45.1 ± 5.8 years; 83.1% women; mean body mass index 40.8 ± 3.8 kg/m2). scWAT showed more CLS (z = −2.72, p < 0.01, r = −0.24) and hypertrophy compared with 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 0.10–0.60), and the number of adipocytes (per mm2) was positively associated with sCoV in the nucleus accumbens (NAcc) (β = 0.34, 95% CI 0.09–0.61). Cognitive function did not correlate with any WAT parameter or 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 0.10–0.56)

Impact of White Adipose Tissue on Brain Structure, Perfusion, and Cognitive Function in Patients With Severe Obesity: The BARICO Study

Background and Objective 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 WAT (oWAT) and subcutaneous WAT (scWAT) with brain structure and perfusion and cognition in adults with severe obesity. Methods Within the cross-sectional BARICO study, brain structure and 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. The number and diameter of adipocytes were quantified together with the amount of crown-like structures (CLS) as an 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 Seventy-one patients were included (mean age 45.1 ± 5.8 years; 83.1% women; mean body mass index 40.8 ± 3.8 kg/m 2). scWAT showed more CLS (z = −2.72, p < 0.01, r = −0.24) and hypertrophy compared with oWAT (F(1,64) = 3.99, p < 0.05, η 2 = 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 0.10–0.60), and the number of adipocytes (per mm 2) was positively associated with sCoV in the nucleus accumbens (NAcc) (β = 0.34, 95% CI 0.09–0.61). Cognitive function did not correlate with any WAT parameter or 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 0.10–0.56)