FGF21 decreases plasma triglycerides (TGs) in rodents and humans; however, the underlying mechanism or mechanisms are unclear. In the present study, we examined the role of FGF21 in production and ...disposal of TG-rich lipoproteins (TRLs) in mice. Treatment with pharmacological doses of FGF21 acutely reduced plasma non-esterified fatty acids (NEFAs), liver TG content, and VLDL-TG secretion. In addition, metabolic turnover studies revealed that FGF21 facilitated the catabolism of TRL in white adipose tissue (WAT) and brown adipose tissue (BAT). FGF21-dependent TRL processing was strongly attenuated in CD36-deficient mice and transgenic mice lacking lipoprotein lipase in adipose tissues. Insulin resistance in diet-induced obese and ob/ob mice shifted FGF21 responses from WAT toward energy-combusting BAT. In conclusion, FGF21 lowers plasma TGs through a dual mechanism: first, by reducing NEFA plasma levels and consequently hepatic VLDL lipidation and, second, by increasing CD36 and LPL-dependent TRL disposal in WAT and BAT.
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•FGF21 reduces VLDL secretion by regulating fatty acid uptake into adipose tissues•The FGF21 triglyceride-lowering effect is facilitated by CD36 and lipoprotein lipase•FGF21 increases lipoprotein disposal into adipose tissues of lean mice•In obesity, FGF21-induced lipid disposal shifts from white to brown adipose tissue
Schlein et al. identify distinct mechanisms whereby FGF21 lowers plasma triglycerides in lean and obese mice. In lean mice, FGF21 reduces liver VLDL secretion and accelerates their disposal in WAT and BAT via CD36 and lipoprotein lipase. In obesity, FGF21-induced lipoprotein disposal shifts from white to brown fat.
Abstract This short review aims to point out the general anatomical features of the autonomic nervous systems of non-mammalian vertebrates. In addition it attempts to outline the similarities and ...also the increased complexity of the autonomic nervous patterns from fish to tetrapods. With the possible exception of the cyclostomes, perhaps the most striking feature of the vertebrate autonomic nervous system is the similarity between the vertebrate classes. An evolution of the complexity of the system can be seen, with the segmental ganglia of elasmobranchs incompletely connected longitudinally, while well developed paired sympathetic chains are present in teleosts and the tetrapods. In some groups the sympathetic chains may be reduced (dipnoans and caecilians), and have yet to be properly described in snakes. Cranial autonomic pathways are present in the oculomotor (III) and vagus (X) nerves of gnathostome fish and the tetrapods, and with the evolution of salivary and lachrymal glands in the tetrapods, also in the facial (VII) and glossopharyngeal (IX) nerves.
Primary prevention of cardiovascular disease often fails because of poor adherence among practitioners and individuals to prevention guidelines. We aimed to investigate whether ultrasound-based ...pictorial information about subclinical carotid atherosclerosis, targeting both primary care physicians and individuals, improves prevention.
Visualization of asymptomatic atherosclerotic disease for optimum cardiovascular prevention (VIPVIZA) is a pragmatic, open-label, randomised controlled trial that was integrated within the Västerbotten Intervention Programme, an ongoing population-based cardiovascular disease prevention programme in northern Sweden. Individuals aged 40, 50, or 60 years with one or more conventional risk factors were eligible to participate. Participants underwent clinical examination, blood sampling, and ultrasound assessment of carotid intima media wall thickness and plaque formation. Participants were randomly assigned 1:1 with a computer-generated randomisation list to an intervention group (pictorial representation of carotid ultrasound plus a nurse phone call to confirm understanding) or a control group (not informed). The primary outcomes, Framingham risk score (FRS) and European systematic coronary risk evaluation (SCORE), were assessed after 1 year among participants who were followed up. This study is registered with ClinicalTrials.gov, number NCT01849575.
3532 individuals were enrolled between April 29, 2013, and June 7, 2016, of which 1783 were randomly assigned to the control group and 1749 were assigned to the intervention group. 3175 participants completed the 1-year follow-up. At the 1-year follow-up, FRS and SCORE differed significantly between groups (FRS 1·07 95% CI 0·11 to 2·03, p=0·0017 and SCORE 0·16 0·02 to 0·30, p=0·0010). FRS decreased from baseline to the 1-year follow-up in the intervention group and increased in the control group (−0·58 95% CI −0·86 to −0·30 vs 0·35 0·08 to 0·63). SCORE increased in both groups (0·13 95% CI 0·09 to 0·18 vs 0·27 0·23 to 0·30).
This study provides evidence of the contributory role of pictorial presentation of silent atherosclerosis for prevention of cardiovascular disease. It supports further development of methods to reduce the major problem of low adherence to medication and lifestyle modification.
Västerbotten County Council, the Swedish Research Council, the Heart and Lung Foundation, the Swedish Society of Medicine, and Carl Bennet Ltd, Sweden.
The coordination of the organ-specific responses regulating systemic energy distribution to replenish lipid stores in acutely activated brown adipose tissue (BAT) remains elusive. Here, we show that ...short-term cold exposure or acute β3-adrenergic receptor (β3AR) stimulation results in secretion of the anabolic hormone insulin. This process is diminished in adipocyte-specific Atgl−/− mice, indicating that lipolysis in white adipose tissue (WAT) promotes insulin secretion. Inhibition of pancreatic β cells abolished uptake of lipids delivered by triglyceride-rich lipoproteins into activated BAT. Both increased lipid uptake into BAT and whole-body energy expenditure in response to β3AR stimulation were blunted in mice treated with the insulin receptor antagonist S961 or lacking the insulin receptor in brown adipocytes. In conclusion, we introduce the concept that acute cold and β3AR stimulation trigger a systemic response involving WAT, β cells, and BAT, which is essential for insulin-dependent fuel uptake and adaptive thermogenesis.
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•Acute cold exposure or β3-AR agonism stimulates insulin release via WAT lipolysis•Insulin is mandatory for efficient lipid uptake into thermogenically activated BAT•Disruption of insulin secretion or signaling compromises BAT energy uptake•Insulin-mediated triglyceride replenishment is important for adaptive thermogenesis
Heine et al. reveal that thermogenic activation via acute cold exposure or β3-adrenergic receptor agonism provokes insulin release via adipose triglyceride lipase activation. Under these conditions, insulin facilitates the uptake of glucose and lipids delivered by triglyceride-rich lipoproteins, and thereby promotes efficient replenishment of BAT energy stores needed for adaptive thermogenesis.
Brown and beige adipocytes combust nutrients for thermogenesis and through their metabolic activity decrease pro-atherogenic remnant lipoproteins in hyperlipidemic mice. However, whether the ...activation of thermogenic adipocytes affects the metabolism and anti-atherogenic properties of high-density lipoproteins (HDL) is unknown. Here, we report a reduction in atherosclerosis in response to pharmacological stimulation of thermogenesis linked to increased HDL levels in APOE*3-Leiden.CETP mice. Both cold-induced and pharmacological thermogenic activation enhances HDL remodelling, which is associated with specific lipidomic changes in mouse and human HDL. Furthermore, thermogenic stimulation promotes HDL-cholesterol clearance and increases macrophage-to-faeces reverse cholesterol transport in mice. Mechanistically, we show that intravascular lipolysis by adipocyte lipoprotein lipase and hepatic uptake of HDL by scavenger receptor B-I are the driving forces of HDL-cholesterol disposal in liver. Our findings corroborate the notion that high metabolic activity of thermogenic adipocytes confers atheroprotective properties via increased systemic cholesterol flux through the HDL compartment.
Atherosclerosis is a chronic inflammatory disease promoted by hyperlipidemia. Several studies support FOXP3-positive regulatory T cells (Tregs) as inhibitors of atherosclerosis; however, the ...mechanism underlying this protection remains elusive. To define the role of FOXP3-expressing Tregs in atherosclerosis, we used the DEREG mouse, which expresses the diphtheria toxin (DT) receptor under control of the Treg-specific Foxp3 promoter, allowing for specific ablation of FOXP3+ Tregs. Lethally irradiated, atherosclerosis-prone, low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice received DEREG bone marrow and were injected with DT to eliminate FOXP3(+) Tregs. Depletion of Tregs caused a 2.1-fold increase in atherosclerosis without a concomitant increase in vascular inflammation. These mice also exhibited a 1.7-fold increase in plasma cholesterol and an atherogenic lipoprotein profile with increased levels of VLDL. Clearance of VLDL and chylomicron remnants was hampered, leading to accumulation of cholesterol-rich particles in the circulation. Functional and protein analyses complemented by gene expression array identified reduced protein expression of sortilin-1 in liver and increased plasma enzyme activity of lipoprotein lipase, hepatic lipase, and phospholipid transfer protein as mediators of the altered lipid phenotype. These results demonstrate that FOXP3(+) Tregs inhibit atherosclerosis by modulating lipoprotein metabolism.
Angiopoietin-like 4 (ANGPTL4) is an important regulator of plasma triglyceride levels and an attractive pharmacological target for lowering plasma lipids and reducing cardiovascular risk. Here we ...aimed to study the efficacy and safety of silencing ANGPTL4 in the livers of mice using hepatocyte-targeting GalNAc-conjugated antisense oligonucleotides (ASO). Compared to injections with negative control ASO, four injections of two different doses of ANGPTL4 ASO over two weeks markedly downregulated ANGPTL4 levels in liver and adipose tissue, which was associated with significantly higher adipose lipoprotein lipase activity and lower plasma triglycerides in fed and fasted mice, as well as lower plasma glucose levels in fed mice. In separate experiments, injection of two different doses of ANGPTL4 ASO over 20 weeks of high-fat feeding reduced hepatic and adipose ANGPTL4 levels but did not trigger mesenteric lymphadenopathy, an acute phase response, chylous ascites, or any other pathological phenotypes. Compared to mice injected with negative control ASO, mice injected with ANGPTL4 ASO showed reduced food intake, reduced weight gain, and improved glucose tolerance. In addition, they exhibited lower plasma triglycerides, total cholesterol, LDL-cholesterol, glucose, serum amyloid A, and liver triglyceride levels. By contrast, no significant difference in plasma alanine aminotransferase activity was observed. Overall, these data suggest that antisense oligonucleotides targeting ANGPTL4 effectively reduce plasma triglyceride levels in mice without raising major safety concerns.
Abstract Since its discovery, apolipoprotein A-V has been considered to be a potent factor affecting plasma triglycerides (TG) in humans and mice. Several single nucleotide polymorphisms in the APOA5 ...gene are associated with increased TG levels in humans, and some nonsense mutations affecting protein structure predispose for familial hypertriglyceridemia and late onset chylomicronemia. It is not clear, how apoA-V decreases plasma TG. There are three major hypotheses: apolipoprotein A-V could work through (1) an intracellular mechanism affecting VLDL production in the liver, (2) stimulation of proteoglycan-bound lipoprotein lipase at the endothelium of capillaries in peripheral organs, or (3) enhancing the clearance of TG-rich lipoproteins via lipoprotein receptors in the liver. There is good evidence for a role of apoA-V in extracellular TG metabolism and increasing support for an additional function of ApoA-V as a receptor ligand. The intracellular role of apoA-V for lipoprotein assembly and secretion is still speculative. This review discusses these possible mechanisms.
In response to cold exposure, thermogenic adipocytes internalize large amounts of fatty acids after lipoprotein lipase-mediated hydrolysis of triglyceride-rich lipoproteins (TRL) in the capillary ...lumen of brown adipose tissue (BAT) and white adipose tissue (WAT). Here, we show that in cold-exposed mice, vascular endothelial cells in adipose tissues endocytose substantial amounts of entire TRL particles. These lipoproteins subsequently follow the endosomal-lysosomal pathway, where they undergo lysosomal acid lipase (LAL)-mediated processing. Endothelial cell-specific LAL deficiency results in impaired thermogenic capacity as a consequence of reduced recruitment of brown and brite/beige adipocytes. Mechanistically, TRL processing by LAL induces proliferation of endothelial cells and adipocyte precursors via beta-oxidation-dependent production of reactive oxygen species, which in turn stimulates hypoxia-inducible factor-1α-dependent proliferative responses. In conclusion, this study demonstrates a physiological role for TRL particle uptake into BAT and WAT and establishes endothelial lipoprotein processing as an important determinant of adipose tissue remodeling during thermogenic adaptation.
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•Endothelial cells of cold-activated BAT and WAT endocytose lipoprotein particles•These triglyceride-rich lipoproteins are processed by LAL•Subsequently, HIF1α is activated via fatty-acid oxidation and ROS production•Endothelial LAL deficiency impairs vascularization and thermogenesis in BAT and WAT
Fischer et al. reveal that endothelial cells of cold-activated BAT and WAT internalize entire triglyceride-rich lipoprotein particles that are targeted toward lysosomes and processed by lysosomal acid lipase. Then, mitochondrial beta-oxidation leads to ROS-dependent HIF1α activation, which promotes vascular and thermogenic remodeling of adipose tissues.
The use of person-centred care promotes the child and adolescent's narratives and emphasizes the use of shared decision-making to be the primary source of pain management decisions. 1 This approach ...is also in line with the United Nation's Convention on the Rights of the Child, 2 and specifically with Article 24 that focusses on health. ...children should be furnished with appropriate means to express themselves for example, using any form of communication, and often using multi-modal forms of communication. ...adults (i.e., all healthcare providers) should engage with children in one-to-one situations in which their opinions are listened to in a respectful and non-judgemental way.
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