P.C.N. Rensen

Exendin-4 decreases liver inflammation and atherosclerosis development simultaneously by reducing macrophage infiltration

The aetiology of inflammation in the liver and vessel wall, leading to non‐alcoholic steatohepatitis (NASH) and atherosclerosis, respectively, shares common mechanisms including macrophage infiltration. To treat both disorders simultaneously, it is highly important to tackle the inflammatory status. Exendin‐4, a glucagon‐like peptide‐1 (GLP‐1) receptor agonist, reduces hepatic steatosis and has been suggested to reduce atherosclerosis; however, its effects on liver inflammation are underexplored. Here, we tested the hypothesis that exendin‐4 reduces inflammation in both the liver and vessel wall, and investigated the common underlying mechanism.

Caspase-1 deficiency in mice reduces intestinal triglyceride absorption and hepatic triglyceride secretion

Caspase-1 is known to activate the proinflammatory cytokines IL-1β and IL-18. Additionally, it can cleave other substrates, including proteins involved in metabolism. Recently, we showed that caspase-1 deficiency in mice strongly reduces high-fat diet-induced weight gain, at least partly caused by an increased energy production. Increased feces secretion by caspase-1-deficient mice suggests that lipid malabsorption possibly further reduces adipose tissue mass. In this study we investigated whether caspase-1 plays a role in triglyceride-(TG)-rich lipoprotein metabolism using caspase-1-deficient and wild-type mice. Caspase-1 deficiency reduced the postprandial TG response to an oral lipid load, whereas TG-derived fatty acid (FA) uptake by peripheral tissues was not affected, demonstrated by unaltered kinetics of [3H]TG-labeled very low-density lipoprotein (VLDL)-like emulsion particles. An oral gavage of [3H]TG-containing olive oil revealed that caspase-1 deficiency reduced TG absorption and subsequent uptake of TG-derived FA in liver, muscle, and adipose tissue. Similarly, despite an elevated hepatic TG content, caspase-1 deficiency reduced hepatic VLDL-TG production. Intestinal and hepatic gene expression analysis revealed that caspase-1 deficiency did not affect FA oxidation or FA uptake but rather reduced intracellular FA transport, thereby limiting lipid availability for the assembly and secretion of TG-rich lipoproteins. The current study reveals a novel function for caspase-1, or caspase-1-cleaved substrates, in controlling intestinal TG absorption and hepatic TG secretion.

The dual PPARα/γ agonist tesaglitazar blocks progression of pre‐existing atherosclerosis in APOE*3Leiden.CETP transgenic mice

Background and purpose:  We have evaluated the effects of a peroxisome proliferator‐activated receptor (PPAR)α/γ agonist on the progression of pre‐existing atherosclerotic lesions in APOE*3Leiden.cholesteryl ester transfer protein (E3L.CETP) transgenic mice.

Aspirin reduces hypertriglyceridemia by lowering VLDL-triglyceride production in mice fed a high-fat diet

Systemic inflammation is strongly involved in the pathophysiology of the metabolic syndrome, a cluster of metabolic risk factors that includes hypertriglyceridemia. Aspirin treatment lowers inflammation via inhibition of NF-κB activity but also reduces hypertriglyceridemia in humans. The aim of this study was to investigate the mechanism by which aspirin improves hypertriglyceridemia. Human apolipoprotein CI (apoCI)-expressing mice (APOC1 mice), an animal model with elevated plasma triglyceride (TG) levels, as well as normolipidemic wild-type (WT) mice were fed a high-fat diet (HFD) and treated with aspirin. Aspirin treatment reduced hepatic NF-κB activity in HFD-fed APOC1 and WT mice, and in addition, aspirin decreased plasma TG levels (-32%, P < 0.05) in hypertriglyceridemic APOC1 mice. This TG-lowering effect could not be explained by enhanced VLDL-TG clearance, but aspirin selectively reduced hepatic production of VLDL-TG in both APOC1 (-28%, P < 0.05) and WT mice (-33%, P < 0.05) without affecting VLDL-apoB production. Aspirin did not alter hepatic expression of genes involved in FA oxidation, lipogenesis, and VLDL production but decreased the incorporation of plasma-derived FA by the liver into VLDL-TG (-24%, P < 0.05), which was independent of hepatic expression of genes involved in FA uptake and transport. We conclude that aspirin improves hypertriglyceridemia by decreasing VLDL-TG production without affecting VLDL particle production. Therefore, the inhibition of inflammatory pathways by aspirin could be an interesting target for the treatment of hypertriglyceridemia.

Gender-dependent effects of high-fat lard diet on cardiac function in C57Bl/6J mice

Increased availability of fatty acids released from insulin-resistant adipose tissue may lead to excess fatty acid uptake in nonadipose organs, including the heart. Accumulation of toxic fatty acid intermediates may affect cardiac function. Our aim was to identify to which extent high-fat diet feeding leads to alterations in cardiac function and whether this depends on gender and (or) duration of high-fat diet feeding. Male and female C57Bl/6J mice (n = 8 per group) of 12 to 16 weeks old were fed a low-fat (10% energy) or high-fat (45% energy) lard diet for 6 or 12 weeks. Plasma lipid levels, echocardiography, and left ventricular pressure-volume relationships were obtained at 2, 1, and 0 weeks before termination, respectively. In both male and female mice, the high-fat diet increased body weight and plasma lipid content. At 10 weeks, significant increases were observed for plasma total cholesterol (males: +44%; females: +86%), phospholipids (+16% and +34%), and triglycerides (+27% and +53%) (all p < 0.001). In male mice, but not in female mice, the high-fat diet significantly affected cardiac function at 12 weeks with increased end-systolic volume (25.4 ± 6.2 vs. 17.0 ± 6.7 µL, p < 0.05), increased end-systolic pressure (72.1 ± 6.9 vs. 63.6 ± 6.9 mm Hg, p < 0.01), and decreased ejection fraction (61.2% ± 4.5% vs. 68.1% ± 3.7%, p < 0.01), indicating reduced systolic function. Multiple linear regression analysis indicated a significant diet-gender interaction for end-systolic volume and ejection fraction. In conclusion, high-fat diet feeding increased body weight and plasma lipid levels in male and in female mice, but resulted in impairment of cardiac function only in males.

Estrogen induced hypertriglyceridemia in an apolipoprotein AV deficient patient

Dear Sir, Occasionally severe hypertriglyceridemia (HTG) might develop or exacerbate in females during pregnancy or by use of exogenous oestrogens [1–3]. Oestrogens might increase production of triglyceride-rich very low density lipoproteins (VLDL) by the liver and impair lipolysis of triglycerides through reduction of the concentration of lipoprotein lipase, and hepatic lipase [4, 5]. These effects might be induced as a result of a decrease of insulin sensitivity by oestrogens [6, 7].

Plasticity of circadian clocks and consequences for metabolism

The increased prevalence of metabolic disorders and obesity in modern society, together with the widespread use of artificial light at night, have led researchers to investigate whether altered patterns of light exposure contribute to metabolic disorders. This article discusses the experimental evidence that perturbed environmental cycles induce rhythm disorders in the circadian system, thus leading to metabolic disorders. This notion is generally supported by animal studies. Distorted environmental cycles, including continuous exposure to light, affect the neuronal organization of the central circadian pacemaker in the suprachiasmatic nucleus (SCN), its waveform and amplitude of the rhythm in electrical activity. Moreover, repeated exposure to a shifted light cycle or the application of dim light at night are environmental cues that cause a change in SCN function. The effects on the SCN waveform are the result of changes in synchronization among the SCNs neuronal cell population, which lead consistently to metabolic disturbances. Furthermore, we discuss the effects of sleep deprivation and the time of feeding on metabolism, as these factors are associated with exposure to disturbed environmental cycles. Finally, we suggest that these experimental studies reveal a causal relationship between the rhythm disorders and the metabolic disorders observed in epidemiological studies performed in humans.

RP105 deficiency aggravates cardiac dysfunction after myocardial infarction in mice

BACKGROUND Toll-like receptor-4 (TLR4), a receptor of the innate immune system, is suggested to have detrimental effects on cardiac function after myocardial infarction (MI). RP105 (CD180) is a TLR4 homolog lacking the intracellular signaling domain that competitively inhibits TLR4-signaling. Thus, we hypothesized that RP105 deficiency, by amplifying TLR4 signaling, would lead to aggravated cardiac dysfunction after MI. METHODS AND RESULTS First, whole blood from RP105-/- and wild-type (WT) male C57Bl/6N mice was stimulated with LPS, which induced a strong inflammatory TNFα response in RP105-/- mice. Then, baseline heart function was assessed by left ventricular pressure-volume relationships which were not different between RP105-/- and WT mice. Permanent ligation of the left anterior descending coronary artery was performed to induce MI. Infarct sizes were analyzed by (immuno)histology and did not differ. Fifteen days post MI heart function was assessed and RP105-/- mice had significantly higher heart rate (+21%, P<0.01), end systolic volume index (+57%, P<0.05), end systolic pressure (+22%, P<0.05) and lower relaxation time constant tau (-12%, P<0.05), and a tendency for increased end diastolic volume index (+42%, P<0.06), compared to WT mice. In the area adjacent to the infarct zone, compared to the healthy myocardium, levels of RP105, TLR4 and the endogenous TLR4 ligand fibronectin-EDA were increased as well as the number of macrophages, however this was not different between both groups. CONCLUSION Deficiency of the endogenous TLR4 inhibitor RP105 leads to an enhanced inflammatory status and more pronounced cardiac dilatation after induction of MI, underscoring the role of the TLR4 pathway in post-infarction remodeling.

The insulin sensitizing effect of topiramate involves KATP channel activation in the central nervous system

Topiramate improves insulin sensitivity, in addition to its antiepileptic action. However, the underlying mechanism is unknown. Therefore, the present study was aimed at investigating the mechanism of the insulin‐sensitizing effect of topiramate both in vivo and in vitro.

IgG is elevated in obese white adipose tissue but does not induce glucose intolerance via Fc gamma-receptor or complement

Background/Objectives:In obesity, B cells accumulate in white adipose tissue (WAT) and produce IgG, which may contribute to the development of glucose intolerance. IgG signals by binding to Fcγ receptors (FcγR) and by activating the complement system. The aim of our study was to investigate whether activation of FcγR and/or complement C3 mediates the development of high-fat diet-induced glucose intolerance.Methods:We studied mice lacking all four FcγRs (FcγRI/II/III/IV−/−), only the inhibitory FcγRIIb (FcγRIIb−/−), only the central component of the complement system C3 (C3−/−), and mice lacking both FcγRs and C3 (FcγRI/II/III/IV/C3−/−). All mouse models and wild-type controls were fed a high-fat diet (HFD) for 15 weeks to induce obesity. Glucose metabolism was assessed and adipose tissue was characterized for inflammation and adipocyte functionality.Results:In obese WAT of wild-type mice, B cells (+142%, P<0.01) and IgG (+128% P<0.01) were increased compared to lean WAT. Macrophages of FcγRI/II/III/IV−/−mice released lower levels of cytokines compared to wild-type mice upon IgG stimulation. Only C3−/− mice showed reduced HFD-induced weight gain as compared to controls (−18%, P<0.01). Surprisingly, FcγRI/II/III/IV−/− mice had deteriorated glucose tolerance (AUC +125%, P<0.001) despite reduced leukocyte number (−30%, P<0.05) in gonadal WAT (gWAT), whereas glucose tolerance and leukocytes within gWAT in the other models were unaffected compared to controls. Although IgG in gWAT was increased (+44 to +174%, P<0.05) in all mouse models lacking FcγRIIb, only FcγRI/II/III/IV/C3−/− mice exhibited appreciable alterations in immune cells in gWAT, for example, increased macrophages (+36%, P<0.001).Conclusions:Lack of FcγRs reduces the activity of macrophages upon IgG stimulation, but neither FcγR nor C3 deficiency protects against HFD-induced glucose intolerance or reduces adipose tissue inflammation. This indicates that if obesity-induced IgG contributes to the development of glucose intolerance, this is not mediated by FcγR or complement activation.