Maintenance of Macrophage Redox Status by ChREBP Limits Inflammation and Apoptosis and Protects against Advanced Atherosclerotic Lesion Formation

Enhanced glucose utilization can be visualized in atherosclerotic lesions and may reflect a high glycolytic rate in lesional macrophages, but its causative role in plaque progression remains unclear. We observe that the activity of the carbohydrate-responsive element binding protein ChREBP is rapidly downregulated upon TLR4 activation in macrophages. ChREBP inactivation refocuses cellular metabolism to a high redox state favoring enhanced inflammatory responses after TLR4 activation and increased cell death after TLR4 activation or oxidized LDL loading. Targeted deletion of ChREBP in bone marrow cells resulted in accelerated atherosclerosis progression in Ldlr−/− mice with increased monocytosis, lesional macrophage accumulation, and plaque necrosis. Thus, ChREBP-dependent macrophage metabolic reprogramming hinders plaque progression and establishes a causative role for leukocyte glucose metabolism in atherosclerosis

Second-generation CK2α inhibitors targeting the αD pocket.

CK2 is a critical cell cycle regulator that also promotes various anti-apoptotic mechanisms. Development of ATP-non-competitive inhibitors of CK2 is a very attractive strategy considering that the ATP binding site is highly conserved among other kinases. We have previously utilised a pocket outside the active site to develop a novel CK2 inhibitor, CAM4066. Whilst CAM4066 bound to this new pocket it was also interacting with the ATP site: herein, we describe an example of a CK2α inhibitor that binds completely outside the active site. This second generation αD-site binding inhibitor, compound CAM4712 (IC50 = 7 μM, GI50 = 10.0 ± 3.6 μM), has numerous advantages over the previously reported CAM4066, including a reduction in the number of rotatable bonds, the absence of amide groups susceptible to the action of proteases and improved cellular permeability. Unlike with CAM4066, there was no need to facilitate cellular uptake by making a prodrug. Moreover, CAM4712 displayed no drop off between its ability to inhibit the kinase in vitro (IC50) and the ability to inhibit cell proliferation (GI50)

ABCA1 Exerts Tumor-Suppressor Function in Myeloproliferative Neoplasms

International audienc

Transgenic <i>Fgfr3</i>^<i>ach/+</i> mice preferentially develop visceral obesity that is prevented upon sFGFR3 treatment.

<p>(<b>A</b>), body weight of vehicle-treated WT and <i>Fgfr3</i>^<i>ach/+</i> mice and sFGFR3 treated <i>Fgfr3</i>^<i>ach/+</i> mice after 10 weeks of ND or HFD challenge. (<b>B</b>), abdominal lean:fat ratio. (<b>C</b>) epididymal adipose tissue (eAT) weight and (<b>D</b>) subcutaneous adipose tissue (scAT) weight per g of body weight. (<b>E</b>) scAT and (<b>F</b>) eAT adipocyte area (μm²). (<b>G</b>) scAT and (<b>H</b>) eAT scattering of adipocytes according to their diameter. Data are represented as mean ± SD (n = 8–10 mice to each group). Data followed normal distribution. *<i>p</i><0.05, **<i>p</i><0.01, ***<i>p</i><0.001 versus vehicle-treated WT, ^#<i>p</i><0.05, ^##<i>p</i><0.01 versus vehicle-treated <i>Fgfr3</i>^<i>ach/+</i>; Student’s <i>t</i> test.</p

Glucose metabolism is altered in transgenic <i>Fgfr3</i>^<i>ach/+</i> mice and restored with sFGFR3 treatment.

<p>Fasting glycemia and insulinemia of mice following 10 weeks of (<b>A</b>) ND or (<b>B</b>) HFD. (<b>C</b>) glucose tolerance test; glucose levels were normalized to the value of time -15 min and area under the curve corresponding to each group of mice. (<b>D</b>) Mice pancreas insulin content (immunohistochemistry of paraffin-embedded sections, red: insulin; green: glucose; blue: DAPI staining), mean of pancreas islets normalized to total surface and mean of islets number in each group under HFD condition. (<b>E</b>) Liver H&E and PAS staining under HFD condition. (<b>F</b>) H&E staining of hepatic nodules. Data are represented as mean ± SD (n = 8–10 mice to each group). Data followed normal distribution. **<i>p</i><0.01, ***<i>p</i><0.001 versus vehicle-treated WT, ^#<i>p</i><0.05, ^##<i>p</i><0.01 versus vehicle-treated <i>Fgfr3</i>^<i>ach/+</i>; Student’s <i>t</i> test.</p

Untreated <i>Fgfr3</i>^<i>ach/+</i> mice displayed an elevated inflammatory baseline prevented by sFGFR3 treatment.

<p>Untreated <i>Fgfr3</i>^<i>ach/+</i> mice displayed an elevated inflammatory baseline prevented by sFGFR3 treatment.</p

MSCs isolated from untreated or sFGFR3-treated <i>Fgfr3</i>^<i>ach/+</i> mice show pre-engagement towards adipogenesis with no alteration of the insulin response compared to WT mice.

<p><b>(A)</b> Expression of genes involved in different steps of adipogenesis differentiation (Genes are listed in <b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0195876#pone.0195876.s005" target="_blank">S2 Table</a></b>). Expression was normalized to HPRT, RPL6 and RPL13a expression and expressed as percent of change compared to WT. (<b>B</b>) Cells were stimulated with 50nM of insulin for 0, 5, 15 or 30 min or with 0, 1, 10, 50 or 100nM of insulin during 5 min. P-Erk1/2 expression, normalized to Erk1/2 total expression, was expressed as normalized value to WT. Data are represented as mean ± SD. Data followed normal distribution. *<i>p</i><0.05, **<i>p</i><0.01, ***<i>p</i><0.001 versus vehicle-treated WT, ^#<i>p</i><0.05, ^##<i>p</i><0.01 versus vehicle-treated <i>Fgfr3</i>^<i>ach/+</i>; Two-way ANOVA with Tukey’s multiple test.</p

Children with achondroplasia preferentially develop abdominal obesity without an increase in blood glucose levels.

<p>(<b>A</b>), Weight, height and BMI measurements and corresponding height-to-age and BMI-to-age z-scores in the three age groups ranging (n = 73 data points in the [0–3] years old group, n = 61 data points in the [4–8] years old group and n = 36 data points in the [9–18] years old group). (<b>B</b>), Schematic representation of the different regions of interest (ROI) evaluated by DXA. (<b>C</b>), Android:gynoid fat ratio measurement in the three age groups ranging (n = 4 data points in the [0–3] years old group, n = 6 data points in the [4–8] years old group and n = 9 data points in the [9–18] years old group). (<b>D</b>), Plasmatic fasting glucose concentration in the two age groups ranging [4–8] and [9–18] years old (n = 16 data points in the [4–8] years old group and n = 12 data points in the [9–18] years old group). Horizontal lines represent normal values. Data are represented as mean ± SD, **<i>p</i><0.01, ***<i>p</i><0.001. Results of post hoc analyses: ^a significantly different between [0–3] and [4–8] groups; ^b significantly different between [0–3] and [9–18] groups; ^c significantly different between [4–8] and [9–18] groups.</p

Early postnatal soluble FGFR3 therapy prevents the atypical development of obesity in achondroplasia

International audienceBackground: Achondroplasia is a rare genetic disease is characterized by abnormal bone development and early obesity. While the bone aspect of the disease has been thoroughly studied, early obesity affecting approximately 50% of them during childhood has been somewhat neglected. It nevertheless represents a major health problem in these patients, and is associated to life-threatening complications including increasing risk of cardiovascular pathologies. We have thus decided to study obesity in patients and to use the mouse model to evaluate if soluble FGFR3 therapy, an innovative treatment approach for achondroplasia, could also impact the development of this significant complication.Methods and findings: To achieve this, we have first fully characterized the metabolic deregulations in these patients by conducting a longitudinal retrospective study, in children with achondroplasia Anthropometric, densitometric measures as well as several blood parameters were recorded and compared between three age groups ranging from [0–3], [4–8] and [9–18] years old. Our results show unexpected results with the development of an atypical obesity with preferential fat deposition in the abdomen that is remarkably not associated with classical complications of obesity such as diabetes or hypercholosterolemia. Because it is not associated with diabetes, the atypical obesity has not been studied in the past even though it is recognized as a real problem in these patients. These results were validated in a murine model of achondroplasia (Fgfr3ach/+) where similar visceral adiposity was observed. Unexpected alterations in glucose metabolism were highlighted during high-fat diet. Glucose, insulin or lipid levels remained low, without the development of diabetes. Very interestingly, in achondroplasia mice treated with soluble FGFR3 during the growth period (from D3 to D22), the development of these metabolic deregulations was prevented in adult animals (between 4 and 14 weeks of age). The lean-over-fat tissues ratio was restored and glucose metabolism showed normal levels. Treating Fgfr3ach/+ mice with soluble FGFR3 during the growth period, prevented the development of these metabolic deregulations in adult animals and restored lean-over-fat tissues ratio as well as glucose metabolism in adult animals.Conclusion: This study demonstrate that achondroplasia patients develop an atypical obesity with preferential abdominal obesity not associated with classical complications. These results suggest that achondroplasia induces an uncommon metabolism of energy, directly linked to the FGFR3 mutation. These data strongly suggest that this common complication of achondroplasia should be included in the clinical management of patients. In this context, sFGFR3 proved to be a promising treatment for achondroplasia by normalizing the biology at different levels, not only restoring bone growth but also preventing the atypical visceral obesity and some metabolic deregulation