Cholesterol, a cell size-dependent signal that regulates glucose metabolism and gene expression in adipocytes.

Enlarged fat cells exhibit modified metabolic capacities, which could be involved in the metabolic complications of obesity at the whole body level. We show here that sterol regulatory element-binding protein 2 (SREBP-2) and its target genes are induced in the adipose tissue of several models of rodent obesity, suggesting cholesterol imbalance in enlarged adipocytes. Within a particular fat pad, larger adipocytes have reduced membrane cholesterol concentrations compared with smaller fat cells, demonstrating that altered cholesterol distribution is characteristic of adipocyte hypertrophy per se. We show that treatment with methyl-beta-cyclodextrin, which mimics the membrane cholesterol reduction of hypertrophied adipocytes, induces insulin resistance. We also produced cholesterol depletion by mevastatin treatment, which activates SREBP-2 and its target genes. The analysis of 40 adipocyte genes showed that the response to cholesterol depletion implicated genes involved in cholesterol traffic (caveolin 2, scavenger receptor BI, and ATP binding cassette 1 genes) but also adipocyte-derived secretion products (tumor necrosis factor alpha, angiotensinogen, and interleukin-6) and proteins involved in energy metabolism (fatty acid synthase, GLUT 4, and UCP3). These data demonstrate that altering cholesterol balance profoundly modifies adipocyte metabolism in a way resembling that seen in hypertrophied fat cells from obese rodents or humans. This is the first evidence that intracellular cholesterol might serve as a link between fat cell size and adipocyte metabolic activity

Decreased resistin expression in mice with different sensitivities to a high-fat diet

The regulation of resistin, a new adipose-derived circulating factor, is the subject of controversy. In particular, the question of its modulation in obesity led to opposite results reported by two different groups. In the current study, we assayed adipocyte resistin mRNA using fluorescent real-time RT-PCR. We studied the expression of resistin in mice which are differently sensitive to diet-induced obesity: the FVB/n strain, which poorly responds to high-fat diet and transgenic mice that express human alpha 2A-AR in adipose tissue in the absence of beta 3-adrenergic receptor (AR) under the FVB genetic background which are highly sensitive to high-fat diet and develop hyperplastic obesity. We observed that FVB mice, which have no significant increased body weight after an 8-week high-fat diet period, exhibited no alteration of resistin expression. In contrast, the transgenic mice developing high-fat diet-induced obesity exhibited markedly downregulated adipocyte resistin mRNA. We also showed that obesity induced by gold thioglucose injection in FVB/n mice reduces the expression of resistin in isolated adipocytes. This argues for decreased expression of resistin as a hallmark of obesity. Moreover, our data show that feeding a high-fat diet is not a primary determinant of resistin regulation

Bonobo Conservation as a means for Local Development: an Innovative Local Initiative of Community-based Conservation in the DemocraticRepublic of the Congo

International audienceThe Democratic Republic of the Congo (DRC) ranks fifth in the world in terms of biodiversity (fauna and flora) and first for mammal diversity in Africa. There are numerous endemic species including bolobos (Pan paniscus). Bolobos are endangered, threatened mainly by deforestation, poaching and diseases, and the current population is estimated from 15,000 to 50,000 individuals. Nowadays, one national park (Salonga National Park) and six reserves exist for wild bolobo conservation, representing about 73,000 km2 of protected areas over an estimated distribution area of 565,000 km2. In the Bolobo Territory, an original local project of bolobo conservation was initiated in 2001 by the Congolese NGO Mbou-Mon-Tour (MMT). From 2008 to 2013, we studied bolobo-habitat-human interactions in this forest-savanna mosaic habitat, totalizing 12 months of survey over six periods. Besides eco-ethological studies, an ethnoecological approach was developed in order to better understand how the MMT project emerged and how it has evolved. We performed semi-structured interviews, participant observation, and informal discussions with local people. We also used grey literature associated to the region. MMT use the bolobo conservation as a means to reach local development goals, which is the opposite of what is frequent in the “community-based conservation” project managed by environmental NGOs. The location of the community forests and the rules established for regulating activities in these forests were decided by the villagers under the organization of traditional chiefs according to their knowledge on bolobo ecology and range, and the disturbance they perceived of the traditional activities in the forest. Such a process is a novel and promising approach for wildlife conservation that maintains the place of local people and traditional authorities in the decision-making process and the governance

Comparison of Clinical and Epidemiologic Characteristics of Young Febrile Infants with and without SARS-CoV-2 Infection.

OBJECTIVE: To determine features that distinguish febrile young infants with SARS-CoV-2 infection. STUDY DESIGN: Retrospective single-center study included febrile infantsChildren\u27s Medical Center of Northwell Health, New Hyde Park, New York during March 1-April 30 of 2018, 2019, and 2020. Sociodemographic and clinical features were compared between those seen during the 2020 COVID-19 pandemic and previous years, as well as between SARS-CoV-2 infected infants and SARS-CoV-2 uninfected infants (SARS-CoV-2 negative or evaluated during 2018 and 2019). RESULTS: In all, 124 febrile infantsidentified; 38 during the 2-month study period in 2018, 33 in 2019, and 53 in 2020. During 2020, fewer febrile infants had a serious bacterial infection (SBI) or a positive respiratory viral panel (RVP) than in prior years (6% versus 21%, P = .02; 15% versus 53%, p CONCLUSIONS: During the peak of the pandemic, SARS-CoV-2 was the predominant pathogen among febrile infants. Socioeconomic, historical, and laboratory features differed significantly between SARS-CoV-2 infected and uninfected infants. None of the 20 infants with SARS-CoV-2 infection had an identified co-viral or serious bacterial infection

Evaluation of a pilot consultation for maternity protection at work in Switzerland.

Switzerland's Labour Law and its Ordonnance on Maternity Protection aim to protect the health of pregnant employees and their unborn children while enabling them to continue to pursue their professional activities. Some companies encounter difficulties implementing the law's provisions. The Department of Occupational and Environmental Health, part of the Center for Primary Care and Public Health (Unisanté), has provided specialist occupational medicine consultations for pregnant employees since 2015. This study aimed to evaluate how well Swiss' maternity protection legislation is implemented by examining a list of relevant indicators measured during the occupational health consultation. The study also sought to investigate the consultation support provided to the relevant stakeholders and the adjustments made to pregnant employees' working conditions. Descriptive variables and indicators relative to the application of the Swiss maternity protection legislation for 83 pregnant employees were collected during the consultation's pilot phase (between 2015 and 2016). Descriptive statistics and cross-analyses of these indicators were made. Most pregnant employees faced multiple exposures to occupational risks. Preventive risk analyses were rare. Few adjustments to workstations were proposed. We found a tendency for employees to leave their workstations early on in their pregnancies due to sick leave certificate prescriptions. Specialist consultation and collaboration with occupational health physicians to recommend interventions for pregnant employees can provide significant benefits and help some pregnant women to continue at their workstations with appropriate adjustments. A specialised occupational health consultation is a useful instrument for identifying occupational hazards for both the pregnant woman and her unborn child. It is also an opportunity to explain employers' legal responsibilities and obligations to safeguard the health of their pregnant employees and to give specific advice for their company's situation. This consultation also enables employers to maintain their employees' valuable professional competencies in the workplace for as long as possible. Finally, occupational health consultation helps and supports healthcare providers who must, according to the law, make decisions about whether pregnant employees can continue working safely or not

Neuropeptide AF and FF modulation of adipocyte metabolism. Primary insights from functional genomics and effects on beta-adrenergic responsiveness.

The presence of a neuropeptide AF and FF receptor (NPFF-R2) mRNA in human adipose tissue (Elshourbagy, N. A., Ames, R. S., Fitzgerald, L. R., Foley, J. J., Chambers, J. K., Szekeres, P. G., Evans, N. A., Schmidt, D. B., Buckley, P. T., Dytko, G. M., Murdock, P. R., Tan, K. B., Shabon, U., Nuthulaganti, P., Wang, D. Y., Wilson, S., Bergsma, D. J., and Sarau, H. M. (2000) J. Biol. Chem. 275, 25965-25971) suggested these peptides, principally recognized for their pain modulating effects, may also impact on adipocyte metabolism, an aspect that has not been explored previously. Our aim was thus to obtain more insights into the actions of these peptides on adipocytes, an approach initially undertaken with a functional genomic assay. First we showed that 3T3-L1 adipocytes express both NPFF-R1 and NPFF-R2 transcripts, and that NPAF binds adipocyte membranes with a nanomolar affinity as assessed by surface plasmon resonance technology. Then, and following a 24-h treatment with NPFF or NPAF (1 microm), we have measured using real-time quantitative reverse transcriptase-PCR the mRNA steady state levels of already well characterized genes involved in key pathways of adipose metabolism. Among the 45 genes tested, few were modulated by NPFF ( approximately 10%) and a larger number by NPAF ( approximately 27%). Interestingly, NPAF increased the mRNA levels of beta2- and beta3-adrenergic receptors (AR), and to a lesser extent those of beta1-ARs. These variations in catecholamine receptor mRNAs correlated with a clear induction in the density of beta2- and beta3-AR proteins, and in the potency of beta-AR subtype-selective agonists to stimulate adenylyl cyclase activity. Altogether, these data show that NPFF-R1 and NPFF-R2 are functionally present in adipocytes and suggest that besides their well described pain modulation effects, NPAF and to a lesser extent NPFF, may have a global impact on body energy storage and utilization

Human alpha 2A-adrenergic receptor gene expressed in transgenic mouse adipose tissue under the control of its regulatory elements.

Catecholamines regulate white adipose tissue function and development by acting through beta- and alpha2-adrenergic receptors (ARs). Human adipocytes express mainly alpha 2A- but few or no beta 3-ARs while the reverse is true for rodent adipocytes. Our aim was to generate a mouse model with a human-like alpha2/beta-adrenergic balance in adipose tissue by creating transgenic mice harbouring the human alpha 2A-AR gene under the control of its own regulatory elements in a combined mouse beta 3-AR-/- and human beta 3-AR+/+ background. Transgenic mice exhibit functional human alpha 2A-ARs only in white fat cells. Interestingly, as in humans, subcutaneous adipocytes expressed higher levels of alpha2-AR than perigonadal fat cells, which are associated with a better antilipolytic response to epinephrine. High-fat-diet-induced obesity was observed in transgenic mice in the absence of fat cell size modifications. In addition, analysis of gene expression related to lipid metabolism in isolated adipocytes suggested reduced lipid mobilization and no changes in lipid storage capacity of transgenic mice fed a high-fat diet. Finally, the development of adipose tissue in these mice was not associated with significant modifications of glucose and insulin blood levels. Thus, these transgenic mice constitute an original model of diet-induced obesity for in vivo physiological and pharmacological studies with respect to the alpha2/beta-AR balance in adipose tissue

Role of Histamine H4 Receptor ligands in Bleomycin-induced pulmonary fibrosis

Fibrosis of lung tissue is a disease where a chronic inflammatory process determines a pathological remodelling of lung parenchyma. The animal model obtained by intra-tracheal administration of bleomycin in C57BL/6 mice is one of the most validated murine model. Bleomycin stimulates oxidative stress and the production of pro-inflammatory mediators. Histamine H4R have recently been implicated in inflammation and immune diseases. This study was focused to investigate the effects of H4R ligands in the modulation of inflammation and in the reduction of lung fibrosis in C57BL/6 mice treated with bleomycin. C57BL/6 mice were treated with vehicle, JNJ7777120 (JNJ, selective H4R antagonist) or ST-1006 (partial H4R agonist), ST-994 (H4R neutral antagonist) and ST-1012 (inverse H4R agonist) at equimolar doses, released by micro-osmotic pumps for 21 days. Airway resistance to inflation was assayed and lung samples were processed to measure malondialdehyde (TBARS); 8-hydroxy-2'-deoxyguanosine (8OHdG); myeloperoxidase (MPO); COX-2 expression and activity as markers of oxidative stress and inflammation. Fibrosis and airway remodelling were evaluated throughout transforming growth factor-β (TGF-β), percentage of positive Goblet cells, smooth muscle layer thickness determination. Our results indicated that JNJ, ST-994 and ST-1012 decreased inflammation and oxidative stress markers, i.e. the number of infiltrating leukocytes evaluated as lung tissue MPO, COX-2 expression and activity, TBARS and 8OHdG production. They also reduced the level of TGF-β, a pro-fibrotic cytokine, collagen deposition, thickness of smooth muscle layer, Goblet cells hyperplasia; resulting in a decrease of airway functional impairment. The results here reported clearly demonstrated that H4R ligands have a beneficial effect in a model of lung fibrosis in the mouse, thus indicating that H4R antagonists or inverse agonists could be a novel therapeutic strategy for lung inflammatory diseases