LES CRUES DE L’OUED ISSIL EN AMONT DE MARRAKECH (MAROC), UN RISQUE NATUREL RECURRENT THE FLOODS OF THE WADI ISSIL UPSTREAM OF MARRAKESH (MOROCCO), A RECURRING NATURAL HAZARD

The wadi Issil originates in the High Atlas of Marrakesh, at altitudes above 2000 m. The mountainous part of the watershed is characterized by significant slopes, a low-permeable bedrock and a widespread dense hydrographic network.Concerning precipitation, the upstream stations of the basin record heavy and high rainfall levels. The average value e.g. in Agaiouar is approximately 582 mm a year, which is close to what can be found in sub-humid lands.This hydrogeomorphic and rainfall situation is conducive to the development of sudden and very fast floods. The recently opened hydrometric station of Aït Bouzguia has recorded some floods over the last years with a fast rising time (from 1h15 to 1h30). Using the data recording at the station of Ouagjdite, located upstream of the basin, response times of 2h30 were collected. These short periods pose a major risk as they do not allow a prediction of such floods in due time.These types of flood are renown for their infrastructure damages in Marrakesh, especially in areas near the wadi Issil. They often lead to substantial costs and sometimes the loss of human lives. Wadi’s overflow phenomenon is also exacerbated by numerous rubble or household waste, being abandoned on the stream bed. These waste materials shrink the wadi’s section and reduce its conveyance accordingly. Furthermore, the reduced diameter of some waste water systems, notably bridges nozzles, increases the risk.Several land-use plannings have been submitted, some others have been applied and some are currently underway. They roughly consist in dredging and raising banks of some sections, and in building new bridges and protective reinforcement walls along the wadi’s shores. These actions should strengthen with the strict prohibition of waste and rubble disposal in the stream bed. This can be done by promoting awareness of people living close to the wadi and an overall improvement of the environment involved. Aside from that, there could be a broader and fruitful coordination between the Wilaya, the water administration, the municipalities and Civil Society

Etude fonctionnelle des variants naturels du CX3CR1, récepteur de la chimiokine Fractalkine (adhérence et transduction du signal)

LE KREMLIN-B.- PARIS 11-BU Méd (940432101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Preclinical Assessment of Leptin Transport into the Cerebrospinal Fluid in Diet‐Induced Obese Minipigs

International audienceObjective: A minipig model was employed to explore the changes in endogenous leptin transport into the central nervous system and in hypothalamic sensitivity to exogenous leptin when individuals are placed on high-fat diet (HFD) compared with standard diet.Methods: Serum and cerebrospinal fluid (CSF) leptin concentrations during 10 weeks of HFD versus standard diet and exogenous leptin-induced STAT3 phosphorylation in the hypothalamus of minipigs were assessed, and the hypothalamic leptin-sensitive cells were characterized by immunofluorescence.Results: The efficiency of the passage of endogenous blood-borne leptin into the CSF (measured as the log [CSF:serum leptin ratio]) decreased over time in minipigs fed a HFD (β = -0.04 ± 0.005 per kilogram of weight gain in HFD; P < 0.0001), while it remained stable in minipigs fed a standard diet. However, the ability of peripherally administered leptin to activate its receptor in hypothalamic neurons was preserved in obese minipigs at 10 weeks of HFD.Conclusions: Together, these data are consistent with the existence of an early-onset tranport deficiency for endogenous circulating leptin into the brain in individuals developing obesity, preceding the acquisition of hypothalamic leptin resistance. Although additional studies are required to identify the underlying mechanisms, our study paves the way for the development of new preclinical pharmacological models targeting the restoration of the shuttling of peripheral leptin into the central nervous system to manage obesity

: PPARβ/δ activation increases gut GLP-1 production

International audienceBACKGROUND & AIMS: Glucagon-like peptide (GLP)-1, an intestinal incretin produced by L cells through proglucagon processing, is secreted after nutrient ingestion and acts on endocrine pancreas beta cells to enhance insulin secretion. Peroxisome proliferator-activated receptor (PPAR) β/δ is a nuclear receptor that improves glucose homeostasis and pancreas islet function in diabetic animal models. Here, we investigated whether PPARβ/δ activation regulates L cell GLP-1 production. METHODS: Proglucagon regulation and GLP-1 release were evaluated in murine GLUTag and human NCI-H716 L cells and in vivo using wild-type, PPARβ/δ-null, and ob/ob C57Bl/6 mice treated with the PPARβ/δ synthetic agonists GW501516 or GW0742. RESULTS: PPARβ/δ activation increased proglucagon expression and enhanced glucose- and bile acid-induced GLP-1 release by intestinal L cells in vitro and ex vivo in human jejunum. In vivo treatment with GW0742 increased proglucagon messenger RNA levels in the small intestine in wild-type but not in PPARβ/δ-deficient mice. Treatment of wild-type and ob/ob mice with GW501516 enhanced the increase in plasma GLP-1 level after an oral glucose load and improved glucose tolerance. Concomitantly, proglucagon and GLP-1 receptor messenger RNA levels increased in the small intestine and pancreas, respectively. Finally, PPARβ/δ agonists activate the proglucagon gene transcription by interfering with the β-catenin/TCF-4 pathway. CONCLUSIONS: Our data show that PPARβ/δ activation potentiates GLP-1 production by the small intestine. Pharmacologic targeting of PPARβ/δ is a promising approach in the treatment of patients with type 2 diabetes mellitus, especially in combination with dipeptidyl peptidase IV inhibitors

PPAR␤/␦ Activation Induces Enteroendocrine L Cell GLP-1 Production

BACKGROUND &amp; AIMS: Glucagon-like peptide (GLP)-1, an intestinal incretin produced by L cells through proglucagon processing, is secreted after nutrient ingestion and acts on endocrine pancreas beta cells to enhance insulin secretion. Peroxisome proliferator-activated receptor (PPAR) ␤/␦ is a nuclear receptor that improves glucose homeostasis and pancreas islet function in diabetic animal models. Here, we investigated whether PPAR␤/␦ activation regulates L cell GLP-1 production. METHODS: Proglucagon regulation and GLP-1 release were evaluated in murine GLUTag and human NCI-H716 L cells and in vivo using wild-type, PPAR␤/␦-null, and ob/ob C57Bl/6 mice treated with the PPAR␤/␦ synthetic agonists GW501516 or GW0742. RESULTS: PPAR␤/␦ activation increased proglucagon expression and enhanced glucose-and bile acid-induced GLP-1 release by intestinal L cells in vitro and ex vivo in human jejunum. In vivo treatment with GW0742 increased proglucagon messenger RNA levels in the small intestine in wild-type but not in PPAR␤/␦-deficient mice. Treatment of wildtype and ob/ob mice with GW501516 enhanced the increase in plasma GLP-1 level after an oral glucose load and improved glucose tolerance. Concomitantly, proglucagon and GLP-1 receptor messenger RNA levels increased in the small intestine and pancreas, respectively. Finally, PPAR␤/␦ agonists activate the proglucagon gene transcription by interfering with the ␤-catenin/TCF-4 pathway. CONCLUSIONS: Our data show that PPAR␤/␦ activation potentiates GLP-1 production by the small intestine. Pharmacologic targeting of PPAR␤/␦ is a promising approach in the treatment of patients with type 2 diabetes mellitus, especially in combination with dipeptidyl peptidase IV inhibitors

: LXR controls macrophage iron metabolism

International audienceRATIONALE: In atherosclerotic plaques, iron preferentially accumulates in macrophages where it can exert pro-oxidant activities. OBJECTIVE: The objective of this study was, first, to better characterize the iron distribution and metabolism in macrophage subpopulations in human atherosclerotic plaques and, second, to determine whether iron homeostasis is under the control of nuclear receptors, such as the liver X receptors (LXRs). METHODS AND RESULTS: Here we report that iron depots accumulate in human atherosclerotic plaque areas enriched in CD68 and mannose receptor (MR)-positive (CD68(+)MR(+)) alternative M2 macrophages. In vitro IL-4 polarization of human monocytes into M2 macrophages also resulted in a gene expression profile and phenotype favoring iron accumulation. However, M2 macrophages on iron exposure acquire a phenotype favoring iron release, through a strong increase in ferroportin expression, illustrated by a more avid oxidation of extracellular low-density lipoprotein by iron-loaded M2 macrophages. In line, in human atherosclerotic plaques, CD68(+)MR(+) macrophages accumulate oxidized lipids, which activate LXRα and LXRβ, resulting in the induction of ABCA1, ABCG1, and apolipoprotein E expression. Moreover, in iron-loaded M2 macrophages, LXR activation induces nuclear factor erythroid 2-like 2 expression, thereby increasing ferroportin expression, which, together with a decrease of hepcidin mRNA levels, promotes iron export. CONCLUSIONS: These data identify a role for M2 macrophages in iron handling, a process regulated by LXR activation

Human adipose tissue macrophages display activation of cancer-related pathways.: ATM link obesity and cancer?

International audienceObesity is associated with a significantly increased risk for cancer suggesting that adipose tissue dysfunctions might play a crucial role therein. Macrophages play important roles in adipose tissue as well as in cancers. Here, we studied whether human adipose tissue macrophages (ATM) modulate cancer cell function. Therefore, ATM were isolated and compared with monocyte-derived macrophages (MDM) from the same obese patients. ATM, but not MDM, were found to secrete factors inducing inflammation and lipid accumulation in human T47D and HT-29 cancer cells. Gene expression profile comparison of ATM and MDM revealed overexpression of functional clusters, such as cytokine-cytokine receptor interaction (especially CXC-chemokine) signaling as well as cancer-related pathways, in ATM. Comparison with gene expression profiles of human tumor-associated macrophages showed that ATM, but not MDM resemble tumor-associated macrophages. Indirect co-culture experiments demonstrated that factors secreted by preadipocytes, but not mature adipocytes, confer an ATM-like phenotype to MDM. Finally, the concentrations of ATM-secreted factors related to cancer are elevated in serum of obese subjects. In conclusion, ATM may thus modulate the cancer cell phenotype