Papers by Mathias Leblanc
Disease tolerance mediated by microbiome E. coli involves inflammasome and IGF-1 signaling
Science (New York, N.Y.), Jan 30, 2015
Infections and inflammation can lead to cachexia and wasting of skeletal muscle and fat tissue by... more Infections and inflammation can lead to cachexia and wasting of skeletal muscle and fat tissue by as yet poorly understood mechanisms. We observed that gut colonization of mice by a strain of Escherichia coli prevents wasting triggered by infections or physical damage to the intestine. During intestinal infection with the pathogen Salmonella Typhimurium or pneumonic infection with Burkholderia thailandensis, the presence of this E. coli did not alter changes in host metabolism, caloric uptake, or inflammation but instead sustained signaling of the insulin-like growth factor 1/phosphatidylinositol 3-kinase/AKT pathway in skeletal muscle, which is required for prevention of muscle wasting. This effect was dependent on engagement of the NLRC4 inflammasome. Therefore, this commensal promotes tolerance to diverse diseases.
The CREB/CRTC2 pathway modulates autoimmune disease by promoting Th17 differentiation
Nature Communications, 2015
Following their activation in response to inflammatory signals, innate immune cells secrete T-cel... more Following their activation in response to inflammatory signals, innate immune cells secrete T-cell-polarizing cytokines that promote the differentiation of naive CD4 T cells into T helper (Th) cell subsets. Among these, Th17 cells play a prominent role in the development of a number of autoimmune diseases. Although regarded primarily as an immunosuppressant signal, cAMP has been found to mediate pro-inflammatory effects of macrophage-derived prostaglandin E2 (PGE2) on Th17 cells. Here we show that PGE2 enhances Th17 cell differentiation via the activation of the CREB co-activator CRTC2. Following its dephosphorylation, CRTC2 stimulates the expression of the cytokines IL-17A and IL-17F by binding to CREB over both promoters. CRTC2-mutant mice have decreased Th17 cell numbers, and they are protected from experimental autoimmune encephalitis, a model for multiple sclerosis. Our results suggest that small molecule inhibitors of CRTC2 may provide therapeutic benefit to individuals with autoimmune disease.
False-positive results after environmental pinworm PCR testing due to Rhabditid nematodes in Corncob bedding
Journal of the American Association for Laboratory Animal Science : JAALAS, 2014
Modern rodent colonies are housed in individually ventilated cages to protect the animals from co... more Modern rodent colonies are housed in individually ventilated cages to protect the animals from contamination with adventitious pathogens. Standard health monitoring through soiled-bedding sentinels does not always detect infections, especially in the context of low pathogen prevalence. Recently proposed alternatives include analyzing environmental samples from the cages or rack exhaust by PCR to improve the detection of rodent pathogens but optimal sampling strategies have not yet been established for different microorganisms. Although generally very sensitive and specific, these molecular assays are not foolproof and subject to false-positive and -negative results and should always be interpreted cautiously with an overall understanding of the intrinsic controls and all the variables that may affect the results. Here, we report a limited Aspiculuris tetraptera outbreak in a mouse barrier facility that was detected by fecal PCR in sentinels and confirmed by fecal flotation and direc...
Molecular and cellular biology, Jan 26, 2015
Almost all cellular functions are powered by continuous energy supply derived from cellular metab... more Almost all cellular functions are powered by continuous energy supply derived from cellular metabolism. However, it is little understood how cellular energy production is coordinated with diverse energy-consuming cellular functions. Here, using the cardiac muscle system, we demonstrate that nuclear receptors ERRα and ERRγ are essential transcriptional coordinators of cardiac energy production and consumption. On the one hand, ERRα and ERRγ together are vital for intact cardiomyocyte metabolism by directly controlling expression of genes important for mitochondrial functions and dynamics. On the other hand, ERRα and ERRγ influence major cardiomyocyte energy-consumption functions through direct transcriptional regulation of key contraction, calcium homeostasis and conduction genes. Mice lacking both ERRα and cardiac ERRγ develop severe bradycardia, lethal cardiomyopathy and heart failure featuring metabolic, contractile and conduction dysfunctions. These results illustrate that the ER...
Cell, 2014
The sensation of pain is associated with increased mortality, but it is unknown whether pain perc... more The sensation of pain is associated with increased mortality, but it is unknown whether pain perception can directly affect aging. We find that mice lacking TRPV1 pain receptors are long-lived, displaying a youthful metabolic profile at old age. Loss of TRPV1 inactivates a calcium-signaling cascade that ends in the nuclear exclusion of the CREB-regulated transcriptional coactivator CRTC1 within pain sensory neurons originating from the spinal cord. In long-lived TRPV1 knockout mice, CRTC1 nuclear exclusion decreases production of the neuropeptide CGRP from sensory endings innervating the pancreatic islets, subsequently promoting insulin secretion and metabolic health. In contrast, CGRP homeostasis is disrupted with age in wild-type mice, resulting in metabolic decline. We show that pharmacologic inactivation of CGRP receptors in old wildtype animals can restore metabolic health. These data suggest that ablation of select pain sensory receptors or the inhibition of CGRP are associated with increased metabolic health and control longevity.
ZASC1 knockout mice exhibit an early bone marrow-specific defect in murine leukemia virus replication
Virology Journal, 2013
ZASC1 is a zinc finger-containing transcription factor that was previously shown to bind to speci... more ZASC1 is a zinc finger-containing transcription factor that was previously shown to bind to specific DNA binding sites in the Moloney murine leukemia virus (Mo-MuLV) promoter and is required for efficient viral mRNA transcription (J. Virol. 84:7473-7483, 2010). To determine whether this cellular factor influences Mo-MuLV replication and viral disease pathogenesis in vivo, we generated a ZASC1 knockout mouse model and completed both early infection and long term disease pathogenesis studies. Mice lacking ZASC1 were born at the expected Mendelian ratio and showed no obvious physical or behavioral defects. Analysis of bone marrow samples revealed a specific increase in a common myeloid progenitor cell population in ZASC1-deficient mice, a result that is of considerable interest because osteoclasts derived from the myeloid lineage are among the first bone marrow cells infected by Mo-MuLV (J. Virol. 73: 1617-1623, 1999). Indeed, Mo-MuLV infection of neonatal mice revealed that ZASC1 is required for efficient early virus replication in the bone marrow, but not in the thymus or spleen. However, the absence of ZASC1 did not influence the timing of subsequent tumor progression or the types of tumors resulting from virus infection. These studies have revealed that ZASC1 is important for myeloid cell differentiation in the bone marrow compartment and that this cellular factor is required for efficient Mo-MuLV replication in this tissue at an early time point post-infection.
Pharmacokinetics of oral dehydroepiandrosterone (DHEA) in the ovariectomised cynomolgus monkey
The Journal of Steroid Biochemistry and Molecular Biology, 2002
Humans and primates are unique in having adrenals that secrete large amounts of DHEA and DHEA-S i... more Humans and primates are unique in having adrenals that secrete large amounts of DHEA and DHEA-S in the circulation. These steroids act as precursors of active androgens and estrogen's in a long series of peripheral target intracrine tissues. The marked decline of serum DHEA and DHEA-S concentrations with age in men and women has been incriminated in the development of various pathologies. This study provides detailed information on the effect of a single 50mg oral dose of DHEA on circulating estrogen's as well as androgens and their metabolites over 10h in adult ovariectomised (OVX) Cynomolgus monkeys. Serum DHEA, DHEA-S, testosterone (Testo) and androstenedione (4-dione) concentrations increased rapidly with a maximal value at approximately 1h after DHEA administration followed by a 60-80% decrease during the next 2-6h. An important sulfatation of DHEA occurs through first hepatic pass, thus, leading to a marked increase in serum DHEA-S. Serum androst-5-ene-3beta,17beta-diol and androsterone glucuronide (ADT-G) levels remained elevated on a plateau for 6h. Androstan-3alpha,17beta-diol-glucuronide, estradiol and estrone levels remained unchanged. The present data indicate the predominant transformation of the adrenal precursor DHEA into active androgens in peripheral tissues and support the importance of measurement of circulating glucuronide derivatives as index of peripheral or intracrine androgen formation and action.
Proceedings of the National Academy of Sciences, 2008
The nuclear receptor corepressor, silencing mediator of retinoid and thyroid hormone receptors (S... more The nuclear receptor corepressor, silencing mediator of retinoid and thyroid hormone receptors (SMRT), is recruited by a plethora of transcription factors to mediate lineage and signal-dependent transcriptional repression. We generated a knockin mutation in the receptor interaction domain (RID) of SMRT (SMRT mRID ) that solely disrupts its interaction with nuclear hormone receptors (NHRs). SMRT mRID mice are viable and exhibit no gross developmental abnormalities, demonstrating that the reported lethality of SMRT knockouts is determined by non-NHR transcription factors. However, SMRT mRID mice exhibit widespread metabolic defects including reduced respiration, altered insulin sensitivity, and 70% increased adiposity. The latter phenotype is illustrated by the observation that SMRT mRID -derived MEFs display a dramatically increased adipogenic capacity and accelerated differentiation rate. Collectively, our results demonstrate that SMRT-RID-dependent repression is a key determinant of the adipogenic set point as well as an integrator of glucose metabolism and whole-body metabolic homeostasis.
Nature Medicine, 2011
Although the lung is a defining feature of air-breathing animals, the pathway controlling the for... more Although the lung is a defining feature of air-breathing animals, the pathway controlling the formation of the type I pneumocyte, the cell that mediates gas exchange, is poorly understood. In contrast, glucocorticoids and their cognate receptor (GR) have long been known to promote type II pneumocyte maturation; prenatal administration of glucocorticoids is commonly used to attenuate the severity of infant respiratory distress syndrome (RDS). Here we show that knock-in mutations of the nuclear corepressor SMRT in C57Bl6 mice (SMRT mRID ) produces a novel respiratory distress syndrome due to prematurity of the type I pneumocyte. Though unresponsive to glucocorticoids, treatment with anti-thyroid hormone drugs (propylthiouracil or methimazole) completely rescues the SMRT-induced RDS, suggesting an unrecognized and essential role for the thyroid hormone receptor (TR) in lung development. We show that TR and SMRT control type I pneumocyte differentiation through Klf2, which in turn appears to directly activate the type I pneumocyte gene program. Conversely, mice without lung Klf2 lack mature type I pneumocytes and die shortly after birth, closely recapitulating the SMRT mRID phenotype. These results identify a second nuclear receptor, the TR, in type I pneumocyte differentiation and suggest a new type of therapeutic option in the treatment of glucocorticoid non-responsive RDS.
Nature Cell Biology, 2012
Lung cancer is one of the leading cancer malignancies with a five-year survival rate of only ~15%... more Lung cancer is one of the leading cancer malignancies with a five-year survival rate of only ~15%. We have developed a lentiviral vector mediated mouse model which allows generation of nonsmall cell lung cancer from less than one hundred alveolar epithelial cells, and investigated the role of IKK2 and NF-κB in lung cancer development. IKK2 depletion in tumour cells significantly attenuated tumour proliferation and significantly prolonged mouse survival. We identified Timp-1, one of the NF-κB target genes, as a key mediator for tumour growth. Activation of Erk signalling pathway and cell proliferation requires Timp-1 and its receptor CD63. Knockdown of either IKK2 or Timp-1 by shRNAs reduced tumour growth in both xenograft and lentiviral models. Our results, thus suggest the possible application of IKK2 and Timp-1 inhibitors in treating lung cancer.
The Journal of Clinical Endocrinology & Metabolism, 2004
In men, orchiectomy (GDX) produces an atherogenic lipid profile, whereas combined androgen blocka... more In men, orchiectomy (GDX) produces an atherogenic lipid profile, whereas combined androgen blockade (CAB) induces a favorable lipid pattern. To better understand the opposite effects of GDX and CAB on lipid metabolism, we have compared the changes in plasma lipoproteins, mesenteric fat metabolism, as well as serum and intratissular sex steroid concentrations in intact, GDX, and GDX؉FLU [GDX male cynomolgus monkeys treated for 3 months with flutamide (FLU)].
The Journal of Clinical Endocrinology & Metabolism, 2003
We have studied the pharmacokinetics of dehydroepiandrosterone (DHEA) administered orally (PO), i... more We have studied the pharmacokinetics of dehydroepiandrosterone (DHEA) administered orally (PO), iv, and during a continuous iv infusion in ovariectomized cynomolgus monkeys under suppression of adrenal DHEA secretion with dexamethasone. The glucocorticoid induced a rapid suppression of serum cortisol, DHEA, and DHEA-sulfate (DHEA-S) as well as their metabolites, thus permitting to use this model to study the pharmacokinetic parameters of DHEA and its metabolites without significant interference by endogenous steroid levels.
Cell Metabolism, 2012
While diet-induced obesity has been exclusively attributed to increased caloric intake from fat, ... more While diet-induced obesity has been exclusively attributed to increased caloric intake from fat, animals fed high fat diet (HFD) ad libitum (ad lib) eat frequently throughout day and night disrupting the normal feeding cycle. To test whether obesity and metabolic diseases result from HFD or disruption of metabolic cycles, we subjected mice to either ad lib or time restricted feeding (tRF) of a HFD for 8 h/day. Mice under tRF consume equivalent calories from HFD as those with ad lib access, yet are protected against obesity, hyperinsulinemia, hepatic steatosis, inflammation, and have improved motor coordination. The tRF regimen improved CREB, mTOR and AMPK pathway function and oscillations of the circadian clock and their target genes' expression. These changes in catabolic and anabolic pathways altered liver metabolome, improved nutrient utilization and energy expenditure. We demonstrate in mice that tRF regimen is a nonpharmacological strategy against obesity and associated diseases.
Cancer Cell, 2009
Mdmx is a critical negative regulator of the p53 pathway that is stoichiometrically limiting in s... more Mdmx is a critical negative regulator of the p53 pathway that is stoichiometrically limiting in some tissues. Post-translational modification and degradation of Mdmx after DNA damage have been proposed to be essential for p53 activation. We tested this model in vivo, where critical stoichiometric relationships are preserved. We generated an Mdmx mutant mouse in which three conserved serines (S341, S367, S402) targeted by DNA damage-activated kinases were replaced by alanines to investigate whether modifications of these residues are important for Mdmx degradation and p53 activation. The mutant mice were remarkably resistant to radiation, and very susceptible to Mycinduced lymphomagenesis. These data demonstrate that Mdmx down-regulation is crucial for effective p53-mediated radiation responses and tumor suppression in vivo.
Dependence of Hippocampal Function on ERRγ-Regulated Mitochondrial Metabolism
Cell Metabolism, 2015
Neurons utilize mitochondrial oxidative phosphorylation (OxPhos) to generate energy essential for... more Neurons utilize mitochondrial oxidative phosphorylation (OxPhos) to generate energy essential for survival, function, and behavioral output. Unlike most cells that burn both fat and sugar, neurons only burn sugar. Despite its importance, how neurons meet the increased energy demands of complex behaviors such as learning and memory is poorly understood. Here we show that the estrogen-related receptor gamma (ERRγ) orchestrates the expression of a distinct neural gene network promoting mitochondrial oxidative metabolism that reflects the extraordinary neuronal dependence on glucose. ERRγ(-/-) neurons exhibit decreased metabolic capacity. Impairment of long-term potentiation (LTP) in ERRγ(-/-) hippocampal slices can be fully rescued by the mitochondrial OxPhos substrate pyruvate, functionally linking the ERRγ knockout metabolic phenotype and memory formation. Consistent with this notion, mice lacking neuronal ERRγ in cerebral cortex and hippocampus exhibit defects in spatial learning and memory. These findings implicate neuronal ERRγ in the metabolic adaptations required for memory formation.
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Papers by Mathias Leblanc