ORCID Profile
0000-0002-5065-5393
Current Organisation
École Polytechnique Fédérale de Lausanne
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Publisher: Public Library of Science (PLoS)
Date: 04-12-2009
Publisher: EMBO
Date: 02-2004
Abstract: The nuclear receptor peroxisome proliferator‐activated receptor‐γ (PPARγ) helps to translate ‘what you eat’ into ‘what you are’ because it allows dietary fatty acids (PPARγ ligands) to modulate gene transcription. Treatments for diabetes include PPARγ activators, as they sensitize the body to insulin. Our understanding of PPARγ function has recently been enhanced by a flurry of human and mouse genetic studies, and the characterization of new PPARγ ligands. This insight has led us to propose that modulating PPARγ activity, rather than activating it, might be the most effective strategy for treating metabolic disorders, as this will improve glucose homeostasis while preventing adipogenesis.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 24-07-2019
DOI: 10.1126/SCITRANSLMED.AAN5662
Abstract: Transplanting the gut microbiota of pathogen-free mice into germ-free mice improves skeletal muscle mass and strength.
Publisher: Elsevier BV
Date: 11-2003
Publisher: Proceedings of the National Academy of Sciences
Date: 05-11-2003
Abstract: Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor, which controls adipocyte differentiation. We targeted with homologous recombination the PPARγ2-specific exon B, resulting in a white adipose tissue knockdown of PPARγ. Although homozygous ( PPAR γ hyp/hyp ) mice are born with similar weight as the WT mice, the PPAR γ hyp/hyp animals become growth retarded and develop severe lipodystrophy and hyperlipidemia. Almost half of these PPAR γ hyp/hyp mice die before adulthood, whereas the surviving PPAR γ hyp/hyp animals overcome the growth retardation, yet remain lipodystrophic. In contrast to most lipodystrophic models, the adult PPAR γ hyp/hyp mice only have mild glucose intolerance and do not have a fatty liver. These metabolic consequences of the lipodystrophy are relatively benign because of the induction of a compensatory gene expression program in the muscle that enables efficient oxidation of excess lipids. The PPAR γ hyp/hyp mice unequivocally demonstrate that PPARγ is the master regulator of adipogenesis in vivo and establish that lipid and glucose homeostasis can be relatively well maintained in the absence of white adipose tissue.
Publisher: SAGE Publications
Date: 2003
DOI: 10.1621/NRS.01006
Publisher: Springer Science and Business Media LLC
Date: 16-01-2013
DOI: 10.1038/SREP01131
Publisher: Springer Science and Business Media LLC
Date: 22-05-2013
DOI: 10.1038/NATURE12188
Publisher: Wiley
Date: 24-01-2005
DOI: 10.1111/J.1365-2362.2005.01456.X
Abstract: The consequence of activating the nuclear hormone receptor, peroxisome proliferator-activated receptor gamma (PPARgamma), which coordinates adipocyte differentiation, validates the concept, 'you are what you eat'. Excessive caloric intake leads to fat formation if the energy from these nutrients is not expended. However, this evolutionary adaptation to store energy in fat, which can be released under the form of fatty acids, potent PPARgamma agonists, has become a disadvantage in today's affluent society as it results in numerous metabolic imbalances, collectively known as the metabolic syndrome. With the surge of human and genetic studies on PPARgamma function, the limitations to the benefits of PPARgamma signalling have been realized. It is now evident that the most effective strategy for resetting the balance of this thrifty gene is through its modulation rather than full activation, with the goal to improve glucose homeostasis while preventing adipogenesis. Finally, as more PPARgamma targeted pathways are revealed such as bone homeostasis, atherosclerosis and longevity, it is most certain that the PPARgamma thrifty gene hypothesis will evolve to incorporate these.
Publisher: Springer Science and Business Media LLC
Date: 16-10-2017
DOI: 10.1038/S41467-017-00931-8
Abstract: Thymocytes must pass both positive and negative selections to become mature T cells. Negative selection purges thymocytes whose T-cell receptors (TCR) exhibit high affinity to self-peptide MHC complexes (self pMHC) to avoid autoimmune diseases, while positive selection ensures the survival and maturation of thymocytes whose TCRs display intermediate affinity to self pMHCs for effective immunity, but whether transcriptional regulation helps conserve positively selected thymocytes from being purged by negative selection remains unclear. Here we show that the specific deletion of nuclear receptor co-repressor 1 (NCoR1) in T cells causes excessive negative selection to reduce mature thymocyte numbers. Mechanistically, NCoR1 protects positively selected thymocytes from negative selection by suppressing Bim expression. Our study demonstrates a critical function of NCoR1 in coordinated positive and negative selections in the thymus.
Publisher: Springer Science and Business Media LLC
Date: 09-12-2019
DOI: 10.1038/S42255-019-0147-3
Abstract: The nature and extent of mitochondrial DNA variation in a population and how it affects traits is poorly understood. Here we resequence the mitochondrial genomes of 169 Drosophila Genetic Reference Panel lines, identifying 231 variants that stratify along 12 mitochondrial haplotypes. We identify 1,845 cases of mitonuclear allelic imbalances, thus implying that mitochondrial haplotypes are reflected in the nuclear genome. However, no major fitness effects are associated with mitonuclear imbalance, suggesting that such imbalances reflect population structure at the mitochondrial level rather than genomic incompatibilities. Although mitochondrial haplotypes have no direct impact on mitochondrial respiration, some haplotypes are associated with stress- and metabolism-related phenotypes, including food intake in males. Finally, through reciprocal swapping of mitochondrial genomes, we demonstrate that a mitochondrial haplotype associated with high food intake can rescue a low food intake phenotype. Together, our findings provide new insight into population structure at the mitochondrial level and point to the importance of incorporating mitochondrial haplotypes in genotype-phenotype relationship studies.
Publisher: EMBO
Date: 10-2004
Abstract: The peroxisome proliferator‐activated receptor gamma (PPARγ) controls adipogenesis and metabolism. We demonstrate here that the absence of PPARγ in fat has potent osteogenic activities, which affect haematopoiesis. The congenital absence of PPARγ in fat of lipodystrophic PPARγ hyp/hyp mice, strongly enhanced bone mass and consequentially reduced the bone‐marrow cavity. Consistent with this, PPARγ hyp/hyp mice had a significant decrease in bone marrow cellularity and resorted to extramedullary haematopoiesis in the spleen to maintain haematopoiesis. Our data indicate that antagonizing PPARγ activity in fat could be an effective way to combat osteoporosis and suggest that haematopoietic function should be scrutinized in lipodystrophic subjects.
Publisher: Springer Science and Business Media LLC
Date: 09-2004
DOI: 10.1038/NG0904-925
Publisher: Springer Science and Business Media LLC
Date: 06-2020
DOI: 10.1038/S41467-020-16537-6
Abstract: Obesity and type 2 diabetes (T2D) are metabolic disorders influenced by lifestyle and genetic factors that are characterized by insulin resistance in skeletal muscle, a prominent site of glucose disposal. Numerous genetic variants have been associated with obesity and T2D, of which the majority are located in non-coding DNA regions. This suggests that most variants mediate their effect by altering the activity of gene-regulatory elements, including enhancers. Here, we map skeletal muscle genomic enhancer elements that are dynamically regulated after exposure to the free fatty acid palmitate or the inflammatory cytokine TNFα. By overlapping enhancer positions with the location of disease-associated genetic variants, and resolving long-range chromatin interactions between enhancers and gene promoters, we identify target genes involved in metabolic dysfunction in skeletal muscle. The majority of these genes also associate with altered whole-body metabolic phenotypes in the murine BXD genetic reference population. Thus, our combined genomic investigations identified genes that are involved in skeletal muscle metabolism.
Publisher: American Physiological Society
Date: 08-2008
DOI: 10.1152/PHYSIOLGENOMICS.90207.2008
Abstract: Establishing standard operating procedures (SOPs) as tools for the analysis of behavioral phenotypes is fundamental to mouse functional genomics. It is essential that the tests designed provide reliable measures of the process under investigation but most importantly that these are reproducible across both time and laboratories. For this reason, we devised and tested a set of SOPs to investigate mouse behavior. Five research centers were involved across France, Germany, Italy, and the UK in this study, as part of the EUMORPHIA program. All the procedures underwent a cross-validation experimental study to investigate the robustness of the designed protocols. Four inbred reference strains (C57BL/6J, C3HeB/FeJ, BALB/cByJ, 129S2/SvPas), reflecting their use as common background strains in mutagenesis programs, were analyzed to validate these tests. We demonstrate that the operating procedures employed, which includes open field, SHIRPA, grip-strength, rotarod, Y-maze, prepulse inhibition of acoustic startle response, and tail flick tests, generated reproducible results between laboratories for a number of the test output parameters. However, we also identified several uncontrolled variables that constitute confounding factors in behavioral phenotyping. The EUMORPHIA SOPs described here are an important start-point for the ongoing development of increasingly robust phenotyping platforms and their application in large-scale, multicentre mouse phenotyping programs.
Publisher: American Society for Clinical Investigation
Date: 09-2022
DOI: 10.1172/JCI151540
Publisher: Wiley
Date: 14-04-2018
DOI: 10.1111/ACEL.12751
Publisher: Wiley
Date: 07-07-2017
Publisher: American Diabetes Association
Date: 27-01-2010
DOI: 10.2337/DB09-1191
Abstract: Sirtuin 1 (SIRT1) is implicated in the regulation of mitochondrial function, energy metabolism, and insulin sensitivity in rodents. No studies are available in humans to demonstrate that SIRT1 expression in insulin-sensitive tissues is associated with energy expenditure and insulin sensitivity. Energy expenditure (EE), insulin sensitivity, and SIRT1 mRNA adipose tissue expression (n = 81) were measured by indirect calorimetry, hyperinsulinemic-euglycemic cl , and quantitative RT-PCR in 247 nondiabetic offspring of type 2 diabetic patients. High EE during the cl (r = 0.375, P = 2.8 × 10−9) and high ΔEE (EE during the cl − EE in the fasting state) (r = 0.602, P = 2.5 × 10−24) were associated with high insulin sensitivity. Adipose tissue SIRT1 mRNA expression was significantly associated with EE (r = 0.289, P = 0.010) and with insulin sensitivity (r = 0.334, P = 0.002) during hyperinsulinemic-euglycemic cl . Furthermore, SIRT1 mRNA expression correlated significantly with the expression of several genes regulating mitochondrial function and energy metabolism (e.g., peroxisome proliferator–activated receptor γ coactivator-1β, estrogen-related receptor α, nuclear respiratory factor-1, and mitochondrial transcription factor A), and with several genes of the respiratory chain (e.g., including NADH dehydrogenase [ubiquinone] 1α subcomplex 2, cytochrome c, cytochrome c oxidase subunit IV, and ATP synthase). Impaired stimulation of EE by insulin and low SIRT1 expression in insulin-sensitive tissues is likely to reflect impaired regulation of mitochondrial function associated with insulin resistance in humans.
Publisher: Springer Science and Business Media LLC
Date: 18-08-2011
DOI: 10.1038/SREP00070
Publisher: Oxford University Press (OUP)
Date: 04-01-2017
DOI: 10.1093/HMG/DDW418
Abstract: To understand the cause of Parkinson's disease (PD), it is important to determine the functional interactions between factors linked to the disease. Parkin is associated with autosomal recessive early-onset PD, and controls the transcription of PGC-1α, a master regulator of mitochondrial biogenesis. These two factors functionally interact to regulate the turnover and quality of mitochondria, by increasing both mitophagic activity and mitochondria biogenesis. In cortical neurons, co-expressing PGC-1α and Parkin increases the number of mitochondria, enhances maximal respiration, and accelerates the recovery of the mitochondrial membrane potential following mitochondrial uncoupling. PGC-1α enhances Mfn2 transcription, but also leads to increased degradation of the Mfn2 protein, a key ubiquitylation target of Parkin on mitochondria. In vivo, Parkin has significant protective effects on the survival and function of nigral dopaminergic neurons in which the chronic expression of PGC-1α is induced. Ultrastructural analysis shows that these two factors together control the density of mitochondria and their interaction with the endoplasmic reticulum. These results highlight the combined effects of Parkin and PGC-1α in the maintenance of mitochondrial homeostasis in dopaminergic neurons. These two factors synergistically control the quality and function of mitochondria, which is important for the survival of neurons in Parkinson's disease.
Publisher: Springer Science and Business Media LLC
Date: 02-2014
DOI: 10.1038/NATURE13024
Publisher: American Association for the Advancement of Science (AAAS)
Date: 08-12-2021
DOI: 10.1126/SCITRANSLMED.ABC7367
Abstract: Exercise activates the lncRNA Cytor , which reestablishes fast-twitch muscle fibers in aged skeletal muscle, improving morphology and function.
Publisher: Proceedings of the National Academy of Sciences
Date: 26-09-2011
Abstract: The formation of myelin by Schwann cells (SCs) occurs via a series of orchestrated molecular events. We previously used global expression profiling to examine peripheral nerve myelination and identified the NAD + -dependent deacetylase Sir-two-homolog 2 (Sirt2) as a protein likely to be involved in myelination. Here, we show that Sirt2 expression in SCs is correlated with that of structural myelin components during both developmental myelination and remyelination after nerve injury. Transgenic mice lacking or overexpressing Sirt2 specifically in SCs show delays in myelin formation. In SCs, we found that Sirt2 deacetylates Par-3, a master regulator of cell polarity. The deacetylation of Par-3 by Sirt2 decreases the activity of the polarity complex signaling component aPKC, thereby regulating myelin formation. These results demonstrate that Sirt2 controls an essential polarity pathway in SCs during myelin assembly and provide insights into the association between intracellular metabolism and SC plasticity.
Publisher: Springer Science and Business Media LLC
Date: 15-02-2022
Location: Switzerland
No related grants have been discovered for Johan Auwerx.