Protein kinase N2 regulates AMP kinase signaling and insulin responsiveness of glucose metabolism in skeletal muscle

Insulin resistance is central to the development of type 2 diabetes and related metabolic disorders. Because skeletal muscle is responsible for the majority of whole body insulin-stimulated glucose uptake, regulation of glucose metabolism in this tissue is of particular importance. Although Rho GTPases and many of their affecters influence skeletal muscle metabolism, there is a paucity of information on the protein kinase N (PKN) family of serine/threonine protein kinases. We investigated the impact of PKN2 on insulin signaling and glucose metabolism in primary human skeletal muscle cells in vitro and mouse tibialis anterior muscle in vivo. PKN2 knockdown in vitro decreased insulin-stimulated glucose uptake, incorporation into glycogen, and oxidation. PKN2 siRNA increased 5′-adenosine monophosphate-activated protein kinase (AMPK) signaling while stimulating fatty acid oxidation and incorporation into triglycerides and decreasing protein synthesis. At the transcriptional level, PKN2 knockdown increased expression of PGC-1α and SREBP-1c and their target genes. In mature skeletal muscle, in vivo PKN2 knockdown decreased glucose uptake and increased AMPK phosphorylation. Thus, PKN2 alters key signaling pathways and transcriptional networks to regulate glucose and lipid metabolism. Identification of PKN2 as a novel regulator of insulin and AMPK signaling may provide an avenue for manipulation of skeletal muscle metabolism

Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver.

International audienceNumerous investigations have shown that mitochondrial dysfunction is a major mechanism of drug-induced liver injury, which involves the parent drug or a reactive metabolite generated through cytochromes P450. Depending of their nature and their severity, the mitochondrial alterations are able to induce mild to fulminant hepatic cytolysis and steatosis (lipid accumulation), which can have different clinical and pathological features. Microvesicular steatosis, a potentially severe liver lesion usually associated with liver failure and profound hypoglycemia, is due to a major inhibition of mitochondrial fatty acid oxidation (FAO). Macrovacuolar steatosis, a relatively benign liver lesion in the short term, can be induced not only by a moderate reduction of mitochondrial FAO but also by an increased hepatic de novo lipid synthesis and a decreased secretion of VLDL-associated triglycerides. Moreover, recent investigations suggest that some drugs could favor lipid deposition in the liver through primary alterations of white adipose tissue (WAT) homeostasis. If the treatment is not interrupted, steatosis can evolve toward steatohepatitis, which is characterized not only by lipid accumulation but also by necroinflammation and fibrosis. Although the mechanisms involved in this aggravation are not fully characterized, it appears that overproduction of reactive oxygen species by the damaged mitochondria could play a salient role. Numerous factors could favor drug-induced mitochondrial and metabolic toxicity, such as the structure of the parent molecule, genetic predispositions (in particular those involving mitochondrial enzymes), alcohol intoxication, hepatitis virus C infection, and obesity. In obese and diabetic patients, some drugs may induce acute liver injury more frequently while others may worsen the pre-existent steatosis (or steatohepatitis)

Drug-Induced Inhibition of Mitochondrial Fatty Acid Oxidation and Steatosis

Mitochondrial Dysfunction and Diseases (H Jaeschke, Section Editor)International audienceDrug-induced inhibition of mitochondrial fatty acid β-oxidation (mtFAO) is a key mechanism whereby drugs can induce steatosis. The type and severity of this liver lesion is dependent on the residual mtFAO flux. Indeed, a severe inhibition of mtFAO leads to microvesicular steatosis, hypoglycemia and liver failure, which can be favored by genetic predispositions. In contrast, moderate impairment of mtFAO can cause macrovacuolar steatosis, which is by itself a benign lesion. In the long-term, however, macrovacuolar steatosis can progress with some drugs to steatohepatitis. Interestingly, drugs that are more likely to cause steatohepatitis are those impairing the mitochondrial respiratory chain (MRC) activity. Indeed, MRC impairment favors not only hepatic fat accretion but also oxidative stress and lipid peroxidation. Drugs inhibiting mtFAO could be more toxic in obese patients with preexisting nonalcoholic fatty liver disease (NAFLD) since higher mtFAO is a key metabolic adaptation to curb fat accretion during NAFLD

Introduction

L’objectif de ce numéro thématique est double. Il s’agit en premier lieu d’introduire l’économétrie spatiale à la communauté des économistes industriels afin d’en montrer l’intérêt et d’en généraliser l’usage. En second lieu, nous avons veillé à présenter des articles empiriques mettant en œuvre dans des contextes différents et pour des objectifs divers ces techniques afin d’en montrer l’intérêt mais surtout la richesse des approches et applications possibles. L’économétrie spatiale consiste ..

Impact of high-wheat bran diet on sows’ microbiota, performances and progeny’s growth and health

Finding alternatives to antimicrobial growth promoters is part of the goal of improving sustainability in pig production. Dietary fibres are considered as health-promoting substances acting on pigs’ microbiota. This study aimed to investigate whether the enrichment of sows’ diet with high levels of wheat bran (WB) could impact the performances of sows and piglets’ health. Seven sows were fed a control diet (CON) and 8 sows a WB diet from day 43 of gestation (WB 240 g/kg DM) until the end of the lactation period (WB 140 g/kg DM). Diets were formulated to be iso-energetic and iso-nitrogenous by changing the proportions of some ingredients. Faeces were sampled at different time points (before treatment, during treatment: in gestation and lactation) to determine microbiota composition (sequencing with Illumina MiSeq). Milk was sampled weekly to determine lactose, fat and protein concentration by mid-infrared technology and IgA and IgG contents by ELISA. Before weaning (d26-27), piglets were euthanized, intestinal contents and tissues sampled for further analyses. Zootechnical performances of sows and piglets were recorded. Statistical analyses were performed using the SAS MIXED procedure and repeated measurements. Treatment never impacted piglets’ weight (P=0.51). Sows’ ingestion during the lactation period was comparable between both treatments until the last 4 days of lactation where the percentage of target ingestion was significantly (P<0.001) lower for the WB (66%) compared to the CON group (89%). No effect on sows’ backfat and weight changes was observed. An increased abundance of Lactobacillus spp. in feces of the WB group was observed in gestation before and after diet change (8.8% vs 15.1% of total bacteria). However, for the overall genera changes between treatments, it only seems to occur for minor groups of bacteria. Milk protein, fat, IgG and IgA were not affected by treatment, but a time-effect (P<0.001) was observed while treatment impacted (P<0.05) lactose content. In conclusion, sows’ performances were not affected by the high WB diet and more research on the piglets’ samples is foreseen

Correction to: Safeguarding and using global banana diversity: a holistic approach

An amendment to this paper has been published and can be accessed via the original article

Congenital hydrocephalus : new Mendelian mutations and evidence for oligogenic inheritance

Peer reviewe

Effets hépatiques et métaboliques de la pentoxifylline chez la souris ob/ob (un exemple d'interaction entre xénobiotiques et obésité)

PARIS-BIUP (751062107) / SudocSudocFranceF

Expériences de recherche collaborative avec des enfants en Afrique de l’Ouest

Cet ouvrage documente et analyse une expérimentation de recherche en sciences sociales menée en Afrique de l’Ouest au sein d’une Organisation Non-Gouvernementale Internationale de développement centrée sur l’enfance – Plan-International. L’histoire de cette aventure explore des questions cruciales : recherche et intervention sont-elles conciliables ? Comment associer des enfants à la recherche ? Quel est leur intérêt à en être ? Avec quelles conséquences ? Cette expérimentation avec les enfants oscille entre la recherche participative et collaborative. Les auteurs défendent le grand intérêt de l’association avec des artistes. Ils indiquent des voies, recommandent des postures, et soulignent les divers effets, les limites ainsi que les défis des techniques d’expression adoptées. L’ouvrage est non seulement une invitation à l’expérimentation permanente et à l’intégration de la recherche dans les institutions d’intervention en faveur de l’enfance comme mode d’action auprès de leurs publics, ainsi qu’une source d’adaptation continue ; il présente aussi des usages de la recherche par les enfants et les jeunes. On y découvre comment ils parviennent à se créer des espaces politiques et des positionnements à travers la curiosité, l’art – notamment le rap – et le débat. Ancrés dans la pratique, les divers exemples et documents issus de cette expérimentation présentés ici témoignent de la sensibilité des chercheurs/ethnographes qui ont réalisé les travaux et de la générosité de leurs interlocuteurs. Ces traces, des photographies et des extraits d’échanges et de performances, proposent une identité générationnelle ouest-africaine forte : des jeunes et des enfants réalistes et dynamiques