Characterising the inhibitory actions of ceramide upon insulin signaling in different skeletal muscle cell models:a mechanistic insight

International audienceCeramides are known to promote insulin resistance in a number of metabolically important tissues including skeletal muscle, the predominant site of insulin-stimulated glucose disposal. Depending on cell type, these lipid intermediates have been shown to inhibit protein kinase B (PKB/Akt), a key mediator of the metabolic actions of insulin, via two distinct pathways: one involving the action of atypical protein kinase C (aPKC) isoforms, and the second dependent on protein phosphatase-2A (PP2A). The main aim of this study was to explore the mechanisms by which ceramide inhibits PKB/Akt in three different skeletal muscle-derived cell culture models; rat L6 myotubes, mouse C2C12 myotubes and primary human skeletal muscle cells. Our findings indicate that the mechanism by which ceramide acts to repress PKB/Akt is related to the myocellular abundance of caveolin-enriched domains (CEM) present at the plasma membrane. Here, we show that ceramide-enriched-CEMs are markedly more abundant in L6 myotubes compared to C2C12 myotubes, consistent with their previously reported role in coordinating aPKC-directed repression of PKB/Akt in L6 muscle cells. In contrast, a PP2A-dependent pathway predominantly mediates ceramide-induced inhibition of PKB/Akt in C2C12 myotubes. In addition, we demonstrate for the first time that ceramide engages an aPKC-dependent pathway to suppress insulin-induced PKB/Akt activation in palmitate-treated cultured human muscle cells as well as in muscle cells from diabetic patients. Collectively, this work identifies key mechanistic differences, which may be linked to variations in plasma membrane composition, underlying the insulin-desensitising effects of ceramide in different skeletal muscle cell models that are extensively used in signal transduction and metabolic studies

Obesity and male breast cancer: Provocative parallels?

While rare compared to female breast cancer the incidence of male breast cancer (MBC) has increased in the last few decades. Without comprehensive epidemiological studies, the explanation for the increased incidence of MBC can only be speculated. Nevertheless, one of the most worrying global public health issues is the exponential rise in the number of overweight and obese people, especially in the developed world. Although obesity is not considered an established risk factor for MBC, studies have shown increased incidence among obese individuals. With this observation in mind, this article highlights the correlation between the increased incidence of MBC and the current trends in obesity as a growing problem in the 21st century, including how this may impact treatment. With MBC becoming more prominent we put forward the notion that, not only is obesity a risk factor for MBC, but that increasing obesity trends are a contributing factor to its increased incidence

Vestibular signal processing in a subject with somatosensory deafferentation: The case of sitting posture

<p>Abstract</p> <p>Background</p> <p>The vestibular system of the inner ear provides information about head translation/rotation in space and about the orientation of the head with respect to the gravitoinertial vector. It also largely contributes to the control of posture through vestibulospinal pathways. Testing an individual severely deprived of somatosensory information below the nose, we investigated if equilibrium can be maintained while seated on the sole basis of this information.</p> <p>Results</p> <p>Although she was unstable, the deafferented subject (DS) was able to remain seated with the eyes closed in the absence of feet, arm and back supports. However, with the head unconsciously rotated towards the left or right shoulder, the DS's instability markedly increased. Small electrical stimulations of the vestibular apparatus produced large body tilts in the DS contrary to control subjects who did not show clear postural responses to the stimulations.</p> <p>Conclusion</p> <p>The results of the present experiment show that in the lack of vision and somatosensory information, vestibular signal processing allows the maintenance of an active sitting posture (i.e. without back or side rests). When head orientation changes with respect to the trunk, in the absence of vision, the lack of cervical information prevents the transformation of the head-centered vestibular information into a trunk-centered frame of reference of body motion. For the normal subjects, this latter frame of reference enables proper postural adjustments through vestibular signal processing, irrespectively of the orientation of the head with respect to the trunk.</p

Identifying Changes in Selective Constraints: Host Shifts in Influenza

The natural reservoir of Influenza A is waterfowl. Normally, waterfowl viruses are not adapted to infect and spread in the human population. Sometimes, through reassortment or through whole host shift events, genetic material from waterfowl viruses is introduced into the human population causing worldwide pandemics. Identifying which mutations allow viruses from avian origin to spread successfully in the human population is of great importance in predicting and controlling influenza pandemics. Here we describe a novel approach to identify such mutations. We use a sitewise non-homogeneous phylogenetic model that explicitly takes into account differences in the equilibrium frequencies of amino acids in different hosts and locations. We identify 172 amino acid sites with strong support and 518 sites with moderate support of different selection constraints in human and avian viruses. The sites that we identify provide an invaluable resource to experimental virologists studying adaptation of avian flu viruses to the human host. Identification of the sequence changes necessary for host shifts would help us predict the pandemic potential of various strains. The method is of broad applicability to investigating changes in selective constraints when the timing of the changes is known

Factors associated with dropout from treatment for eating disorders: a comprehensive literature review

<p>Abstract</p> <p>Background</p> <p>Dropout (DO) is common in the treatment of eating disorders (EDs), but the reasons for this phenomenon remain unclear. This study is an extensive review of the literature regarding DO predictors in EDs.</p> <p>Methods</p> <p>All papers in PubMed, PsycINFO and Cochrane Library (1980-2009) were considered. Methodological issues and detailed results were analysed for each paper. After selection according to inclusion criteria, 26 studies were reviewed.</p> <p>Results</p> <p>The dropout rates ranged from 20.2% to 51% (inpatient) and from 29% to 73% (outpatient). Predictors of dropout were inconsistent due to methodological flaws and limited sample sizes. There is no evidence that baseline ED clinical severity, psychiatric comorbidity or treatment issues affect dropout. The most consistent predictor is the binge-purging subtype of anorexia nervosa. Good evidence exists that two psychological traits (high maturity fear and impulsivity) and two personality dimensions (low self-directedness, low cooperativeness) are related to dropout.</p> <p>Conclusion</p> <p>Implications for clinical practice and areas for further research are discussed. Particularly, these results highlight the need for a shared definition of dropout in the treatment of eating disorders for both inpatient and outpatient settings. Moreover, the assessment of personality dimensions (impulse control, self-efficacy, maturity fear and others) as liability factors for dropout seems an important issue for creating specific strategies to reduce the dropout phenomenon in eating disorders.</p

Mother knows best: occurrence and associations of resighted humpback whales suggest maternally derived fidelity to a southern hemisphere coastal feeding ground

Site fidelity is common among migratory cetaceans, including humpback whales (Megaptera novaeangliae). In the Northern Hemisphere it has been found that fidelity to humpback whale feeding grounds is transferred maternally but this has never been shown for the species in the Southern Hemisphere. We examined this in a unique feeding area off west South Africa using resighting data of 68 individually identified humpback whales by means of photographic (tail flukes and dorsal fins) and/or molecular methods (microsatellite genotyping) over an 18 year span. We found short-term association patterns and recurrent visits typical of other feeding grounds. Males and females had different seasonality of attendance. Significant female-dominated presence corresponded to timing of an expected influx of females on their southward migration from the breeding ground: firstly non-nursing (possibly pregnant) females in mid-spring, and mothers and calves in mid-to late summer. The potential benefit of this mid-latitude feeding area for females is illustrated by a record of a cow with known age of at least 23 years that produced calves in three consecutive years, each of which survived to at least six months of age: the first record of successful post-partum ovulation for this species in the Southern Hemisphere. We recorded association of a weaned calf with its mother, and a recurring association between a non-lactating female and male over more than two years. Moreover, three animals first identified as calves returned to the same area in subsequent years, sometimes on the same day as their mothers. This, together with numerous Parent-Offspring relations detected genetically among and between resighted and non-resighted whales is strongly suggestive of maternally derived site fidelity at a small spatial scale by a small sub-population of humpback whales.National Research Foundation (NRF), South Africa [2047517]; PADI Project AWARE (UK) [095]; Earthwatch Institute (project title "Whales of South Africa"