Defective STIM-mediated store operated Ca2+ entry in hepatocytes leads to metabolic dysfunction in obesity

Defective Ca2+ handling is a key mechanism underlying hepatic endoplasmic reticulum (ER) dysfunction in obesity. ER Ca2+ level is in part monitored by the store-operated Ca2+ entry (SOCE) system, an adaptive mechanism that senses ER luminal Ca2+ concentrations through the STIM proteins and facilitates import of the ion from the extracellular space. Here, we show that hepatocytes from obese mice displayed significantly diminished SOCE as a result of impaired STIM1 translocation, which was associated with aberrant STIM1 O-GlycNAcylation. Primary hepatocytes deficient in STIM1 exhibited elevated cellular stress as well as impaired insulin action, increased glucose production and lipid droplet accumulation. Additionally, mice with acute liver deletion of STIM1 displayed systemic glucose intolerance. Conversely, over-expression of STIM1 in obese mice led to increased SOCE, which was sufficient to improve systemic glucose tolerance. These findings demonstrate that SOCE is an important mechanism for healthy hepatic Ca2+ balance and systemic metabolic control

Comparative Network Analysis of Preterm vs. Full-Term Infant-Mother Interactions

Several studies have reported that interactions of mothers with preterm infants show differential characteristics compared to that of mothers with full-term infants. Interaction of preterm dyads is often reported as less harmonious. However, observations and explanations concerning the underlying mechanisms are inconsistent. In this work 30 preterm and 42 full-term mother-infant dyads were observed at one year of age. Free play interactions were videotaped and coded using a micro-analytic coding system. The video records were coded at one second resolution and studied by a novel approach using network analysis tools. The advantage of our approach is that it reveals the patterns of behavioral transitions in the interactions. We found that the most frequent behavioral transitions are the same in the two groups. However, we have identified several high and lower frequency transitions which occur significantly more often in the preterm or full-term group. Our analysis also suggests that the variability of behavioral transitions is significantly higher in the preterm group. This higher variability is mostly resulted from the diversity of transitions involving non-harmonious behaviors. We have identified a maladaptive pattern in the maternal behavior in the preterm group, involving intrusiveness and disengagement. Application of the approach reported in this paper to longitudinal data could elucidate whether these maladaptive maternal behavioral changes place the infant at risk for later emotional, cognitive and behavioral disturbance

Chronic enrichment of hepatic ER-mitochondria contact sites leads to calcium dependent mitochondrial dysfunction in obesity

Proper function of the endoplasmic reticulum (ER) and mitochondria is critical for cellular homeostasis, and dysfunction at either site has been linked to pathophysiological states including metabolic diseases. Although ER and mitochondria play distinct cellular roles, these organelles also form physical interactions at sites defined as mitochondria associated ER-membranes (MAMs), which are essential for Ca2+, lipid and metabolite exchange. Here we show that in the liver, obesity leads to a significant reorganization of MAMs resulting in mitochondrial Ca2+ overload, compromised mitochondrial oxidative capacity and augmented oxidative stress. Experimental induction of ER-mitochondria interactions results in oxidative stress and impaired metabolic homeostasis, while down-regulation of PACS-2 or IP3R1, proteins important for ER-mitochondria tethering and calcium transport respectively, improves mitochondrial oxidative capacity and insulin sensitivity in obese animals. These findings establish excessive ER-mitochondrial coupling as an essential component of organelle dysfunction in obesity, which may contribute to the development of metabolic pathologies such as insulin resistance

Total effect of mutations of single cells in the tissue.

<p>Starting from three different equilibrated tissues formed by cell division and migration (A), lateral growth (B) and random initial conditions (C), respectively, each cell of the tissue is mutated by the following rule: <i>silenced active</i> or <i>active silenced</i>. The mutated cell is kept in the state it is set to after mutation. Panel (D–F): the color scheme indicates the sum of the activity changes over the entire tissue due to the mutation of one single cell. The lower panels (G–I) display the number of nodes affected by the mutation of the given cell. We note that the effects of mutations in the ordered tissue (A,D,G) are small. The tissues with disordered patches are very sensitive to mutations on the default lines separating these two phases. This is also apparent in the preformed tissue starting with cells being in random initial conditions where a larger effect occurs all along the default boundaries.</p

Tissue growth under cell division where in each cell cycle, a random cell is chosen and multiplied such that the daughter cell is born in the same state as the mother cell.

<p>The new cell pushes existing states in a random direction. The cells are graded from black (active cell) down to light gray (silenced cell). Note that the center of the tissue becomes completely ordered, i.e. each active cell is surrounded by six silenced cells.</p

Behavioral transitions which have at least 0.5 higher transition rates in the full term group.

<p>Results of χ² tests and the corresponding right-tail probability values (1, N = 3593) are shown for each transition. Directions of behavioral transitions are also indicated in the codes (< and >).</p

Disordered patches appear when cells are mutated during tissue growth and when grown with accelerated speed.

<p>(1A–C) Mutations during growth. In 5% of the cell divisions, the mother cell is mutated (and kept) in either a silenced (yellow) or active state (green) state. This creates a tissue with strongly disordered patches. (2A–C) Effect of growth speed on the activity pattern. The equilibration time between each cell cycle is now of the size of the degradation time and is thus much shorter than the equilibration time used in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0048772#pone-0048772-g002" target="_blank">Figure 2</a>. Both disordered and ordered patches now appear side by side in the tissue.</p

Structural features of the preterm and full-term interaction networks.

<p>Structural features of the preterm and full-term interaction networks.</p