Scalable Group Level Probabilistic Sparse Factor Analysis

Many data-driven approaches exist to extract neural representations of functional magnetic resonance imaging (fMRI) data, but most of them lack a proper probabilistic formulation. We propose a group level scalable probabilistic sparse factor analysis (psFA) allowing spatially sparse maps, component pruning using automatic relevance determination (ARD) and subject specific heteroscedastic spatial noise modeling. For task-based and resting state fMRI, we show that the sparsity constraint gives rise to components similar to those obtained by group independent component analysis. The noise modeling shows that noise is reduced in areas typically associated with activation by the experimental design. The psFA model identifies sparse components and the probabilistic setting provides a natural way to handle parameter uncertainties. The variational Bayesian framework easily extends to more complex noise models than the presently considered.Comment: 10 pages plus 5 pages appendix, Submitted to ICASSP 1

AMPK and insulin action--responses to ageing and high fat diet.

The 5'-AMP-activated protein kinase (AMPK) is considered "a metabolic master-switch" in skeletal muscle reducing ATP- consuming processes whilst stimulating ATP regeneration. Within recent years, AMPK has also been proposed as a potential target to attenuate insulin resistance, although the exact role of AMPK is not well understood. Here we hypothesized that mice lacking α2AMPK activity in muscle would be more susceptible to develop insulin resistance associated with ageing alone or in combination with high fat diet. Young (∼4 month) or old (∼18 month) wild type and muscle specific α2AMPK kinase-dead mice on chow diet as well as old mice on 17 weeks of high fat diet were studied for whole body glucose homeostasis (OGTT, ITT and HOMA-IR), insulin signaling and insulin-stimulated glucose uptake in muscle. We demonstrate that high fat diet in old mice results in impaired glucose homeostasis and insulin stimulated glucose uptake in both the soleus and extensor digitorum longus muscle, coinciding with reduced insulin signaling at the level of Akt (pSer473 and pThr308), TBC1D1 (pThr590) and TBC1D4 (pThr642). In contrast to our hypothesis, the impact of ageing and high fat diet on insulin action was not worsened in mice lacking functional α2AMPK in muscle. It is concluded that α2AMPK deficiency in mouse skeletal muscle does not cause muscle insulin resistance in young and old mice and does not exacerbate obesity-induced insulin resistance in old mice suggesting that decreased α2AMPK activity does not increase susceptibility for insulin resistance in skeletal muscle

Body composition and metabolic characterization.

<p>Body composition, VO2 and RER were determined in young and old AMPK KD mice and WT littermates on chow diet (CHO) or in old mice after 17 weeks of high fat diet (FA).</p>‡<p>Main effect of fasting vs. fed conditions, p<0.001.</p>#<p>Main effect of diet, p<0.01.</p>$<p>Main effect of age, p<0.005.</p>†<p>Main effect of genotype, p<0.05. Values are means ± SE. n = 7–16.</p

Akt Ser473 phosphorylation.

<p>Basal (0 µU/ml) and insulin (500 µU/ml) stimulated Akt Ser473 phosphorylation measured by Western blot analyses in m. Soleus (SOL) and m. Extensor Digitorum Longus (EDL). Measurements were made in young and old AMPK KD mice and WT littermates on chow diet (CHO) or in old mice after 17 weeks of high fat diet (FA). *: Main effect of insulin, p<0.001. ‡: Interaction between diet and insulin action, p<0.001. †: Main effect of genotype in either CHO fed or Old groups, p<0.05. Values are means ± SE. n = 11–15.</p

<i>In vitro</i> glucose uptake.

<p>Basal (0 µU/ml) and insulin (500 µU/ml) stimulated glucose uptake measured <i>in vitro</i> in m. Soleus (SOL) and m. Extensor Digitorum Longus (EDL). Measurements were made in young and old AMPK KD mice and WT littermates on chow diet (CHO) or in old mice after 17 weeks of high fat diet (FA). *: Main effect of insulin, p<0.001. #: Main effect of diet, p<0,001. ‡: Interaction between diet and insulin action, p<0.001. Values are means ± SE. n = 11–15.</p

Characterization of whole body glucose homeostasis.

<p>(A) OGGT (2 g/kg body weight) and C) ITT (0.5 U/kg body weight) were conducted after 5 hours of fasting. Values are expressed as AUC based on weighted means of all glucose measurements (t = −15, 20, 40, 60, 90 and 120 min). <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0062338#pone-0062338-g001" target="_blank">Figure 1B</a> shows plasma insulin concentrations before (0 min) and after 20 min in response to the OGTT. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0062338#pone-0062338-g001" target="_blank">Figure 1D</a> illustrates calculated HOMA-IR index values based on basal glucose and insulin concentrations obtained after 5 hour of fasting. Measurements were made in young and old AMPK KD mice and WT littermates on chow diet (CHO) or in old mice after 17 weeks of high fat diet (FA). $: Main effect of age, p<0.001. #: Main effect of diet, p<0,001. †: Main effect of genotype, p<0.005. ‡: Main effect of time, p<0.001. Values are means ± SE. n = 11–17.</p

TBC1D1 Thr590 phosphorylation.

<p>Basal (0 µU/ml) and insulin (500 µU/ml) stimulated TBC1D1 Thr590 phosphorylation measured by Western blot analyses in m. Soleus (SOL) and m. Extensor Digitorum Longus (EDL). Measurements were made in young and old AMPK KD mice and WT littermates on chow diet (CHO) or in old mice after 17 weeks of high fat diet (FA). *: Main effect of insulin, p<0.001. #: Main effect of diet p<0.001. †: Main effect of genotype, p<0.05. Values are means ± SE. n = 11–15.</p

Protein content of GLUT4, HK2, TBC1D1, TBC1D4, Akt2 and TRB-3.

<p>Protein content of GLUT4 (A), HK2 (B), TBC1D1(C), TBC1D4 (D), Akt2 (E) and TRB-3 (F) was measured by Western blot analyses in basal muscle samples from m. Soleus (SOL) and m. Extensor Digitorum Longus (EDL). Measurements were made in young and old AMPK KD mice and WT littermates on chow diet (CHO) or in old mice after 17 weeks of high fat diet (FA). #: Main effect of diet, p<0.05. $: Main effect of age, p<0.05. †: Main effect of genotype, p<0.05. Values are means ± SE. n = 11–15.</p