Ablation of PGC-1β Results in Defective Mitochondrial Activity, Thermogenesis, Hepatic Function, and Cardiac Performance

The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1β (PGC-1β) has been implicated in important metabolic processes. A mouse lacking PGC-1β (PGC1βKO) was generated and phenotyped using physiological, molecular, and bioinformatic approaches. PGC1βKO mice are generally viable and metabolically healthy. Using systems biology, we identified a general defect in the expression of genes involved in mitochondrial function and, specifically, the electron transport chain. This defect correlated with reduced mitochondrial volume fraction in soleus muscle and heart, but not brown adipose tissue (BAT). Under ambient temperature conditions, PGC-1β ablation was partially compensated by up-regulation of PGC-1α in BAT and white adipose tissue (WAT) that lead to increased thermogenesis, reduced body weight, and reduced fat mass. Despite their decreased fat mass, PGC1βKO mice had hypertrophic adipocytes in WAT. The thermogenic role of PGC-1β was identified in thermoneutral and cold-adapted conditions by inadequate responses to norepinephrine injection. Furthermore, PGC1βKO hearts showed a blunted chronotropic response to dobutamine stimulation, and isolated soleus muscle fibres from PGC1βKO mice have impaired mitochondrial function. Lack of PGC-1β also impaired hepatic lipid metabolism in response to acute high fat dietary loads, resulting in hepatic steatosis and reduced lipoprotein-associated triglyceride and cholesterol content. Altogether, our data suggest that PGC-1β plays a general role in controlling basal mitochondrial function and also participates in tissue-specific adaptive responses during metabolic stress

Increasing Incidence of Geomyces destructans Fungus in Bats from the Czech Republic and Slovakia

BACKGROUND: White-nose syndrome is a disease of hibernating insectivorous bats associated with the fungus Geomyces destructans. It first appeared in North America in 2006, where over a million bats died since then. In Europe, G. destructans was first identified in France in 2009. Its distribution, infection dynamics, and effects on hibernating bats in Europe are largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: We screened hibernacula in the Czech Republic and Slovakia for the presence of the fungus during the winter seasons of 2008/2009 and 2009/2010. In winter 2009/2010, we found infected bats in 76 out of 98 surveyed sites, in which the majority had been previously negative. A photographic record of over 6000 hibernating bats, taken since 1994, revealed bats with fungal growths since 1995; however, the incidence of such bats increased in Myotis myotis from 2% in 2007 to 14% by 2010. Microscopic, cultivation and molecular genetic evaluations confirmed the identity of the recently sampled fungus as G. destructans, and demonstrated its continuous distribution in the studied area. At the end of the hibernation season we recorded pathologic changes in the skin of the affected bats, from which the fungus was isolated. We registered no mass mortality caused by the fungus, and the recorded population decline in the last two years of the most affected species, M. myotis, is within the population trend prediction interval. CONCLUSIONS/SIGNIFICANCE: G. destructans was found to be widespread in the Czech Republic and Slovakia, with an epizootic incidence in bats during the most recent years. Further development of the situation urgently requires a detailed pan-European monitoring scheme

UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality

SummaryAs original studies of UCP1-ablated mice failed to demonstrate an obesogenic effect, alternative mechanisms for adaptive adrenergic thermogenesis have been sought. However, we demonstrate here that in C57Bl6 mice exempt from thermal stress (i.e., kept at thermoneutrality), UCP1 ablation in itself induced obesity, even in mice fed control diet, and vastly augmented diet-induced obesity (high-fat diet); i.e., the mice exhibited increased metabolic efficiency. In wild-type mice, high-fat diet increased norepinephrine-induced thermogenesis; i.e., diet-induced thermogenesis was observed, but no such effect was observed in UCP1-ablated mice, demonstrating that diet-induced thermogenesis fully emanates from UCP1 activity. We conclude that ambient temperature is qualitatively determinative for the outcome of metabolic studies, that no other protein and no other mechanism can substitute for UCP1 in mediating diet-induced adrenergic thermogenesis, and that UCP1 activity can be determinative for obesity development in mice and possibly in humans

Hypoxia-independent angiogenesis in adipose tissues during cold acclimation

The molecular mechanisms of angiogenesis in relation to adipose tissue metabolism remain poorly understood. Here, we show that exposure of mice to cold led to activation of angiogenesis in both white and brown adipose tissues. In the inguinal depot, cold exposure resulted in elevated expression levels of brown-fat-associated proteins, including uncoupling protein-1 (UCP1) and PGC-1 alpha. Proangiogenic factors such as VEGF were upregulated, and endogenous angiogenesis inhibitors, including thrombospondin, were downregulated. In wild-type mice, the adipose tissues became hypoxic during cold exposure; in UCP1(-/-) mice, hypoxia did not occur, but, remarkably, the augmented angiogenesis was unaltered and was thus hypoxia independent. Intriguingly, VEGFR2 blockage abolished the cold-induced angiogenesis and significantly impaired nonshivering thermogenesis capacity. Unexpectedly, VEGFR1 blockage resulted in the opposite effects: increased adipose vascularity and nonshivering thermogenesis capacity. Our findings have conceptual implications concerning application of angiogenesis modulators for treatment of obesity and metabolic disorders.Cell BiologyEndocrinology & MetabolismSCI(E)0ARTICLE199-109

The PGC1βKO Mouse Has Altered Metabolism under Standard Environmental Conditions

<div><p>(A) Growth curves of male (left panel) and female (right panel) mice on normal diet. WT (solid circles) and PGC1βKO (open circles) mice, <i>n</i> = 18–21 mice per group.</p> <p>(B) Assessment of fat content by DEXA in 8- and 32-wk-old male WT (solid bars) and PGC1βKO mice (open bars), <i>n</i> = 8–12 mice per group.</p> <p>(C) Representative histological sections of tissues from WAT (<i>n</i> = 6).</p> <p>(D) Size distribution of adipocytes from WT and PGC1βKO mice. Two fields from each section from epididymal adipose tissue depot (<i>n</i> = 4 mice per genotype) were analysed to obtain the mean cell area per animal.</p> <p>(E) Epididymal WAT gene expression from 12-wk-old PGC1βKO (white bars) and WT littermates (black bars). Individual measurements are standardized using 18S, and then the average of the WT group was set to 1. <i>n</i> = 5–8 mice per group.</p></div

PGC1βKO Hearts Display a Blunted Heart Rate Response to Dobutamine Stimulation In Vivo

<div><p>PGC1βKO and WT littermates (male, 26-wk-old) were treated as stated in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0040369#s4" target="_blank">Material and Methods</a> and infused with 10 or 40 ng/min/g BW dobutamine to measure in vivo hemodynamic responses WT, solid line; KO, dashed line.</p> <p>(A) Percentage change in heart rate from basal during dobutamine infusion.</p> <p>(B and C) Measurement of ventricular performance, <i>dP</i>/<i>dt</i>, during infusion. The arrow marks the increase in dobutamine concentration in the infusion from 10 to 40 ng/min/g BW. <i>n</i> = 5 mice per genotype.</p></div

PGC1βKO Mice Demonstrate Increased Liver Mass and Development of Fatty Liver after 24 h HFD

<div><p>Female 8-wk-old mice were given normal chow or Surwit HFD (Sur) for 24 h. Tissues were then collected for analysis.</p> <p>(A) Liver weight, as standardized by body weight (LW/BW) for WT (black bars) and PGC1βKO (white bars) after 24 h diets.</p> <p>(B) Representative histological sections from mice given normal or Surwit diet for 24 h. <i>n</i> = 6–7 mice per group.</p></div

PGC-1β Ablation Results in Major Changes in BAT Metabolic Gene Expression

<p>Expression levels of mRNA were assessed on interscapular BAT from 12-wk-old male WT (black bars) and PGC1βKO (white bars) mice. Individual measurements are standardized using 18S, and the average of the WT group set to 1. <i>n</i> = 5–7 mice per group.</p