Metabolic suppression in mammalian hibernation: the role of mitochondria.

Hibernation evolved in some small mammals that live in cold environments, presumably to conserve energy when food supplies are low. Throughout the winter, hibernators cycle spontaneously between torpor, with low metabolism and near-freezing body temperatures, and euthermia, with high metabolism and body temperatures near 37°C. Understanding the mechanisms underlying this natural model of extreme metabolic plasticity is important for fundamental and applied science. During entrance into torpor, reductions in metabolic rate begin before body temperatures fall, even when thermogenesis is not active, suggesting active mechanisms of metabolic suppression, rather than passive thermal effects. Mitochondrial respiration is suppressed during torpor, especially when measured in liver mitochondria fuelled with succinate at 37°C in vitro. This suppression of mitochondrial metabolism appears to be invoked quickly during entrance into torpor when body temperature is high, but is reversed slowly during arousal when body temperature is low. This pattern may reflect body temperature-sensitive, enzyme-mediated post-translational modifications of oxidative phosphorylation complexes, for instance by phosphorylation or acetylation

Metabolism of brain cortex and cardiac muscle mitochondria in hibernating 13-lined ground squirrels Ictidomys tridecemlineatus.

During bouts of torpor, mitochondrial metabolism is known to be suppressed in the liver and skeletal muscle of hibernating mammals. This suppression is rapidly reversed during interbout euthermic (IBE) phases, when whole-animal metabolic rate and body temperature (T(b)) return spontaneously to euthermic levels. Such mitochondrial suppression may contribute significantly to energy savings, but the capacity of other tissues to suppress mitochondrial metabolism remains unclear. In this study we compared the metabolism of mitochondria from brain cortex and left ventricular cardiac muscle between animals sampled while torpid (stable T(b) near 5°C) and in IBE (stable T(b) near 37°C). Instead of isolating mitochondria using the traditional methods of homogenization and centrifugation, we permeabilized tissue slices with saponin, allowing energetic substrates and inhibitors to access mitochondria. No significant differences in state 3 or state 4 respiration were observed between torpor and IBE in either tissue. In general, succinate produced the highest oxidation rates followed by pyruvate and then glutamate, palmitoyl carnitine, and β-hydroxybutyrate. These findings suggest that there is no suppression of mitochondrial metabolism or change in substrate preference in these two tissues despite the large changes in whole-animal metabolism seen between torpor and IBE

Altered fetal skeletal muscle nutrient metabolism following an adverse in utero environment and the modulation of later life insulin sensitivity

The importance of the in utero environment as a contributor to later life metabolic disease has been demonstrated in both human and animal studies. In this review, we consider how disruption of normal fetal growth may impact skeletal muscle metabolic development, ultimately leading to insulin resistance and decreased insulin sensitivity, a key precursor to later life metabolic disease. In cases of intrauterine growth restriction (IUGR) associated with hypoxia, where the fetus fails to reach its full growth potential, low birth weight (LBW) is often the outcome, and early in postnatal life, LBW individuals display modifications in the insulin-signaling pathway, a critical precursor to insulin resistance. In this review, we will present literature detailing the classical development of insulin resistance in IUGR, but also discuss how this impaired development, when challenged with a postnatal Western diet, may potentially contribute to the development of later life insulin resistance. Considering the important role of the skeletal muscle in insulin resistance pathogenesis, understanding the in utero programmed origins of skeletal muscle deficiencies in insulin sensitivity and how they may interact with an adverse postnatal environment, is an important step in highlighting potential therapeutic options for LBW offspring born of pregnancies characterized by placental insufficiency

Regulation of succinate-fuelled mitochondrial respiration in liver and skeletal muscle of hibernating thirteen-lined ground squirrels.

Hibernating ground squirrels (Ictidomys tridecemlineatus) alternate between two distinct metabolic states throughout winter: torpor, during which metabolic rate (MR) and body temperature (Tb) are considerably suppressed, and interbout euthermia (IBE), during which MR and Tb briefly return to euthermic levels. Previous studies showed suppression of succinate-fuelled respiration during torpor in liver and skeletal muscle mitochondria; however, these studies used only a single, saturating succinate concentration. Therefore, they could not address whether mitochondrial metabolic suppression occurs under physiological substrate concentrations or whether differences in the kinetics of mitochondrial responses to changing substrate concentration might also contribute to mitochondrial metabolic regulation during torpor. The present study confirmed that succinate oxidation is reduced during torpor in liver and skeletal muscle at 37 and 10°C over a 100-fold range of succinate concentrations. At 37°C, this suppression resulted from inhibition of succinate dehydrogenase (SDH), which had a greater affinity for oxaloacetate (an SDH inhibitor) during torpor. At 10°C, SDH was not inhibited, suggesting that SDH inhibition initiates but does not maintain mitochondrial suppression during torpor. Moreover, in both liver and skeletal muscle, mitochondria from torpid animals maintained relatively higher respiration rates at low succinate concentrations, which reduces the extent of energy savings that can be achieved during torpor, but may also maintain mitochondrial oxidative capacity above some lower critical threshold, thereby preventing cellular and/or mitochondrial injury during torpor and facilitating rapid recruitment of oxidative capacity during arousal

Mind-Body Skills Groups for Adolescents with Depression in Primary Care: A Pilot Study

Objective: To determine acceptability and preliminary effectiveness of Mind-Body Skills Groups (MBSGs) as a treatment for depressed adolescents in primary care. Methods: A single arm clinical trial was conducted. A 10-week MBSG program was implemented in primary care. Participants completed self-report measures at baseline, post-intervention, and 3-months following the MBSGs. Measures included the Children’s Depression Inventory-2, Suicidal Ideation Questionnaire, Mindful Attention Awareness Scale, Self-Efficacy for Depressed Adolescents, rumination subscale of the Children’s Response Style Questionnaire, and a short acceptability questionnaire. Results: Participants included 43 adolescents. The total depression scores significantly improved following the MBSG intervention and continued to improve significantly from post-treatment to follow-up. Mindfulness, self-efficacy, rumination, and suicidal ideation all had significant improvement following the intervention. Acceptability of the program was strong, and attendance was excellent. Discussion: Preliminary evidence suggests that MBSGs are an acceptable treatment for primary care settings and lead to improved depression symptoms in adolescents.Sandra Eskenazi Mental Health Center and the Herbert Simon Family Foundation (070241-00002B

Identification of a lipid-rich depot in the orbital cavity of the thirteen-lined ground squirrel

We discovered a previously undescribed orbital lipid depot in the thirteen-lined ground squirrel during the first ever magnetic resonance image (MRI) of this common experimental model of mammalian hibernation. In animals housed at constant ambient temperatures (5°C or 25°C, 12 h:12 h light:dark photoperiod), the volume of this depot increased in the autumn and decreased in the spring, suggesting an endogenous circannual pattern. Water-fat MRI revealed that throughout the year this depot is composed of ∼40% lipid, similar to brown adipose tissue (BAT). During arousal from torpor, thermal images showed higher surface temperatures near this depot before the rest of the head warmed, suggesting a thermoregulatory function. This depot, however, does not contain uncoupling protein 1, a BAT biomarker, or uncoupling protein 3. Histology shows blood vessels in close proximity to each other, suggesting it may serve as a vascular rete, perhaps to preferentially warm the eye and brain during arousals

Nominal Logic Programming

Nominal logic is an extension of first-order logic which provides a simple foundation for formalizing and reasoning about abstract syntax modulo consistent renaming of bound names (that is, alpha-equivalence). This article investigates logic programming based on nominal logic. We describe some typical nominal logic programs, and develop the model-theoretic, proof-theoretic, and operational semantics of such programs. Besides being of interest for ensuring the correct behavior of implementations, these results provide a rigorous foundation for techniques for analysis and reasoning about nominal logic programs, as we illustrate via examples.Comment: 46 pages; 19 page appendix; 13 figures. Revised journal submission as of July 23, 200

Identification of a lipid-rich depot in the orbital cavity of the 13-lined ground squirrel

We discovered a previously undescribed orbital lipid depot in the 13-lined ground squirrel during the first ever magnetic resonance image (MRI) of this common experimental model of mammalian hibernation. In animals housed at constant ambient temperatures (5ºC or 25ºC, 12h L:12h D photoperiod) the volume of this depot increased in the autumn and decreased in the spring, suggesting an endogenous circannual pattern. Water-fat MRI revealed that throughout the year this depot is composed of ~40% lipid, similar to brown adipose tissue (BAT). During arousal from torpor, thermal images showed higher surface temperatures near this depot before the rest of the head warmed, suggesting a thermoregulatory function. This depot, however, does not contain uncoupling protein 1, a BAT biomarker, or uncoupling protein 3. Histology shows blood vessels in close proximity to each other, suggesting it may serve as a vascular rete, perhaps to preferentially warm the eye and brain during arousals