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Brown adipose tissue (BAT), a specialized fat that dissipates energy to produce heat, plays an important role in the regulation of energy balance. Two types of thermogenic adipocytes with distinct developmental and anatomical features exist in rodents and humans: classical brown adipocytes and beige (also referred to as brite) adipocytes. While classical brown adipocytes are located mainly in dedicated BAT depots of rodents and infants, beige adipocytes sporadically reside with white adipocytes and emerge in response to certain environmental cues, such as chronic cold exposure, a process often referred to as 'browning' of white adipose tissue. Recent studies indicate the existence of beige adipocytes in adult humans, making this cell type an attractive therapeutic target for obesity and obesity-related diseases, including type 2 diabetes. This Review aims to cover recent progress in our understanding of the anatomical, developmental, and functional characteristics of brown and beige adipocytes and discuss emerging questions, with a special emphasis on adult human BAT., Historical perspective on human BAT Brown adipose tissue (BAT) evolved as a natural defense system against hypothermia in mammals. BAT is composed of a specialized form of adipocytes that contain [...]

The protein content of the diet has long been investigated for its influence on food behavior. High-protein diets promote satiety and reduce calorie intake, whereas results for low-protein diets are more contradictory and less established. Protein sensing might take place in the oral cavity or in the post-oral gastrointestinal tract, where specific receptors have been found. Protein signaling to the brain may act through the vagal nerve and involve gastric hormones, such as cholecystokinin and peptide YY. Other pathways are post-absorptive signaling and the direct influence of brain levels of amino acids. High-protein diet enhances the activity of brain satiety centers, mainly the nucleus of the solitary tract and arcuate nucleus, although the activity of brain reward centers might also be modified. A better understanding of the role of both homeostatic and hedonic systems is needed to fully describe the influence of protein on food intake. European Journal of Clinical Nutrition (2013) 67, 455-461;doi: 10.1038/ejcn.2013.73 Keywords: protein requirement; feeding behavior; nutrient sensing; reward system, INTRODUCTION Protein is a mandatory constituent of the diet as the source of nitrogen and indispensable amino acids for the body. Insufficient intake of dietary protein is incompatible with growth [...]

The measurement of energy expenditure (EE) is recommended as an important component of comprehensive clinical nutrition assessments in patients with altered metabolic states, who failed to respond to nutrition support and with critical illness that require individualized nutrition support. There is evidence that EE is variable in patients with metabolic diseases, such as chronic renal disease, cirrhosis, HIV, cancer cachexia, cystic fibrosis and patients under intensive care. By using appropriate techniques and interpretations of basal or resting EE, clinicians can facilitate the adequate nutrition support with minimum negative impacts from under-or overfeeding in these patients. This review is based on our current understanding of the different components of EE and the techniques to measure them, and to re-examine advances and challenges to determine energy needs in clinical populations with more focuses on the obese, pediatric and elderly patients. In addition, technological advances have expanded the choices of market-available equipments for assessing EE, which also bring specific challenges and rewards in selecting the right equipment with specific performance criteria. Lastly, analytical considerations of interpreting the results of EE in the context of changing body composition are presented and discussed. European Journal of Clinical Nutrition (2013) 67, 436-442;doi: 10.1038/ejcn.2013.38; published online 27 February 2013 Keywords: basal metabolic rate; indirect calorimetry; oxygen consumption; obesity; children; elderly, INTRODUCTION Establishing a patient's energy expenditure (EE) is an important step in determining nutritional needs. EE has three main components: basal metabolic rate, thermic effect of food or diet-induced thermogenesis, [...]

OBJECTIVES: Factors that influence weight gain during the menopausal transition are not fully understood. The purpose of this study was to investigate changes in energy expenditure (EE) across the menopausal transition. METHODS: In all, 102 premenopausal women (age: 49.9 ± 1.9 years;body mass index: 23.3 ± 2.2 kg/[m.sup.2]) were followed for 5 years. Body composition (dual-energy X-ray absorptiometry), physical activity EE (accelerometer), resting EE and thermic effect of food (indirect calorimetry) were measured annually. RESULTS: Total EE decreased significantly over time in postmenopausal women (P CONCLUSION: These results suggest that menopausal transition is accompanied with a decline in EE mainly characterized by a decrease in physical activity EE and a shift to a more sedentary lifestyle. European Journal of Clinical Nutrition (2013) 67, 407-411; doi: 10.1038/ejcn.2013.33; published online 20 February 2013 Keywords: energy balance; energy expenditure; menopausal transition; body composition, INTRODUCTION The menopausal transition is associated with a risk to increase body weight and adiposity. (1) Weight gain observed in middle-aged women at this time seems to be more closely [...]

BACKGROUND/OBJECTIVES: Physical activity (PA) may have an impact on vitamin D status. The aim of the present study is to assess the contribution of different characteristics of PA (duration, intensity as estimated by energy expenditure, location) to vitamin D status. SUBJECTS/METHODS: The study was conducted in 1255 community-dwelling older men and women of the Longitudinal Aging Study Amsterdam (LASA). Cross-sectional relationships between PA and serum 25-hydroxyvitamin D (25(OH)D) concentrations were examined. RESULTS: Total PA, both indoor and outdoor PA, expressed in kcal/d was positively associated with 25(OH)D in women (P CONCLUSIONS: Daily time spent on total PA is often included when studying the association between sum of PA and 25(OH)D, while our study showed that energy expenditure might be a better unit. Individual types of outdoor PA with a high intensity, such as gardening and cycling, were associated with 25(OH)D. European Journal of Clinical Nutrition (2013) 67, 360-365; doi: 10.1038/ejcn.2013.22; published online 13 February 2013 Keywords: physical activity; outdoor; energy expenditure; vitamin D; aged, INTRODUCTION As reviewed by Pfeifer et al., (1) treatment with vitamin D in vitamin D-deficient states is associated with an increase in muscle strength. However, the reverse, an increase in [...]

Recent studies on diel vertical migration (DVM) of two coregonid species (Coregonus spp.) in Lake Stechlin (Germany) have suggested that the nocturnal distribution of fish is linked with metabolic benefits. We used a spatially explicit bioenergetics-based foraging model to test whether energetic constraints contribute to explain DVM of both species. The newly parameterized model was compared with independent data from Lake Stechlin that covered a 9 month period. Predicted growth rates matched observed growth rates of each fish species reasonably well. The simulation of different migration scenarios showed that even slight changes in night-time depths modified growth rates, primarily owing to temperature-dependent respiration. Fish that performed DVM grew faster than nonmigratory fish that occupied deep hypolimnetic water over a diel cycle. However, the most energy-efficient strategy simulated had fish remaining within the metalimnion. Here, energetic benefits (foraging) clearly outweighed higher energetic costs (respiration) in the warmer waters. Although DVM can be energetically beneficial, it is not the most efficient strategy performed by coregonids in Lake Stechlin. We suggest that multiple factors, rather than bioenergetics efficiency alone, are the evolutionary basis for DVM of many freshwater fish species. Des etudes recentes sur la migration verticale journaliere (DVM) de deux especes de coregonides (Coregonus spp.) dans le lac de Stechlin (Allemagne) indiquent que la repartition des poissons la nuit s'explique par des benefices metaboliques. Un modele de recherche de nourriture base sur la bioenergetique et spatialement explicite nous permet de verifier si les contraintes energetiques expliquent la DVM chez les deux especes. Le modele nouvellement parametre a ete compare a des donnees independantes prelevees au lac de Stechlin sur une periode de neuf mois. Les taux de croissance predits correspondent raisonnablement bien aux taux de croissance observes chez chaque espece de poisson. La simulation de divers scenarios de migration montre que meme de faibles changements dans les profondeurs utilisees la nuit modifient les taux de croissance surtout a cause de la respiration qui est dependante de la temperature. Les poissons qui font une DMV croissent plus rapidement que les poissons non migrateurs qui restent dans les eaux hypolimnetiques profondes durant le cycle journalier. Cependant la strategie la plus efficace energetiquement dans les simulations est celle dans laquelle les poissons demeurent dans le metalimnion. A ces profondeurs, les benefices energetiques (alimentation) surpassent nettement les couts energetiques accrus (respiration) dans les eaux plus chaudes. Bien que la DVM puisse etre avantageuse du point de vue energetique, ce n'est pas la strategie la plus efficace que les coregones utilisent dans le lac de Stechlin. Nous croyons que c'est une multitude de facteurs plutot que la seule efficacite energetique qui est la base evolutive de la DVM chez plusieurs especes de poissons d'eau douce. [Traduit par la Redaction], Introduction Diel vertical migration (DVM) is a behavioral strategy commonly observed in many aquatic organisms (Brett 1971a; Lampert 1989; Gjelland et al. 2009). The usual DVM pattern is to stay [...]

In addition to its role in reproduction, estradiol-17β is critical to the regulation of energy balance and body weight. Estrogen receptor α-null ([Erα.sup.-/-]) mutant mice develop an obese state characterized by decreased energy expenditure, decreased locomotion, increased adiposity, altered glucose homeostasis, and hyperleptinemia. Such features are reminiscent of the propensity of postmenopausal women to develop obesity and type 2 diabetes. The mechanisms by which ERα signaling maintains normal energy balance, however, have remained unclear. Here we used knockin mice that express mutant ERα that can only signal through the noncanonical pathway to assess the role of nonclassical ERα signaling in energy homeostasis. In these mice, we found that nonclassical ERα signaling restored metabolic parameters dysregulated in [Erα.sup.-/-] mutant mice to normal or near-normal values. The rescue of body weight and metabolic function by nonclassical ERα signaling was mediated by normalization of energy expenditure, including voluntary locomotor activity. These findings indicate that nonclassical ERα signaling mediates major effects of estradiol-17β on energy balance, raising the possibility that selective ERα agonists may be developed to reduce the risks of obesity and metabolic disturbances in postmenopausal women., Introduction In addition to its critical functions as a reproductive hormone, estradiol-17β ([E.sub.2]) plays a vital role in the regulation of energy balance and body weight (1). Estrogen deficiency at [...]

Huntington disease (HD) is an autosomal dominant neurodegenerative disease with complete penetrance. Although the understanding of the cellular mechanisms that drive neurodegeneration in HD and account for the characteristic pattern of neuronal vulnerability is incomplete, defects in energy metabolism, particularly mitochondrial function, represent a common thread in studies of HD pathogenesis in humans and animal models. Here we review the clinical, biochemical, and molecular evidence of an energy deficit in HD and discuss the mechanisms underlying mitochondrial and related alterations., Introduction Huntington disease (HD) is an autosomal dominant neurodegenerative disease with age-dependent complete penetrance. HD is caused by a CAG repeat expansion in the first exon of the HTT gene [...]

Neuropeptide Y receptors are critical regulators of energy homeostasis and are well known for their powerful influence on feeding, but their roles in other important aspects of energy homeostasis, such as energy expenditure and their functional interactions in these processes, are largely unknown. Here we show that mice lacking both Y2 and Y4 receptors exhibited a reduction in adiposity, more prominent in intra-abdominal vs. subcutaneous fat, and an increase in lean mass as determined by dual-energy X-ray absorptiometry. These changes were more pronounced than those seen in mice with Y2 or Y4 receptor single deletion, demonstrating the important roles and synergy of Y2 and Y4 signaling in the regulation of body composition. These changes in body composition occurred without significant changes in food intake, but energy expenditure and physical activity were significantly increased in [Y4.sup.-/-] and particularly in [Y2.sup.-/-] [Y4.sup.-/-] but not in [Y2.sup.-/-] mice, suggesting a critical role of Y4 signaling and synergistic interactions with Y2 signaling in the regulation of energy expenditure and physical activity. [Y2.sup.-/-] and [Y4.sup.-/-] mice also exhibited a decrease in respiratory exchange ratio with no further synergistic decrease in [Y2.sup.-/-][Y4.sup.-/-] mice, suggesting that Y2 and Y4 signaling each play important and independent roles in the regulation of substrate utilization. The synergy between [Y2.sup.-/-] and [Y4.sup.-/-] signaling in regulating fat mass may be related to differences in mitochondrial oxidative capacity, since [Y2.sup.-/-][Y4.sup.-/-] but not [Y2.sup.-/-] or [Y4.sup.-/-] mice showed significant increases in muscle protein levels of peroxisome proliferator-activated receptor (PPAR)[gamma] coactivator (PGC)-1[alpha], and mitochondrial respiratory chain complexes I and III. Taken together, this work demonstrates the critical roles of Y2 and Y4 receptors in the regulation of body composition and energy metabolism, highlighting dual antagonism of Y2 and Y4 receptors as a potentially effective anti-obesity treatment. neuropeptide Y receptors; lipid oxidation; lean and fat tissue mass doi: 10.1152/ajpregu.00345.2010

Nociceptin/orphanin FQ (N/OFQ), the nociceptin opioid peptide (NOP) receptor ligand, increases feeding when injected centrally. Initial data suggest that N/OFQ blocks the development of a conditioned taste aversion (CTA). The current project further characterized the involvement of N/OFQ in the regulation of hunger vs. aversive responses in rats by employing behavioral, immunohistochemical, and real-time PCR methodology. We determined that the same low dose of the NOP antagonist [[Nphe.sup.1]]N/OFQ(1-13)[NH.sub.2] delivered via the lateral ventricle diminishes both N/OFQ-and deprivation-induced feeding. This anorexigenic effect did not stem from aversive consequences, as the antagonist did not cause the development of a CTA. When [[Nphe.sup.1]]N/OFQ(1-13)[NH.sub.2] was administered with LiC1, it moderately delayed extinction of the LiC1-induced CTA. Injection of LiC1 + antagonist compared with LiC1 alone generated an increase in c-Fos immunoreactivity in the central nucleus of the amygdala. The antagonist alone elevated Fos immunoreactivity in the paraventricular nucleus of the hypothalamus, nucleus of the solitary tract, and central nucleus of the amygdala. Hypothalamic NOP mRNA levels were decreased during energy intake restriction induced by aversion, as well as in non-CTA rats food-restricted to match CTA-reduced consumption. Brain stem NOP was upregulated only in aversion. Prepro-N/OFQ mRNA showed a trend toward upregulation in restricted rats (P = 0.068). We conclude that the N/OFQ system promotes feeding by affecting the need to replenish lacking calories and by reducing aversive responsiveness. It may belong to mechanisms that shift a balance between the drive to ingest energy and avoidance of potentially tainted food. food intake; conditioning; hypothalamus; brain stem; amygdala; lithium chloride; NOP receptor; ORLI doi: 10.1152/ajpregu.00556.2009.

Amylin is an important player in the control of nutrient fluxes. Amylin reduces eating via a meal size effect by promoting meal-ending satiation. This effect seems to depend on a direct action in the area postrema (AP), which is an area rich in amylin receptors. Subsequent to the activation of AP neurons, the neural signal is conveyed to the forebrain via relays involving the nucleus of the solitary tract (NTS) and the lateral parabrachial nucleus (IPBN) to the lateral hypothalamic area (LHA) and other hypothalamic nuclei. While the NTS and IPBN seem to be necessary for amylin's eating inhibitory effect, the role of the LHA has not yet been fully investigated. Amylin may also act as an adiposity signal. Plasma levels of amylin are higher in obese individuals, and chronic infusion of amylin into the brain reduces body weight gain and adiposity; chronic infusion of an amylin receptor antagonist into the brain increases body adiposity. Amylin increases energy expenditure in rats; this effect occurs under various experimental conditions after peripheral and central administration. Together, these animal data, but also clinical data in humans, indicate that amylin is a promising candidate for the treatment of obesity; effects are most pronounced when amylin is combined with leptin. Finally, recent findings indicate that amylin acts as a neurotrophic factor in specific brain stem areas. Whether this effect may be relevant under physiological conditions requires further studies. energy expenditure; hindbrain; area postrema; trophic effect; leptin doi: 10.1152/ajpregu.00703.2009.

We tested the hypothesis that food deprivation alters body temperature ([T.sub.b]) responses to bacterial LPS by enhancing inflammatory signaling that decreases [T.sub.b] (cryogenic signaling) rather than by suppressing inflammatory signaling that increases [T.sub.b] (febrigenic signaling). Free-feeding or food-deprived (24 h) rats received LPS at doses (500 and 2,500 [micro]g/kg iv) that are high enough to activate both febrigenic and cryogenic signaling. At these doses, LPS caused fever in rats at an ambient temperature of 30[degrees]C, but produced hypothermia at an ambient temperature of 22[degrees]C. Whereas food deprivation had little effect on LPS fever, it enhanced LPS hypothermia, an effect that was particularly pronounced in rats injected with the higher LPS dose. Enhancement of hypothermia was not due to thermogenic incapacity, since food-deprived rats were fully capable of raising [T.sub.b] in response to the thermogenic drug CL316,243 (1 mg/kg iv). Neither was enhancement of hypothermia associated with altered plasma levels of cytokines (TNF-[alpha], IL-l[beta], and IL-6) or with reduced levels of an anti-inflammatory hormone (corticosterone). The levels of [PGD.sub.2] and [PGE.sub.2] during LPS hypothermia were augmented by food deprivation, although the ratio between them remained unchanged. Food deprivation, however, selectively enhanced the responsiveness of rats to the cryogenic action of [PGD.sub.2] (100 ng icy) without altering the responsiveness to febrigenic [PGE.sub.2] (100 ng icy). These findings support our hypothesis and indicate that cryogenic signaling via [PGD.sub.2] underlies enhancement of LPS hypothermia by food deprivation. energy balance; fasting; inflammation; LPS; prostaglandins; temperature; fever; hypothermia doi: 10.1152/ajpregu.00158.2010.

Structural features of neurons create challenges for effective production and distribution of essential metabolic energy. We investigated how metabolic energy is distributed between cellular compartments in photoreceptors. In avascular retinas, aerobic production of energy occurs only in mitochondria that are located centrally within the photoreceptor. Our findings indicate that metabolic energy flows from these central mitochondria as phosphocreatine toward the photoreceptor's synaptic terminal in darkness. In light, it flows in the opposite direction as ATP toward the outer segment. Consistent with this model, inhibition of creatine kinase in avascular retinas blocks synaptic transmission without influencing outer segment activity. Our findings also reveal how vascularization of neuronal tissue can influence the strategies neurons use for energy management. In vascularized retinas, mitochondria in the synaptic terminals of photoreceptors make neurotransmission less dependent on creatine kinase. Thus, vasculature of the tissue and the intracellular distribution of mitochondria can play key roles in setting the strategy for energy distribution in neurons. energy metabolism | phototransduction doi/10.1073/pnas.1002471107

The purpose of this study was to determine in vivo myocardial energy metabolism and function in a nutritional model of type 2 diabetes. Wistar rats rendered insulin-resistant and mildly hyperglycemic, hyperinsulinemic, and hypertriglyceridemic with a high-fructose/high-fat diet over a 6-wk period with injection of a small dose of streptozotocin (HFHFS) and control rats were studied using micro-PET ([micro]PET) without or with a euglycemic hyperinsulinemic clamp. During glucose clamp, myocardial metabolic rate of glucose measured with [[sup.18]F]fluorodeoxyglucose ([[sup.18]F]FDG) was reduced by ~81% (P < 0.05), whereas myocardial plasma nonesterified fatty acid (NEFA) uptake as determined by [[sup.18]F]fluorothia-6-heptadecanoic acid ([[sup.18]F]FTHA) was not significantly changed in HFHFS vs. control rats. Myocardial oxidative metabolism as assessed by [[sup.11]C]acetate and myocardial perfusion index as assessed by [[sup.13]N]ammonia were similar in both groups, whereas left ventricular ejection fraction as assessed by [micro]PET was reduced by 26% in HFHFS rats (P < 0.05). Without glucose clamp, NEFA uptake was ~40% lower in HFHFS rats (P < 0.05). However, myocardial uptake of [[sup.18]F]FTHA administered by gastric gavage was significantly higher in HFHFS rats (P < 0.05). These abnormalities were associated with reduced Glut4 mRNA expression and increased Cd36 mRNA expression and mitochondrial carnitine palmitoyltransferase 1 activity (P < 0.05). HFHFS rats display type 2 diabetes complicated by left ventricular contractile dysfunction with profound reduction in myocardial glucose utilization, activation of fatty acid metabolic pathways, and preserved myocardial oxidative metabolism, suggesting reduced myocardial metabolic efficiency. In this model, increased myocardial fatty acid exposure likely occurs from circulating triglyceride, but not from circulating plasma NEFA. type 2 diabetes; heart failure; cardiomyopathy; energy metabolism; positron emission tomography; nonesterified fatty acids; glucose metabolism; triacylglycerol doi:10.1152/ajpendo.00560.2009.

Effective control of body weight and energy homeostasis requires stringent regulation of caloric intake and energy expenditure. Gut-brain interactions comprise a central axis for the control of energy homeostasis by integrating the intake of nutrients with an effective utilization of ingested calories either by storage or by expenditure as cellular fuel. Ghrelin, a stomach-derived peptide, is the only known circulating orexigenic hormone. It is acylated with a medium-chain fatty acid by the enzyme ghrelin O-acetyltransferase (GOAT) and displays a broad range of activity, from central control of food intake to peripheral functions such as gastric emptying and insulin secretion. PYY, a peptide produced by L cells of the small intestine and rectum, has been shown to inhibit gut motility and is proposed to stimulate a powerful central satiety response. In recent years, pharmacological studies in animals and clinical studies in humans have contributed to our knowledge of principal ghrelin and PYY actions. However, valuable findings from studies using ghrelin-deficient mice, ghrelin receptor [growth hormone secretagogue receptor-la (GHSR1a)]-deficient mice, double-knockout mice (for ghrelin and GHSR), and GOAT-deficient or -overexpressor mice, as well as mice deficient for PYY or neuropeptide Y receptors have allowed better definition of the actual physiological functions of ghrelin and PYY. This review summarizes findings from mutant mouse studies with emphasis on respective gene knockout and transgenic animals and describes how these studies contribute to the current understanding of how endogenous ghrelin and PYY as two major representatives of endocrine gut-brain communications may regulate energy and glucose homeostasis. peptide YY; neuropeptide Y; ghrelin O-acetyltransferase doi:10.1152/ajpendo.00191.2009.

Recent studies suggest that the cost of muscle contraction may be reduced in old age, which could be an important mediator of age-related differences in muscle fatigue under some circumstances. We used phosphorus magnetic resonance spectroscopy and electrically elicited contractions to examine the energetic cost of ankle dorsiflexion in 9 young (Y; 26 [+ or -] 3.8 yr; mean [+ or -] SD) and 9 older healthy men (O; 72 [+ or -] 4.6). We hypothesized that the energy cost of twitch and tetanic contractions would be lower in O and that this difference would be greater during tetanic contractions at [f.sub.50] (frequency at 50% of peak force from force-frequency relationship) than at 25 Hz. The energy costs of a twitch (O = 0.13 [+ or -] 0.04 mM ATP/twitch, Y = 0.18 [+ or -] 0.06; P = 0.045) and a 60-s tetanus at 25 Hz (O = 1.5 [+ or -] 0.4 mM ATP/s, Y = 2.0 [+ or -] 0.2; P = 0.01) were 27% and 26% lower in O, respectively, while the respective force, time integrals were not different. In contrast, energy cost during a 90-s tetanus at [f.sub.50] (O = 10.9 [+ or -] 2.0 Hz, Y = 14.8 [+ or -] 2.1 Hz; P = 0.002) was 49% lower in O (1.0 [+ or -] 0.2 mM ATP/s) compared with Y (1.9 [+ or -] 0.2; P < 0.001). Y had greater three potentiation during the [f.sub.50] protocol, which accounted for the greater age difference in energy cost at [f.sub.50] compared with 25 Hz. These results provide novel evidence of an age-related difference in human contractile energy cost in vivo and suggest that intramuscular changes contribute to the lower cost of contraction in older muscle. This difference in energetics may provide an important mechanism for the enhanced fatigue resistance often observed in older individuals. bioenergetics; magnetic resonance; dorsiflexors; twitch; ATP; force-frequency doi:10.1152/ajpregu.00713.2009

We investigated the role of glucose-dependent insulintropic polypeptide (GIP) in the regulation of gastric emptying (GE), appetite, energy intake (EI), energy expenditure (EE), plasma levels of triglycerides (TAG), and free fatty acids (FFA) in humans. First, 20 healthy males received intravenous infusion of GIP (0.8 pmol x [kg.sup.-1] x [min.sup.-1]) or saline for 300 min during and after a fixed meal (protocol 1). GE was measured using paracetamol, appetite sensations using visual analog scales, EE using indirect calorimetry, and EI during a subsequent ad libitum meal (at 300 min). Next, 10 healthy males received intravenous infusions of Intralipid, glucose, or Intralipid plus glucose, with and without GIP (1.5 pmol x [kg.sup.-1] x [min.sup.-1]) for 300 min (protocol 2). In protocol 1, GIP did not have any effect on GE, EI, EE, removal of TAG, or FFA and did not influence the subjective feeling of hunger, satiety, fullness or prospective food consumption compared with saline. In protocol 2, no difference was seen in the plasma TAG on Intralipid + GIP/saline and Intralipid + glucose + GIP/saline days. FFA concentrations were lower on Intralipid + glucose + GIP/saline days (P < 0.05) compared with Intralipid + GIP/saline days and on Intralipid + GIP day (P < 0.004) compared with Intralipid + saline day. Insulin increased on all GIP days compared with saline days (P < 0.05). In conclusion, while confirming its insulinotropic effects, these data suggest that GIP does not affect GE, appetite, energy intake, EE, or the clearance rate of the applied TAG formulation in humans. However, both insulin and GIP lower post-Intralipid FFA concentration, GIP probably via stimulation of insulin secretion, increasing FFA reesterification. gastric emptying; energy intake; energy expenditure; appetite; insulin doi:10.1152/ajpendo.00639.2009.

Complex interactions between carbohydrate, fat, and protein metabolism underlie the body's remarkable ability to adapt to a variety of diets. But any imbalances between the intake and utilization rates of these macronutrients will result in changes in body weight and composition. Here, I present the first computational model that simulates how diet perturbations result in adaptations of fuel selection and energy expenditure that predict body weight and composition changes in both obese and nonobese men and women. No model parameters were adjusted to fit these data other than the initial conditions for each subject group (e.g., initial body weight and body fat mass). The model provides the first realistic simulations of how diet perturbations result in adaptations of whole body energy expenditure, fuel selection, and various metabolic fluxes that ultimately give rise to body weight change. The validated model was used to estimate free-living energy intake during a long-term weight loss intervention, a variable that has never previously been measured accurately. mathematical model; energy metabolism; macronutrient metabolism; body composition doi:10.1152/ajpendo.00559.2009.

Akt is involved in the regulation of diverse cellular functions such as cell proliferation, energy metabolism, and apoptosis. Although three Akt isoforms are known, the function of each isoform is poorly understood. To gain a better understanding of each Akt isoform, we examined the subcellular localization and expression of each isoform in transformed and nontransformed cells. Aktl was localized in the cytoplasm, which is in agreement with the currently accepted model that cytoplasmic Akt is translocated and activated at the inner leaflet of the plasma membrane. Interestingly, HEK-293 and HEK-293T cells contained Aktl in the nucleus and cytoplasm, respectively, suggesting that SV40 T-antigen plays a crucial role in the cytoplasmic localization and activation of Aktl in HEK-293T. Akt2 was colocalized with the mitochondria, while Akt3 was localized in both the nucleus and nuclear membrane. The subcellular localization of the Akt isoforms was not substantially altered in response to ionizing radiation or EGF. Furthermore, the ablation of one Akt isoform by small interfering RNA (siRNA) did not alter the subcellular location of the remaining isoforms, suggesting that the major function of one isoform is not compensated for by other isoforms. Together, our data support the notion that Akt2 and Akt3 are regulated at the mitochondrial and nuclear membranes, respectively. The mitochondrial localization of Akt2 raises the possibility that this isoform may be involved in both glucose-based energy metabolism and suppression of apoptosis, two Akt functions previously identified with anti-pan-Akt antibodies. phosphatidylinositol 3-kinase; signal transduction; subcellular localization; mitochondria; radiation doi:10.1152/ajpcell.00375.2009

Background. Falls are the number one cause of unintentional injury in older adults. The protective response of 'breaking the fall' with the outstretched hand is often essential for avoiding injury to the hip and head. In this study, we compared the ability of young and older women to absorb the impact energy of a fall in the outstretched arms. Methods. Twenty young (mean age = 21 years) and 20 older (M = 78 years) women were instructed to slowly lower their body weight, similar to the descent phase of a push-up, from body lean angles ranging from 15[degrees] to 90[degrees]. Measures were acquired of peak upper extremity energy absorption, arm deflection, and hand contact force. Results. On average, older women were able to absorb 45% less energy in the dominant arm than young women (1.7 [+ or -] 0.5% vs 3.1 [+ or -] 0.4% of their body weight x body height; p < .001). These results suggest that, even when both arms participate equally, the average energy content of a forward fall exceeds by 5-fold the average energy that our older participants could absorb and exceeds by 2.7-fold the average energy that young participants could absorb. Conclusions. During a descent movement that simulates fall arrest, the energy-absorbing capacity of the upper extremities in older women is nearly half that of young women. Absorbing the full energy of a fall in the upper extremities is a challenging task even for healthy young women. Strengthening of upper extremity muscles should enhance this ability and presumably reduce the risk for injury to the hip and head during a fail. Key Words: Hip fracture--Wrist fracture--Falls--Biomechanics--Aging. doi: 10.1093/gerona/glp153

Obesity is a major risk factor for chronic disease. A new study in mice reveals that lowering levels of the signaling molecule serotonin outside of the brain reduces obesity and [...]

Chotechuang N, Azzout-Marniche D, Bos C, Chaumontet C, Gausser/s N, Steiler T, Gaudichon C, Tome D. mTOR, AMPK, and GCN2 coordinate the adaptation of hepatic energy metabolic pathways in response to protein intake in the rat. Am J Physiol Endocrinol Metab 297: E 1313-E 1323, 2009. First published September 8, 2009; doi: 10.1152/ajpendo.91000.2008.--Three transduction pathways are involved in amino acid (AA) sensing in liver: mammalian target of rapamycin (roTOR), AMP-activated protein kinase (AMPK), and general control nondepressible kinase 2 (GCN2). However, no study has investigated the involvement of these signaling pathways in hepatic AA sensing. To address the question of liver AA sensing and signaling in response to a high-protein (HP) dietary supply, we investigated the changes in the phosphorylation state of hepatic mTOR (p-mTOR), AMPK[alpha] (p-AMPK[alpha]), and GCN2 (p-GCN2) by Western blotting. In rats fed a HP diet for 14 days, the hepatic p-AMPK[alpha] and p-GCN2 were lower (P < 0.001), and those of both the p-roTOR and eukaryotic initiation factor 4E-binding protein-1 phosphorylation (p-4E-BP1) were higher (P < 0.01) compared with rats receiving a normal protein (NP) diet. In hepatocytes in primary culture, high AA concentration decreased AMPK[alpha] phosphorylation whether insulin was present or not (P < 0.01). Either AAs or insulin can stimulate p-roTOR, but this is not sufficient for 4E-BP1 phosphorylation that requires both (P < 0.01). As expected, branchedchain AAs (BCAA) or leucine stimulated the phosphorylation of mTOR, but both insulin and BCAA or leucine are required for 4E-BP1 phosphorylation. GCN2 phosphorylation was reduced by both AAs and insulin(P < 0.01), suggesting for the first time that the translation inhibitor GCN2 senses not only the AA deficiency but also the AA increase in the liver. The present findings demonstrate that AAs and insulin exert a coordinated action on translation and involved mTOR, AMPK, and GCN2 transduction pathways. mammalian target of rapamycin; adenosine 5'-monophosphate-activated protein kinase; general control nondepressible kinase 2; transduction pathways; translation; high-protein diet doi: 10.1152/ajpendo.91000.2008

Zhang W, Majumder A, Wu X, Mulholland MW. Regulation of food intake and body weight by recombinant proghrelin. Am J Physiol Endocrinol Metab 297: E1269-E1275, 2009. First published September 29, 2009; doi: 10.1152/ajpendo.00337.2009.--Ghrelin is a 28-amino-acid hormone derived from the endoproteolytic processing of its prehormone proghrelin. Although ghrelin has been reported to regulate food intake and body weight, it is still unknown whether proghrelin exercises any biological function. Here we show that recombinant proghrelin alters food intake and energy metabolism in mice. After intraperitoneal administration of recombinant proghrelin (100 nmol/kg body wt), cumulative food intake was significantly increased at days 1, 2, and 3 (6 [+ or -] 0.3, 13 [+ or -] 0.5, and 20 [+ or -] 0.8 g vs. 5 [+ or -] 0.2, 10 [+ or -] 0.2, and 16 [+ or -] 0.3 g of the control mice receiving normal saline, respectively, n = 6, P < 0.05). Twelve-hour cumulative food intake in the light photo period in mice treated with proghrelin increased significantly relative to the control (2.1 [+ or -] 0.04 vs. 1.3 [+ or -] 0.2 g, n = 6, P < 0.05). No change in 12-h cumulative food intake in the dark photo period was observed between mice treated with proghrelin and vehicle (4.2 [+ or -] 0.6 vs. 4.3 [+ or -] 0.6 g, n = 6, P > 0.05). This is associated with a decrease in body weight (0.42 [+ or -] 0.04 g) for mice treated with proghrelin, whereas control animals gained body weight (0.31 [+ or -] 0.04 g). Mice treated with proghrelin demonstrate a significant decrease in respiratory quotient, indicating an increase in fat consumption. Recombinant proghrelin is functionally active with effects on food intake and energy metabolism. ghrelin; proghrelin; food intake; body weight; respiratory quotient doi: 10.1152/ajpendo.00337.2009.

A 400-m runner relies primarily on the lactate system for energy production. Although several running distances and schemes are used in training for this event, it is not clear which one(s) causes maximal activation of the lactate system so as to optimize adaptations of the lactic capacity. This study examined the effect of 4 running workouts differing in distance (300 vs. 400 m) and mode of execution (continuous/single vs. intermittent) on stimulation of the lactate system and biochemical markers of metabolism and muscle damage. Twelve young men performed 4 runs at maximal effort: 300, 3 x 100, 400, and 2 x 200 m. Blood was drawn before and after exercise for the measurement of lactate, glucose, creatinine, and creatine kinase (CK). Average speed was higher (p < 0.001) in the 300- vs. 400-m tests (7.52 [+ or -] 0.50 vs. 7.08 [+ or -] 0.59 m*[s.sup.-1]) and in the intermittent vs. continuous tests (7.45 [+ or -] 0.50 vs. 7.15 [+ or -] 0.58 m*[s.sup.1]). Lactate was higher in the intermittent vs. continuous tests (16.3 [+ or -] 2.2 vs. 15.0 [+ or -] 2.0 mmol*[L.sup.-1], p < 0.05). Serum glucose, creatinine, and CK increased after exercise (p [less than or equal to] 0.001), and glucose was higher in the 400- vs. 300-m trials (5.76 [+ or -] 0.46 vs. 5.33 [+ or -] 0.30 mmol*[L.sup.1], p = 0.032). In conclusion, although all 4 running regimens greatly stimulated the lactate system, it appears that the intermittent workouts are superior compared with continuous ones of the same total distance in increasing the ability for energy production via the lactate system. Thus, intermittent workouts can be successfully used by 400-m athletes to develop specific (speed) endurance and should be considered to precede the continuous runs of racing distance within a macrocycle. KEY WORDS lactate, glucose, creatinine, creatine kinase, intermittent, interval

Chronic restriction of a basic biological need induces adaptations to help meet requisites for survival. The adaptations to chronic restriction of sleep are unknown. A single episode of 10 days of partial sleep loss in rats previously was shown to be tolerated and to result in increased food intake and loss of body weight as principal signs. The purpose of the present experiment was to investigate the extent to which adaptation to chronic sleep restriction would ameliorate short-term effects and result in a changed internal phenotype. Rats were studied during 10 wk of multiple periods of restricted and unrestricted sleep to allow adaptive changes to develop. Control rats received the same ambulatory requirements only consolidated into periods that lessened interruptions of their sleep. The results indicate a latent period of relatively stable food and water intake without weight gain, followed by a dynamic phase marked by enormous increases in food and water intake and progressive loss of body weight, without malabsorption of calories. Severe consequences ensued, marked especially by changes to the connective tissues, and became fatal for two individuals. The most striking changes to internal organs in sleep-restricted rats included lengthening of the small intestine, decreased size of adipocytes, and increased incidence of multilocular adipocytes. Major organs accounted for an increased proportion of total body mass. These changes to internal tissues appear adaptive in response to high energy production, decomposition of lipids, and increased need to absorb nutrients, but ultimately insufficient to compensate for inadequate sleep. sleep rebound; adaptation; metabolism; adiposity; connective tissues; visceral organs doi: 10.1152/ajpregu.00230.2009.

Reduced food intake brings about an adaptive decrease in energy expenditure that contributes to the recidivism of obesity after weight loss. Insulin and leptin inhibit food intake through actions in [...]

The relationship between cardiac energy metabolism and the depression of myocardial performance during oxygen deprivation has remained enigmatic. Here, we combine in vivo [sup.31]P-NMR spectroscopy and MRI to provide the first temporal profile of in vivo cardiac energetics and cardiac performance of an anoxia-tolerant vertebrate, the freshwater turtle (Trachemys scripta) during long-term anoxia exposure (~3 h at 21[degrees]C and 11 days at 5[degrees]C). During anoxia, phosphocreatine (PCr), unbound levels of inorganic phosphate (effective [P.sup.2-.sub.i]), intracellular pH ([pH.sub.i]), and free energy of ATP hydrolysis (dG/d[xi]) exhibited asymptotic patterns of change, indicating that turtle myocardial high-energy phosphate metabolism and energetic state are reset to new, reduced steady states during long-term anoxia exposure. At 21[degrees]C, anoxia caused a reduction in pHi from 7.40 to 7.01, a 69% decrease in PCr and a doubling of effective [P.sup.2-.sub.i]. ATP content remained unchanged, but the free energy of ATP hydrolysis (dG/d[xi]) decreased from -59.6 to -52.5 k J/tool. Even so, none of these cellular changes correlated with the anoxic depression of cardiac performance, suggesting that autonomic cardiac regulation may override putative cellular feedback mechanisms. In contrast, during anoxia at 5[degrees]C, when autonomic cardiac control is severely blunted, the decrease of phi from 7.66 to 7.12, 1.9-fold increase of effective [P.sup.2-.sub.i] , and 6.4 k J/tool decrease of dG/d[xi] from -53.8 to -47.4 kJ/mol were significantly correlated to the anoxic depression of cardiac performance. Our results provide the first evidence for a close, long-term coordination of functional cardiac changes with cellular energy status in a vertebrate, with a potential for autonomic control to override these immediate relationships. high-energy phosphate metabolism: anoxic turtle cardiac performance; in vivo magnetic resonance spectroscopy

Neuromedin U (NMU) is known to have potent actions on appetite and energy expenditure. Deletion of the NMU gene in mice leads to an obese phenotype, characterized by hyperphagia and decreased energy expenditure. Conversely, transgenic mice that overexpress proNMU exhibit reduced body weight and fat storage. Here, we show that central administration of NMU or the related peptide neuromedin S (NMS) dose-dependently decreases food intake, increases metabolic rate, and leads to significant weight loss in mice. The effects of NMU and NMS on both feeding and metabolism are almost completely lost in mice lacking the putative CNS receptor for NMU and NMS, NMUr2. However, NMUr2 knockout mice do not exhibit overt differences in body weight or energy expenditure compared with wild-type mice, suggesting that the dramatic phenotype of the NMU gene knockout mouse is not due simply to the loss of NMU/NMUr2 signaling. Putative proteolytic cleavage sites indicate that an additional peptide is produced from the NMU precursor protein, which is extremely well conserved between human, mouse, and rat. Here, we demonstrate that this peptide, [proNMU.sub.104-136], has a pronounced effect on energy balance in mice. Specifically, central administration of [proNMU.sub.104-136] causes a significant but transient (~4 h) increase in feeding, yet both food intake and body weight are decreased over the following 24 h. [proNMU.sub.104-136] administration also significantly increased metabolic rate. These results suggest that [proNMU.sub.104-136] is a novel modulator of energy balance and may contribute to the phenotype exhibited by NMU knockout mice. metabolism; neuromedin S; neuromedin U receptor 2; obesity; energy expenditure

The objective of this study was to investigate the differences in the muscle proteome of grass-fed and grain-fed cattle. Eight Japanese Black Cattle 10 mo of age were separated randomly into 2 groups: 1) grazing (grass-fed) and 2) concentrate (grain-fed) groups. All cattle were first housed individually in a stall barn and fed a combination of concentrate ad libitum and Italian ryegrass hay until 21 mo of age. After this control period, the 4 grass-fed cattle were placed on outdoor pasture, whereas the other 4 grain-fed cattle continued on the concentrate diet. The cattle were slaughtered at 27 mo of age, and tissues from the semi-tendinosus muscle were obtained for use in proteome analysis. Differential expression of muscle proteins in the 2 groups was carried out using 2-dimensional gel electrophoresis (2DE) and Western blot analyses, with subsequent mass spectrometry. Approximately 200 individual protein spots were detected and compared in each group using 2DE, of which 20 and 9 spots, respectively, showed differences in the spot intensity fox' the sarcoplasmic fraction and myofibrillar fraction. In the grazing group, the relative intensity of spots was significantly greater for adenylate kinase 1 and myoglobin in the sarcoplasmic fraction, and for slow-twitch myosin light chain 2 in the myofibrillar fraction (P < 0.05), than the concentrate group. The relative spot intensity of several glycolytic enzymes was significantly greater in the grazing group, such as [beta]-enolase 3, fructose-1,6-bis-phosphate aldolase A, triosephosphate isomerase, and heat shock 27 kDa protein (P < 0.05). Moreover, significantly greater slow twitch of troponin T, troponin I, and myosin heavy chain of semitendinosus muscle was detected in the grazing group than in the concentrate group using Western blot analysis (P < 0.05). Several previous reports have described that the slow-twitch muscle contents affect elements of nutrition, flavor, and food texture of meat. This study revealed muscle fiber type conversion to slow-twitch tissues from fast-twitch tissues occurring with change in the energy metabolic enzyme when cattle were grazed in the latter fattening period. Although analyses of the influence on elements of nutrition, flavor, and food texture were not done for this study, these results show that slow-twitch converted muscle resulting from the grazing of cattle might modify several meat characteristics. Key words: beef cattle, grazing, muscle, myofibrillar protein, proteome analysis, sarcoplasmic protein

The hepatic energy state, defined by adenine nucleotide levels, couples metabolic pathways with energy requirements. This coupling is fundamental in the adaptive response to many conditions and is impaired in metabolic disease. We have found that the hepatic energy state is substantially reduced following exercise, fasting, and exposure to other metabolic stressors in C57BL/6 mice. Glucagon receptor signaling was hypothesized to mediate this reduction because increased plasma levels of glucagon are characteristic of metabolic stress and because this hormone stimulates energy consumption linked to increased gluconeogenic flux through cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) and associated pathways. We developed what we believe to be a novel hyperglucagonemic-euglycemic clamp to isolate an increment in glucagon levels while maintaining fasting glucose and insulin. Metabolic stress and a physiological rise in glucagon lowered the hepatic energy state and amplified AMP-activated protein kinase signaling in control mice, but these changes were abolished in glucagon receptor--null mice and mice with liver-specific PEPCK-C deletion. 129X1/Sv mice, which do not mount a glucagon response to hypoglycemia, displayed an increased hepatic energy state compared with C57BL/6 mice in which glucagon was elevated. Taken together, these data demonstrate in vivo that the hepatic energy state is sensitive to glucagon receptor activation and requires PEPCK-C, thus providing new insights into liver metabolism., Introduction The energy state in the cell is defined by adenine nucleotide levels and is critically coupled to nearly all metabolic processes (1). In the cell, the adenine nucleotides ATP, [...]

Byline: Alex Gnaegi (1), Francois Feihl (1), Olivier Boulat (2), Bernard Waeber (1), Lucas Liaudet (1,3) Keywords: ARDS; Sepsis; Hypercapnia; Mechanical ventilation; Energy metabolism Abstract: Purpose Low tidal volume ventilation and permissive hypercapnia are required in patients with sepsis complicated by ARDS. The effects of hypercapnia on tissue oxidative metabolism in this setting are unknown. We therefore determined the effects of moderate hypercapnia on markers of systemic and splanchnic oxidative metabolism in an animal model of endotoxemia. Methods Anesthetized rats maintained at a PaCO.sub.2 of 30, 40 or 60 mmHg were challenged with endotoxin. A control group (PaCO.sub.2 40 mmHg) received isotonic saline. Hemodynamic variables, arterial lactate, pyruvate, and ketone bodies were measured at baseline and after 4 h. Tissue adenosine triphosphate (ATP) and lactate were measured in the small intestine and the liver after 4 h. Results Endotoxin resulted in low cardiac output, increased lactate/pyruvate ratio and decreased ketone body ratio. These changes were not influenced by hypercapnia, but were more severe with hypocapnia. In the liver, ATP decreased and lactate increased independently from PaCO.sub.2 after endotoxin. In contrast, the drop of ATP and the rise in lactate triggered by endotoxin in the intestine were prevented by hypercapnia. Conclusions During endotoxemia in rats, moderate hypercapnia prevents the deterioration of tissue energetics in the intestine. Author Affiliation: (1) Division of Clinical Pathophysiology and Medical Teaching, Faculty of Biology and Medicine, University Hospital Center, CHUV-BH 08-621, 1011, Lausanne, Switzerland (2) Central Laboratory of Clinical Chemistry, Faculty of Biology and Medicine, University Hospital Center, CHUV-BH 08-621, 1011, Lausanne, Switzerland (3) Department of Intensive Care Medicine, Faculty of Biology and Medicine, University Hospital Center, 1011, Lausanne, Switzerland Article History: Registration Date: 30/03/2009 Received Date: 28/10/2008 Accepted Date: 22/03/2009 Online Date: 17/04/2009

Central nervous system nutrient sensing and afferent endocrine signaling have been established as parallel systems communicating metabolic status and energy availability in vertebrates. The only afferent endocrine signal known to require modification with a fatty acid side chain is the orexigenic hormone ghrelin. We find that the ghrelin O-acyl transferase (GOAT), which is essential for ghrelin acylation, is regulated by nutrient availability, depends on specific dietary lipids as acylation substrates and links ingested lipids to energy expenditure and body fat mass. These data implicate the ghrelin-GOAT system as a signaling pathway that alerts the central nervous system to the presence of dietary calories, rather than to their absence as is commonly accepted., Two discoveries have softened the traditional differentiation between the classic model of nutrient sensing (1) and the concept of endocrine signals controlling energy status (2) by drawing attention to the [...]

Substrate use switches from fatty acids toward glucose in pressure overload-induced cardiac hypertrophy with an acceleration of glycolysis being characteristic. The activation of AMP-activated protein kinase (AMPK) observed in hypertrophied hearts provides one potential mechanism for the acceleration of glycolysis. Here, we directly tested the hypothesis that AMPK causes the acceleration of glycolysis in hypertrophied heart muscle cells. The H9c2 cell line, derived from the embryonic rat heart, was treated with arginine vasopressin (AVP; 1 [micro]M) to induce a cellular model of hypertrophy. Rates of glycolysis and oxidation of glucose and palmitate were measured in nonhypertrophied and hypertrophied H9c2 cells, and the effects of inhibition of AMPK were determined. AMPK activity was inhibited by 6-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-3-pyridin-4-yl-pyrrazolo-[1,5- a]pyrimidine (compound C) or by adenovirus-mediated transfer of dominant negative AMPK. Compared with nonhypertrophied cells, glycolysis was accelerated and palmitate oxidation was reduced with no significant alteration in glucose oxidation in hypertrophied cells, a metabolic profile similar to that of intact hypertrophied hearts. Inhibition of AMPK resulted in the partial reduction of glycolysis in AVP-treated hypertrophied H9c2 cells. Acute exposure of H9c2 cells to AVP also activated AMPK and accelerated glycolysis. These elevated rates of glycolysis were not altered by AMPK inhibition but were blocked by agents that interfere with [Ca.sup.2+] signaling, including extracellular EGTA, dantrolene, and 2-aminoethoxydiphenyl borate. We conclude that the acceleration of glycolysis in AVP-treated hypertrophied heart muscle cells is partially dependent on AMPK, whereas the acute glycolytic effects of AVP are AMPK independent and at least partially [Ca.sup.2+] dependent. cardiac hypertrophy; energy metabolism; glucose utilization

Birds have rapidly responding respiratory chemoreceptors [intrapulmonary chemoreceptors (IPC)] that provide vagal sensory feedback about breathing pattern. IPC are exquisitely sensitive to C[O.sub.2] but are unaffected by hypoxia. IPC continue to respond to C[O.sub.2] during hypoxic and even anoxic conditions, suggesting that they may generate ATP needed for signal transduction anaerobically. To assess IPC energy metabolism, single-cell action potential discharge and acid-base status were recorded from 26 pentobarbital-anesthetized Anas platyrhynchos before and after intravenous infusion of the glycolytic blocker iodoacetate (10-70 mg/kg), mitochondrial blocker rotenone (2 mg/kg), and/or mitochondrial uncoupler 2,4-dinitrophenol (5-15 mg/kg). After 5 min exposure at the highest dosages, iodoacetate inhibited IPC discharge 65% (15.9 [+ or -] 0.3 [s.sup.-1] to 5.5 [+ or -] 0.3 [s.sup.-1], p < 0.05), rotenone inhibited discharge 80% (12.9 [+ or -] 0.5 [s.sup.-1] to 2.6 [+ or -] 0.6 [s.sup.-1] p < 0.05), and 2,4-dinitrophenol inhibited discharge 19% (14.0 [+ or -] 0.3 [s.sup.-1] to 11.3 [+ or -] 0.3 [s.sup.-1], P < 0.05). These results suggest that IPC utilize glucose, require an intact glycolytic pathway, and metabolize the products of glycolysis to C[O.sub.2] and [H.sub.2]O by mitochondrial respiration. The small but significant effect of 2,4-dinitrophenol suggests that ATP production by glycolysis may be sufficient to meet IPC energy demands if NADH can be oxidized to NAD experimentally by uncoupling mitochondria, or physiologically by transient lactate production. A model for IPC spike frequency adaptation is proposed, whereby the rapid onset of phasic IPC discharge requires ATP from anaerobic glycolysis, using lactate as the electron acceptor, and the roll-off in IPC discharge reflects transient acidosis due to intracellular lactic acid accumulation. glycolysis; oxidative phosphorylation; NAD; ATP; action potential; ionic homeostasis; energy; spike frequency adaptation; respiration; Anas platyrhynchos

Maternal nutrient restriction (NR) from early to midgestation has marked effects on endocrine sensitivity and organ function of the resulting offspring. We hypothesized that early NR may reset the expression profile of genes central to myocardial energy metabolism, influencing ectopic lipid deposition and cardiac function in the obese adult offspring. NR offspring were exposed to an 'obesogenic' environment, and their cardiac function and molecular indexes of myocardial energy metabolism were assessed to explore the hypothesis that an obese individual's risk of heart disease may be modified after maternal NR. Pregnant sheep were fed 100% (control) or 50% (NR) energy requirement from dab's 30 to 80 of gestation and 100% energy requirement thereafter. At weaning, offspring were exposed to an obesogenic environment or remained lean. At ~1 yr of age, the hemodynamic response of these offspring to hypotension, together with left ventricular expression profiles of fatty acid-binding protein 3 (FABP3), peroxisome proliferator-activated receptor-[gamma] (PPAR[gamma]) and its coactivator (PGC)-l[alpha], acetyl-CoA carboxylase (ACC), AMP-activated protein kinase (AMPK)-[[alpha].sub.2], and voltage-dependent anion channel 1 (VDAC1), was determined. Obesity produced left ventricular hypertrophy in all animals, with increased ectopic (myocardial) lipid in NR offspring. Obesity per se significantly reduced myocardial transcript expression of PGC-1[alpha], AMPK[[alpha].sub.2], VDAC1, and ACC and increased expression of PPAR[gamma] and FABP3. However, although NR animals were similarly obese, their transcript expression of ACC, PPAR[gamma] and FABP3 was similar to that of lean animals, indicating altered cardiac energy metabolism. Indeed, blunted tachycardia and an amplified inotropic response to hypotension characterized cardiac function in obese NR offspring. The results suggest that maternal NR during early organo-genesis can precipitate an altered myocardial response to hypotension and increased myocardial lipid deposition in the adult offspring after adolescent-onset obesity, potentially rendering these individuals more at risk of early heart failure as they age. lipid infiltration; hypotensive challenge; myocardial energy metabolism; ectopic lipid deposition; insulin resistance

Intraduodenal infusions of both lipid and glucose modulate antropyloroduodenal motility and stimulate plasma CCK, with lipid being more potent than glucose. Both stimulate glucagon-like peptide-1, but only lipid stimulates peptide YY (PYY), while only glucose raises blood glucose and stimulates insulin. When administered in combination, lipid and carbohydrate may, thus, have additive effects on energy intake. However, elevated blood glucose levels do not suppress energy intake, and the effect of insulin is controversial. We hypothesized that increasing the ratio of maltodextrin, a complex carbohydrate, relative to lipid would be associated with a reduction in effects on antropyloroduodenal pressures, gut hormones, appetite, and energy intake, when compared with lipid alone. Ten healthy males were studied on three occasions in double-blind, randomized order. Antropyloroduodenal pressures, plasma CCK, PYY and insulin, blood glucose, and appetite were measured during 90-min intraduodenal infusions of 1) 3 kcal/min lipid (L3), 2) 2 kcal/min lipid and 1 kcal/min maltodextrin (L2/CHO1), or 3) 1 kcal/min lipid and 2 kcal/min maltodextrin (L1/CHO2). Energy intake at a buffet lunch consumed immediately after the infusion was quantified. Reducing the lipid (thus, increasing the carbohydrate) content of the infusion was associated with reduced stimulation of basal pyloric pressures (r = 0.76, P < 0.01), plasma CCK (r = 0.66, P < 0.01), and PYY (r = 0.98, P < 0.001), and reduced suppression of antral (r = -0.64, P < 0.05) and duodenal (r = -0.69, P < 0.05) pressure waves, desire-to-eat (r = -0.8, P < 0.001), and energy intake (r = 0.74, P < 0.01), with no differences in phasic (isolated) pyloric pressures. In conclusion, in healthy males, intraduodenal lipid is a more potent modulator of gut function, associated with greater suppression of energy intake, when compared with isocaloric combinations of lipid and maltodextrin. long-chain triglyceride; maltodextrin; cholecystokinin; peptide YY; energy intake

Histone deacetylase (HDAC) inhibitors show remarkable therapeutic potential for a variety of disorders, including cancer, neurological disease, and cardiac hypertrophy. However, the specific HDAC isoforms that mediate their actions are unclear, as are the physiological and pathological functions of individual HDACs in vivo. To explore the role of Hdac3 in the heart, we generated mice with a conditional Hdac3 null allele. Although global deletion of Hdac3 resulted in lethality by E9.5, mice with a cardiac-specific deletion of Hdac3 survived until 3-4 months of age. At this time, they showed massive cardiac hypertrophy and upregulation of genes associated with fatty acid uptake, fatty acid oxidation, and electron transport/oxidative phosphorylation accompanied by fatty acid--induced myocardial lipid accumulation and elevated triglyceride levels. These abnormalities in cardiac metabolism can be attributed to excessive activity of the nuclear receptor PPAR[alpha]. The phenotype associated with cardiac-specific Hdac3 gene deletion differs from that of all other Hdac gene mutations. These findings reveal a unique role for Hdac3 in maintenance of cardiac function and regulation of myocardial energy metabolism., Introduction Heart failure is a complex disorder that arises from multiple pathological insults including myocardial infarction, hypertension, and coronary artery disease. Initially, these insults are followed by an increase in [...]

Purpose: Muscle energy metabolism is associated with speed, endurance, and effort during walking, yet data regarding muscle metabolism during walking in persons with poststroke hemiparesis have not been published. The [...]

The gulf toadfish (Opsanus beta) intestine secretes base mainly in the form of HC[O.sup.-.sub.3] via apical anion exchange to serve [Cl.sup.-] and water absorption for osmoregulatory purposes. Luminal HC[O.sup.-.sub.3] secretion rates measured by pH-stat techniques in Ussing chambers rely on oxidative energy metabolism and are highly temperature sensitive. At 25[degrees]C under in vivo-like conditions, secretion rates averaged 0.45 [micro]mol x [cm.sup.-2] x [h.sup.-1], of which 0.25 [micro]mol x [cm.sup.-2] x [h.sup.-1] can be accounted for by hydration of endogenous C[O.sub.2] partly catalyzed by carbonic anhydrase. Complete polarity of secretion of HC[O.sup.-.sub.3] and [H.sup.+] arising from the C[O.sub.2] hydration reaction is evident from equal rates of luminal HC[O.sup.-.sub.3] secretion via anion exchange and basolateral [H.sup.+] extrusion. When basolateral [H.sup.+] extrusion is partly inhibited by reduction of serosal pH, luminal HC[O.sub.3] secretion is reduced. Basolateral [H.sup.+] secretion occurs in exchange for [Na.sup.+] via an ethylisopropylamilorideinsensitive mechanism and is ultimately fueled by the activity of the basolateral [Na.sup.+]-[K.sup.+]-ATPase. Fluid absorption by the toadfish intestine to oppose diffusive water loss to the concentrated marine environment is accompanied by a substantial basolateral [H.sup.+] extrusion, intimately linking osmoregulation and acid-base balance. bicarbonate transport; chloride absorption; epithelial water transport; seawater ingestion; pH-stat titrations

Calorie restriction (CR) without malnutrition increases maximal life span in diverse species. It has been proposed that reduction in energy expenditure and reactive oxygen species (ROS) production could be a mechanism for life span extension with CR. As a step toward testing this theory, mitochondrial proton leak, [H.sub.2][O.sub.2] production, and markers of oxidative stress were measured in liver from [FBNF.sub.1] rats fed control or 40% CR diets for 12 or 18 too. CR was initiated at 6 mo of age. Proton leak kinetics curves, generated from simultaneous measures of oxygen consumption and membrane potential, indicated a decrease in proton leak after 18 mo of CR, while only a trend toward a proton leak decrease was observed after 12 mo. Significant shifts in phosphorylation and substrate oxidation curves also occurred with CR; however, these changes occurred in concert with the proton leak changes. Metabolic control analysis indicated no difference in the overall pattern of control of the oxidative phosphorylation system between control and CR animals. At 12 too, no significant differences were observed between groups for [H.sub.2][O.sub.2] production or markers of oxidative stress. However, at 18 too, protein carbonyl content was lower in CR animals, as was [H.sub.2][O.sub.2] production when mitochondria were respiring on either succinate alone or pyruvate plus malate in the presence of rotenone. These results indicate that long-term CR lowers mitochondrial proton leak and [H.sub.2][O.sub.2] production, and this is consistent with the idea that CR may act by decreasing energy expenditure and ROS production. energy expenditure; aging; oxidative stress; food restriction

To investigate the hypothesis that caloric restriction alters mitochondrial function in situ, intact hepatocytes were isolated from fully fed and calorie-restricted (55% of control food intake, 4 months duration) male Brown-Norway rats at 6 months of age, and various parameters were determined. Overall, the production of reactive oxygen species was not affected by caloric restriction, neither were the mitochondrial membrane potential, oxygen consumption driving proton leak, or oxygen consumption driving ATP turnover. It is concluded that while isolated mitochondria from liver tissue of calorie-restricted animals display a reduction in the generation of reactive oxygen species, it was not possible to confirm this effect in isolated hepatocytes. Further work is required to establish what effect, if any, caloric restriction has on the rate of generation of reactive oxygen species in intact cells and tissues and importantly at the whole-animal level.

Most studies of selenium and thyroid hormone have used sodium selenite in rats. However, rats regulate thyroid hormone differently, and selenite, which has unique pharmacologic activities, does not occur in foods. We hypothesized that selenium in food would have different effects in humans. Healthy men were fed foods naturally high or low in selenium for 120 d while confined to a metabolic research unit. Selenium intake for all subjects was 47[micro]g/d (595 nmol/d) for the first 21 d, and then changed to either 14 (n = 6) or 297 (n = 5)[micro]g/d (177 nmol/d or 3.8 [micro]mol/d) for the remaining 99 d, causing significant changes in blood selenium and glutathione peroxidase. Serum 3,3',5-triiodothyronine [T.sub.3] decreased in the high selenium group, increased in the low selenium group, and was significantly different between groups from d 45 onward. A compensatory increase of thyrotropin occurred in the high selenium group as [T.sub.3] decreased. The changes in [T.sub.3] were opposite in direction to those reported in rats, but were consistent with other metabolic changes. By d 64, the high selenium group started to gain weight, whereas the low selenium group began to lose weight, and the weight changes were significantly different between groups from d 92 onward. Decreases of serum [T.sub.3] and compensatory increases in thyrotropin suggest that a subclinical hypothyroid response was induced in the high selenium group, leading to body weight increases. Increases of serum [T.sub.3] and serum triacylglycerol accompanied by losses of body fat suggest that a subclinical hyperthyroid response was induced in the low selenium group, leading to body weight decreases. KEY WORDS: * selenium * thyroid * thyrotropin * body weight * energy metabolism

Two experiments, Trial 1 (in vitro) and Trial 2 (in vivo), were conducted to examine the effects of ionophores, monensin, laidlomycin, and laidlomycin propionate on whole-animal [O.sub.2] consumption, organ weights, jejunal glucose absorption, and [0.sub.2] utilization, as well as growth, feed and water consumption, and feed efficiency. In Trial 1, 30 male Swiss-Webster mice, 8 wk old, were used to measure the in vitro effects of each of the ionophores at concentrations of 1.62 or 16.2 mM. Six combinations of three ionophores at two concentrations resulted in a total of eight treatments. All eight treatments were exposed to jejunal rings from a single mouse for a total of 30 observations per treatment. Jejunal rings were exposed to each ionophore treatment for 15 min. Laidlomycin propionate (16.2 mM) decreased (P < 0.2) glucose absorption, as estimated by [H.sup.3]-3-O-methyl glucose uptake compared with all other treatments, whereas laidlomycin propionate (1.62 mM) increased (P = 0.032)jejunal DM content compared with 16.2 mM laidlomycin propionate. In Trial 2, 40 5-wk-old mice were allotted into four treatments--control and 16.2 mM each of monensin, laidlomycin, and laidlomycin propionate--for a total of 10 observations per treatment. Ionophores were administered via the drinking water for 14 d. No ionophore treatment had any effect on whole-mouse [O.sub.2] consumption. Monensin increased (P = 0.004) stomach size and decreased (P = 0.049) the efficiency of BW gain compared with controls. Laidlomycin propionate decreased (P = 0.032) the percentage of whole jejunum oxygen consumption due to oubain-sensitive respiration compared with control. The efficiency of intestinal glucose absorption was not changed due to treatment in either trial. Under the conditions of these studies, monensin, laidlomycin, and laidlomycin propionate had minimal and inconsistent effects on jejunal function and energy utilization in mice. This investigation suggests that changes in the energetic requirements of animals treated with ionophores are not an issue in animal production. Key Words: Absorption, Glucose, Intestines, Ionophores, Mice

Two experiments were conducted to determine the effect of phytase on energy availability in pigs. In Exp. 1, barrows (initial and final BW of 26 and 52 kg) were allotted to four treatments in a 2 x 2 factorial arrangement. Corn--soybean meal (C-SBM) diets were fed at two energy levels (2.9 and 3.2 x maintenance [M]) with and without the addition of 500 phytase units/ kg of diet. The diets contained 115% of the requirement for Ca, available P (aP), and total lysine, and Ca and aP were decreased by 0.10% in diets with added phytase. Pigs were penned individually and fed daily at 0600 and 1700, and water was available constantly. Eight pigs were killed and ground to determine initial body composition. At the end of Exp. 1, all 48 pigs were killed for determination of carcass traits and protein and fat content by total-body electrical conductivity (TOBEC) analysis. Six pigs per treatment were ground for chemical composition. In Exp. 2, 64 barrows and gilts (initial and final BW of 23 and 47 kg) were allotted to two treatments (C-SBM with 10% defatted rice bran or that diet with reduced Ca and aP and 500 phytase units/kg of diet), with five replicate pens of barrows and three replicate pens of gilts (four pigs per pen). In Exp. 1, ADG was increased (P < 0.01) in pigs fed at 3.2 x M. Based on chemical analyses, fat deposition, kilograms of fat, retained energy (RE) in the carcass and in the carcass [+ or -] viscera, fat deposition in the organs, and kilograms of protein in the carcass were increased (P < 0.10) in pigs fed the diets at 3.2 vs. 2.9 x M. Based on TOBEC analysis, fat deposition, percentage of fat increase, and RE were increased (P < 0.09) in pigs fed at 3.2 x M. Plasma urea N concentrations were increased in pigs fed at 3.2 x M with no added phytase but were not affected when phytase was added to the diet (phytase x energy, P < 0.06). Fasting plasma glucose measured on d 28, ultrasound longissimus muscle area (LMA), and 10th-rib fat depth were increased (P < 0.08) in pigs fed phytase, but many other response variables were numerically affected by phytase addition. In Exp. 2, phytase had no effect (P > 0.10) on ADG, ADFI, gain:feed, LMA, or 10th-rib fat depth. These results suggest that phytase had small, mostly nonsignificant effects on energy availability in diets for growing pigs; however, given that phytase increased most of the response variables measured, further research on its possible effects on energy availability seems warranted. Key Words: Energy, Fat, Growth, Phytase, Pigs, Protein

Background and aims: Ghrelin, an endogenous ligand for growth hormone secretagogue receptor (GHS-R), is an appetite stimulatory signal from the stomach with structural resemblance to motilin. We examined the effects [...]

Byline: Pedro Diaz-Parejo (1), Nils Stahl (2), Wangbin Xu (3), Peter Reinstrup (4), Urban Ungerstedt (5), Carl-Henrik Nordstrom (2) Keywords: Hyperglycemia Head injury Cerebral microdialysis Glucose Lactate Glutamate Abstract: Objective. To study whether transient hyperglycemia adversely affects cerebral energy metabolism in patients with severe traumatic brain lesions. Design and setting. Prospective, nonrandomized study in the neurosurgical intensive care unit of a university hospital. Patients. 108 patients treated for severe traumatic brain lesions. Interventions. All patients were treated according to neurosurgical intensive care routine including monitoring of intracranial pressure. One microdialysis catheter was inserted via a burr hole frontally to that used for the intraventricular catheter ('better' position). In patients with focal lesions one or more catheters were inserted into cerebral cortex surrounding an evacuated focal contusion or underlying an evacuated hematoma ('worse' position). Perfusion rate was 0.3 Aul/min and samples were taken every 30 or 60 min. The levels of glucose, pyruvate, lactate, glutamate, and glycerol were analyzed and displayed bedside. Measurements and results. There were 18 episodes of moderate (12--15 mmol/l) and 6 episodes of pronounced (>15 mmol/l) hyperglycemia. Moderate hyperglycemia did not change intracerebral levels of lactate, pyruvate, glutamate, glycerol, or lactate/pyruvate ratio. Lactate concentrations increased during pronounced hyperglycemia. Pronounced cerebral lactic acidosis and a moderate increase in interstitial glycerol concentration indicating cell membrane degradation was observed in a single patient with pronounced, long-lasting hyperglycemia. Conclusions. Cerebral energy metabolism was affected by transient hyperglycemia only at blood glucose concentration above 15 mmol/l as shown by a moderate increase in interstitial lactate level. Author Affiliation: (1) Department of Intensive Care, University Hospital Virgen del Rocio, Seville, Spain (2) Department of Clinical Neuroscience, Lund University Hospital, 22185, Lund, Sweden (3) Intensive Care Unit, Kunming Medical College, Kunming, China (4) Department of Anaesthesiology and Intensive Care, Lund University Hospital, 22185, Lund, Sweden (5) Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden Article History: Received Date: 02/04/2002 Accepted Date: 10/01/2003 Article note: Electronic Publication