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Circadian disruption is widespread and increases the risk of obesity. Timing of therapeutic interventions may promote coherent and efficient gating of metabolic processes and restore energy homeostasis. To characterize the diurnal postexercise metabolic state in mice and to identify the influence of diet-induced obesity on identified outcomes. C57BL6/NTac male mice (6 wks of age) were fed a standard chow or high-fat diet for 5 weeks. At week 5, mice were subjected to a 60-min (16 m/min, 5 % incline) running bout (or sham) during the early rest (day) or early active (night) phase. Tissue and serum samples were collected immediately post-exercise (n = 6/group). In vivo glucose oxidation was measured after oral administration of 13C-glucose via 13CO 2 exhalation analysis in metabolic cages. Basal and isoproterenol-stimulated adipose tissue lipolysis was assessed ex vivo for 1 h following exercise. Lean mice displayed exercise-timing-specific plasticity in metabolic outcomes, including phase-specificity in systemic glucose metabolism and adipose-tissue-autonomous lipolytic activity depending on time of day. Conversely, obesity impaired temporal postexercise differences in whole-body glucose oxidation, as well as the phase- and exercise-mediated induction of lipolysis in isolated adipose tissue. This obesity-induced alteration in diurnal metabolism, as well as the indistinct response to exercise, was observed concomitant with disruption of core clock gene expression in peripheral tissues. Overall, high-fat fed obese mice exhibit metabolic inflexibility, which is also evident in the diurnal exercise response. Our study provides physiological insight into exercise timing-dependent aspects in the dynamic regulation of metabolism and the influence of obesity on this biology. [Display omitted] • Lean mice exhibit timing-specific plasticity in postexercise metabolic outcomes. • Biological rhythms and diurnal metabolic flexibility are impaired in obese mice. • Obesity reduces temporal differences in postexercise glucose and lipid metabolism. • Altered diurnal metabolism in obesity is coupled to peripheral clock disruption. • Timing of exercise bouts may fine-tune substrate utilization throughout the day. [ABSTRACT FROM AUTHOR]

Highlights • Supplementation of algae-derived β-glucan alleviated diarrhea of weaned pigs. • Dietary algae-derived β-glucan reduced gut permeability of E. coli challenged pigs. • Algae-derived β-glucan reduced systemic inflammation of E. coli challenged pigs. • Algae-derived β-glucan may improve the overall health of weaned pigs. Abstract Most of the commercially available β-glucans are derived from yeast, while there are limited research on algae-derived β-glucan in pigs. Therefore, the objective of this experiment was to investigate the influence of dietary supplementation of algae-derived β-glucan on diarrhea, gut permeability, and immune responses of weaned pigs experimentally infected with a pathogenic Escherichia coli (E. coli). Thirty-six weaned pigs (7.69 ± 0.77 kg BW) were individually housed in disease containment rooms and randomly allotted to one of three dietary treatments (n = 12): control diet and 2 additional diets containing either 54 or 108 mg/kg of β-glucan. The experiment lasted 17 d [5 d before and 12 d post inoculation (PI)]. The inoculum used in this experiment was F18 E. coli , containing heat-labile toxin, heat-stable toxin b, and shiga-lie toxin 2. The inoculation doses were 1010 cfu/3 mL oral dose daily for 3 days. Diarrhea score (1, normal, to 5, watery diarrhea) was recorded for each pig daily to calculate frequency of diarrhea. Blood samples were collected on d 0 before E. coli challenge, and on d 2, 5, 8, and 12 PI to measure total and differential blood cell count in whole blood and several inflammatory markers in serum. Fresh jejunal tissues were collected from 4 pigs in the control group and high dose β-glucan group to analyze gut permeability on d 5 and d 12 PI with Ussing Chamber. Jejunal and ileal mucosa were also collected to measure the mRNA expression of several genes related to gut barrier function and immune responses. Results of this experiment revealed that inclusion of high dose β-glucan reduced (P < 0.05) frequency of diarrhea (29.01% vs. 17.28%) for the entire experimental period. This was likely due to the reduced (P < 0.05) gut permeability and increased (P < 0.05) mRNA expression of gut barrier function genes (Claudin , Occludin , and MUC2) in jejunal mucosa of E. coli challenged pigs as β-glucan supplemented. Supplementation of β-glucan also reduced (P < 0.05) white blood cells, neutrophils, serum tumor necrosis factor (TNF)-α, cortisol, and haptoglobin, and down-regulated (P < 0.05) the mRNA expression of several immune genes (IL1B , IL6 , and TNFA) in ileal mucosa of E. coli challenged pigs, compared with the control diet. In conclusion, in feed supplementation of algae-derived β-glucan alleviated diarrhea of F18 E. coli infected pigs by enhancing gut integrity. Feeding β-glucan also boosted host immune response against E. coli infection. [ABSTRACT FROM AUTHOR]

Except for latitudes close to the equator, seasonal variation in light hours can change dramatically between summer and winter. Yet investigations into the interplay between energy metabolism and circadian rhythms typically use a 12 h light:12 h dark photoperiod corresponding to the light duration at the equator. We hypothesized that altering the seasonal photoperiod affects both the rhythmicity of peripheral tissue clocks and energy homeostasis. Mice were housed at photoperiods representing either light hours in summer, winter, or the equinox. Mice housed at a winter photoperiod exhibited an increase in the amplitude of rhythmic lipid metabolism and a modest reduction in fat mass and liver triglyceride content. Comparing melatonin-proficient and -deficient mice, the effect of seasonal light on energy metabolism was largely driven by differences in the rhythmicity of food intake and not melatonin. Together, these data indicate that seasonal light impacts energy metabolism by modulating the timing of eating. [Display omitted] • Seasonal light impacts energy metabolism by modulating the timing of eating • Photoperiod affects the rhythmicity of fasting-associated metabolites • Photoperiod alters the phase of core clock transcripts in peripheral tissues • These effects are largely independent of a functioning melatonergic system Circadian disruption influences energy metabolism in mammals; however, the impact of day length on non-seasonal animals is not well understood. Small et al. investigated the effect of different seasonal photoperiods on energy metabolism and diurnal rhythmicity and reported that seasonal light impacts energy metabolism by modulating the timing of eating. [ABSTRACT FROM AUTHOR]

Abstract: Objectives:: To describe the risk factors, etiology and referral patterns of elderly patients treated for minor burns in an urban emergency department (ED). Methods:: A retrospective chart review was conducted of persons aged 65 years and older who were treated for a minor burn and discharged home from the ED. Medical records were reviewed for 77 burn patients that presented over a 6-year period. Results:: Burn patients had significant co-morbid medical illness. The etiology of the burns was scalds (58%), contact (27%) and flame (12%). Sixty-eight percent of the burns were cooking related. Heating pads, curling irons or hot pipes accounted for the majority of contact burns. Three percent of burn patients were referred to a home care agency for a home safety evaluation at the time of discharge from the ED. Conclusion:: Cooking-related activities accounted for the majority of minor burns in this series. Common consumer items or environmental hazards were responsible for most contact burns. Elderly patients seen in the ED with minor burns were rarely referred to a home care agency. [Copyright &y& Elsevier]

The glucose tolerance test (GTT) is widely used in preclinical research to investigate glucose metabolism, but there is no standardised way to administer glucose. The aim of this study was to directly compare the effect of the route of glucose administration on glucose and insulin kinetics during a GTT in mice. A GTT was performed in lean male and female mice and obese male mice and glucose was administered via the oral or intraperitoneal (I.P.) route. Samples were collected frequently during the GTT to provide a full time-course of the insulin and glucose excursions. In another cohort of lean male mice, plasma concentrations of insulin, c-peptide, and incretin hormones were measured at early time points after glucose administration. A stable-isotope labelled GTT (SiGTT) was then performed to delineate the contribution of exogenous and endogenous glucose to glycemia during the GTT, comparing both methods of glucose administration. Finally, we present a method to easily measure insulin from small volumes of blood during a GTT by directly assaying whole-blood insulin using ELISA and show a good concordance between whole-blood and plasma insulin measurements. We report that I.P. glucose administration results in an elevated blood glucose excursion and a largely absent elevation in blood insulin and plasma incretin hormones when compared to oral administration. Utilising stable-isotope labelled glucose, we demonstrate that the difference in glucose excursion between the two routes of administration is mainly due to the lack of suppression of glucose production in I.P. injected mice. Additionally, rates of exogenous glucose appearance into circulation were different between lean and obese mice after I.P., but not after oral glucose administration. Reflecting on these data, we suggest that careful consideration be given to the route of glucose administration when planning a GTT procedure in mice and that in most circumstances the oral route of glucose administration should be preferred over the I.P. route to avoid possible artifacts originating from a non-physiological route. • Intraperitoneal glucose administration does not promote insulin secretion. • Exogenous glucose appearance is delayed in obese mice after intraperitoneal administration. • Hepatic glucose production is suppressed after administering oral not intraperitoneal glucose. • Measuring insulin from whole blood is comparable to that from plasma. [ABSTRACT FROM AUTHOR]

Tissue sensitivity and response to exercise vary according to the time of day and alignment of circadian clocks, but the optimal exercise time to elicit a desired metabolic outcome is not fully defined. To understand how tissues independently and collectively respond to timed exercise, we applied a systems biology approach. We mapped and compared global metabolite responses of seven different mouse tissues and serum after an acute exercise bout performed at different times of the day. Comparative analyses of intra- and inter-tissue metabolite dynamics, including temporal profiling and blood sampling across liver and hindlimb muscles, uncovered an unbiased view of local and systemic metabolic responses to exercise unique to time of day. This comprehensive atlas of exercise metabolism provides clarity and physiological context regarding the production and distribution of canonical and novel time-dependent exerkine metabolites, such as 2-hydroxybutyrate (2-HB), and reveals insight into the health-promoting benefits of exercise on metabolism. [Display omitted] • Time of exercise defines system-wide activation of energy metabolism • Exercise timing rewires intra-tissue and inter-tissue metabolite correlations • Maintenance of inter-tissue metabostasis is specified by exercise time • Comparative analyses reveal time- and tissue-dependent exerkines Tissue sensitivity and response to exercise vary according to time of day. Sato et al. present an atlas of exercise metabolism, including global metabolomics profiling of multiple tissues, combined with arteriovenous sampling of hindlimb muscle and sampling across the liver to verify net uptake and release of time- and exercise-dependent signaling biochemicals. [ABSTRACT FROM AUTHOR]

NAD+ is a co-factor and substrate for enzymes maintaining energy homeostasis. Nicotinamide phosphoribosyltransferase (NAMPT) controls NAD+ synthesis, and in skeletal muscle, NAD+ is essential for muscle integrity. However, the underlying molecular mechanisms by which NAD+ synthesis affects muscle health remain poorly understood. Thus, the objective of the current study was to delineate the role of NAMPT-mediated NAD+ biosynthesis in skeletal muscle development and function. To determine the role of Nampt in muscle development and function, we generated skeletal muscle-specific Nampt KO (SMNKO) mice. We performed a comprehensive phenotypic characterization of the SMNKO mice, including metabolic measurements, histological examinations, and RNA sequencing analyses of skeletal muscle from SMNKO mice and WT littermates. SMNKO mice were smaller, with phenotypic changes in skeletal muscle, including reduced fiber area and increased number of centralized nuclei. The majority of SMNKO mice died prematurely. Transcriptomic analysis identified that the gene encoding the mitochondrial permeability transition pore (mPTP) regulator Cyclophilin D (Ppif) was upregulated in skeletal muscle of SMNKO mice from 2 weeks of age, with associated increased sensitivity of mitochondria to the Ca2+-stimulated mPTP opening. Treatment of SMNKO mice with the Cyclophilin D inhibitor, Cyclosporine A, increased membrane integrity, decreased the number of centralized nuclei, and increased survival. Our study demonstrates that NAMPT is crucial for maintaining cellular Ca2+ homeostasis and skeletal muscle development, which is vital for juvenile survival. • NAD+ salvage capacity is important for skeletal muscle development and survival. • Skeletal muscle-specific Nampt knockout mice exhibit a dystrophy-like phenotype. • Nampt deletion alters Ca2+ homeostasis and impairs mitochondrial function. • Low NAD+ levels signals mitochondrial permeability transition pore opening. • Cyclosporin A treatment improves sarcolemma integrity and increases survival rate. [Display omitted] [ABSTRACT FROM AUTHOR]

The metabolic master-switch AMP-activated protein kinase (AMPK) mediates insulin-independent glucose uptake in muscle and regulates the metabolic activity of brown and beige adipose tissue (BAT). The regulatory AMPKγ3 isoform is uniquely expressed in skeletal muscle and potentially in BAT. Herein, we investigated the role that AMPKγ3 plays in mediating skeletal muscle glucose uptake and whole-body glucose clearance in response to small-molecule activators that act on AMPK via distinct mechanisms. We also assessed whether γ3 plays a role in adipose thermogenesis and browning. Global AMPKγ3 knockout (KO) mice were generated. A systematic whole-body, tissue, and molecular phenotyping linked to glucose homeostasis was performed in γ3 KO and wild-type (WT) mice. Glucose uptake in glycolytic and oxidative skeletal muscle ex vivo as well as blood glucose clearance in response to small molecule AMPK activators that target the nucleotide-binding domain of the γ subunit (AICAR) and allosteric drug and metabolite (ADaM) site located at the interface of the α and β subunit (991, MK-8722) were assessed. Oxygen consumption, thermography, and molecular phenotyping with a β3-adrenergic receptor agonist (CL-316,243) treatment were performed to assess BAT thermogenesis, characteristics, and function. Genetic ablation of γ3 did not affect body weight, body composition, physical activity, and parameters associated with glucose homeostasis under chow or high-fat diet. γ3 deficiency had no effect on fiber-type composition, mitochondrial content and components, or insulin-stimulated glucose uptake in skeletal muscle. Glycolytic muscles in γ3 KO mice showed a partial loss of AMPKα2 activity, which was associated with reduced levels of AMPKα2 and β2 subunit isoforms. Notably, γ3 deficiency resulted in a selective loss of AICAR-, but not MK-8722-induced blood glucose-lowering in vivo and glucose uptake specifically in glycolytic muscle ex vivo. We detected γ3 in BAT and found that it preferentially interacts with α2 and β2. We observed no differences in oxygen consumption, thermogenesis, morphology of BAT and inguinal white adipose tissue (iWAT), or markers of BAT activity between WT and γ3 KO mice. These results demonstrate that γ3 plays a key role in mediating AICAR- but not ADaM site binding drug-stimulated blood glucose clearance and glucose uptake specifically in glycolytic skeletal muscle. We also showed that γ3 is dispensable for β3-adrenergic receptor agonist-induced thermogenesis and browning of iWAT. • Loss of AMPKγ3 reduces glucose uptake in glycolytic skeletal muscle and whole-body glucose clearance with AMP-mimetic drug. • γ 3 is not required for muscle glucose uptake and whole-body glucose clearance with ADaM site-targeted allosteric activators. • γ 3 is present and forms a trimeric complex with α 2 and β 2 in brown adipose tissue. • γ 3 is dispensable for adipose thermogenesis and browning in response to a β3-adrenergic receptor agonist. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To examine how often hospitalized older adults with a diagnosis of heel ulcers are evaluated with noninvasive vascular tests and to determine the impact of invasive vascular or surgical procedures on 1-year mortality. Design: Retrospective review using an electronic database and chart review of all patients discharged with a diagnosis of heel ulcer between 2006 and 2009. Setting: Urban teaching hospital. Participants: A total of 506 participants aged 65 years and older. Measurements: Data collected included resident characteristics (demographics, medical history, and severity of illness using the Charlson comorbidity index), staging of heel ulcers, rates of noninvasive vascular assessments, vascular and surgical procedures, length of stay, and 1-year mortality. Results: Thirty-one percent (155/506) of patients with a heel ulcer underwent noninvasive vascular testing and of these 83% (129/155) were found to have underlying ischemia. Twenty-six percent (130/506) of patients underwent at least 1 vascular or surgical procedure. The 1-year mortality rate for patients with stage 1 or 2 disease was 55%; this rose to 70% for patients with stage 3 or 4 ulcers (P = .01), and could not be explained by differences in the Charlson comorbidity index. Patients who underwent a vascular or surgical procedure had a significantly lower mortality compared with those who did not (59% vs 68% P = .04). Conclusion: Older adults with a heel ulcer in the acute care setting are frequently not assessed for underlying ischemia of the lower extremities. The diagnosis carries high 1-year mortality rates. Evidence-based protocols need to be developed to determine which older adults should have a vascular assessment and then undergo an invasive procedure. [Copyright &y& Elsevier]