UCP1-dependent brown adipose activation accelerates cardiac metabolic remodeling and reduces initial hypertrophic and fibrotic responses to pathological stress.

Brown adipose tissue (BAT) is correlated to cardiovascular health in rodents and humans, but the physiological role of BAT in the initial cardiac remodeling at the onset of stress is unknown. Activation of BAT via 48 h cold (16°C) in mice following transverse aortic constriction (TAC) reduced cardiac gene expression for LCFA uptake and oxidation in male mice and accelerated the onset of cardiac metabolic remodeling, with an early isoform shift of carnitine palmitoyltransferase 1 (CPT1) toward increased CPT1a, reduced entry of long chain fatty acid (LCFA) into oxidative metabolism (0.59 ± 0.02 vs. 0.72 ± 0.02 in RT TAC hearts, p < .05) and increased carbohydrate oxidation with altered glucose transporter content. BAT activation with TAC reduced early hypertrophic expression of ß-MHC by 61% versus RT-TAC and reduced pro-fibrotic TGF-ß1 and COL3α1 expression. While cardiac natriuretic peptide expression was yet to increase at only 3 days TAC, Nppa and Nppb expression were elevated in Cold TAC versus RT TAC hearts 2.7- and 2.4-fold, respectively. Eliminating BAT thermogenic activation with UCP1 KO mice eliminated differences between Cold TAC and RT TAC hearts, confirming effects of BAT activation rather than autonomous cardiac responses to cold. Female responses to BAT activation were blunted, with limited UCP1 changes with cold, partly due to already activated BAT in females at RT compared to thermoneutrality. These data reveal a previously unknown physiological mechanism of UCP1-dependent BAT activation in attenuating early cardiac hypertrophic and profibrotic signaling and accelerating remodeled metabolic activity in the heart at the onset of cardiac stress.

Hepatic protein kinase Cbeta deficiency mitigates late-onset obesity.

Although aging is associated with progressive adiposity and a decline in liver function, the underlying molecular mechanisms and metabolic interplay are incompletely understood. Here, we demonstrate that aging induces hepatic protein kinase Cbeta (PKCß) expression, while hepatocyte PKCß deficiency (PKCßHep-/-) in mice significantly attenuates obesity in aged mice fed a high-fat diet. Compared with control PKCßfl/fl mice, PKCßHep-/- mice showed elevated energy expenditure with augmentation of oxygen consumption and carbon dioxide production which was dependent on ß3-adrenergic receptor signaling, thereby favoring negative energy balance. This effect was accompanied by induction of thermogenic genes in brown adipose tissue (BAT) and increased BAT respiratory capacity, as well as a shift to oxidative muscle fiber type with an improved mitochondrial function, thereby enhancing oxidative capacity of thermogenic tissues. Furthermore, in PKCßHep-/- mice, we determined that PKCß overexpression in the liver mitigated elevated expression of thermogenic genes in BAT. In conclusion, our study thus establishes hepatocyte PKCß induction as a critical component of pathophysiological energy metabolism by promoting progressive hepatic and extrahepatic metabolic derangements in energy homeostasis, contributing to late-onset obesity. These findings have potential implications for augmenting thermogenesis as a means of combating aging-induced obesity.

Metabolic trade-offs in Neonatal sepsis triggered by TLR4 and TLR1/2 ligands result in unique dysfunctions in neural breathing circuits.

Neonatal sepsis remains one of the leading causes of mortality in newborns. Several brainstem-regulated physiological processes undergo disruption during neonatal sepsis. Mechanistic knowledge gaps exist at the interplay between metabolism and immune activation to brainstem neural circuits and pertinent physiological functions in neonates. To delineate this association, we induced systemic inflammation either by TLR4 (LPS) or TLR1/2 (PAM3CSK4) ligand administration in postnatal day 5 mice (PD5). Our findings show that LPS and PAM3CSK4 evoke substantial changes in respiration and metabolism. Physiological trade-offs led to hypometabolic-hypothermic responses due to LPS, but not PAM3CSK4, whereas to both TLR ligands blunted respiratory chemoreflexes. Neuroinflammatory pathways modulation in brainstem showed more robust effects in LPS than PAM3CSK4. Brainstem neurons, microglia, and astrocyte gene expression analyses showed unique responses to TLR ligands. PAM3CSK4 did not significantly modulate gene expression changes in GLAST-1 positive brainstem astrocytes. PD5 pups receiving PAM3CSK4 failed to maintain a prolonged metabolic state repression, which correlated to enhanced gasping latency and impaired autoresuscitation during anoxic chemoreflex challenges. In contrast, LPS administered pups showed no significant changes in anoxic chemoreflex. Electrophysiological studies from brainstem slices prepared from pups exposed to either TLR4 or PAM3CSK4 showed compromised transmission between preBötzinger complex and Hypoglossal as an exclusive response to the TLR1/2 ligand. Spatial gene expression analysis demonstrated a region-specific modulation of PAM3CSK4 within the raphe nucleus relative to other anatomical sites evaluated. Our findings suggest that metabolic changes due to inflammation might be a crucial tolerance mechanism for neonatal sepsis preserving neural control of breathing.

A Novel Endocrine Role for the BAT-Released Lipokine 12,13-diHOME to Mediate Cardiac Function.

BACKGROUND: Brown adipose tissue (BAT) is an important tissue for thermogenesis, making it a potential target to decrease the risks of obesity, type 2 diabetes, and cardiovascular disease, and recent studies have also identified BAT as an endocrine organ. Although BAT has been implicated to be protective in cardiovascular disease, to this point there are no studies that identify a direct role for BAT to mediate cardiac function. METHODS: To determine the role of BAT on cardiac function, we utilized a model of BAT transplantation. We then performed lipidomics and identified an increase in the lipokine 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME). We utilized a mouse model with sustained overexpression of 12,13-diHOME and investigated the role of 12,13-diHOME in a nitric oxide synthase type 1 deficient (NOS1-/-) mouse and in isolated cardiomyocytes to determine effects on function and respiration. We also investigated 12,13-diHOME in a cohort of human patients with heart disease. RESULTS: Here, we determined that transplantation of BAT (+BAT) improves cardiac function via the release of the lipokine 12,13-diHOME. Sustained overexpression of 12,13-diHOME using tissue nanotransfection negated the deleterious effects of a high-fat diet on cardiac function and remodeling, and acute injection of 12,13-diHOME increased cardiac hemodynamics via direct effects on the cardiomyocyte. Furthermore, incubation of cardiomyocytes with 12,13-diHOME increased mitochondrial respiration. The effects of 12,13-diHOME were absent in NOS1-/- mice and cardiomyocytes. We also provide the first evidence that 12,13-diHOME is decreased in human patients with heart disease. CONCLUSIONS: Our results identify an endocrine role for BAT to enhance cardiac function that is mediated by regulation of calcium cycling via 12,13-diHOME and NOS1.

Brown adipose tissue prevents glucose intolerance and cardiac remodeling in high-fat-fed mice after a mild myocardial infarction.

BACKGROUND: Obesity increases the risk of developing impaired glucose tolerance (IGT) and type 2 diabetes (T2D) after myocardial infarction (MI). Brown adipose tissue (BAT) is important to combat obesity and T2D, and increasing BAT mass by transplantation improves glucose metabolism and cardiac function. The objective of this study was to determine if BAT had a protective effect on glucose tolerance and cardiac function in high-fat diet (HFD) fed mice subjected to a mild MI. METHODS: Male C57BL/6 mice were fed a HFD for eight weeks and then divided into Sham (Sham-operated) and +BAT (mice receiving 0.1 g BAT into their visceral cavity). Sixteen weeks post-transplantation, mice were further subdivided into ±MI (Sham; Sham-MI; +BAT; +BAT-MI) and maintained on a HFD. Cardiac (echocardiography) and metabolic function (glucose and insulin tolerance tests, body composition and exercise tolerance) were assessed throughout 22 weeks post-MI. Quantitative PCR (qPCR) was performed to determine the expression of genes related to metabolic function of perigonadal adipose tissue (pgWAT), subcutaneous white adipose tissue (scWAT), liver, heart, tibialis anterior skeletal muscle (TA); and BAT. RESULTS: +BAT prevented the increase in left ventricle mass (LVM) and exercise intolerance in response to MI. Similar to what is observed in humans, Sham-MI mice developed IGT post-MI, but this was negated in +BAT-MI mice. IGT was independent of changes in body composition. Genes involved in inflammation, insulin resistance, and metabolism were significantly altered in pgWAT, scWAT, and liver in Sham-MI mice compared to all other groups. CONCLUSIONS: BAT transplantation prevents IGT, the increase in LVM, and exercise intolerance following MI. MI alters the expression of several metabolic-related genes in WAT and liver in Sham-MI mice, suggesting that these tissues may contribute to the impaired metabolic response. Increasing BAT may be an important intervention to prevent the development of IGT or T2D and cardiac remodeling in obese patients post-MI.

Differential Responses to Sigma-1 or Sigma-2 Receptor Ablation in Adiposity, Fat Oxidation, and Sexual Dimorphism.

Obesity is increasing at epidemic rates across the US and worldwide, as are its co-morbidities, including type-2 diabetes and cardiovascular disease. Thus, targeted interventions to reduce the prevalence of obesity are of the utmost importance. The sigma-1 receptor (S1R) and sigma-2 receptor (S2R; encoded by Tmem97) belong to the same class of drug-binding sites, yet they are genetically distinct. There are multiple ongoing clinical trials focused on sigma receptors, targeting diseases ranging from Alzheimer's disease through chronic pain to COVID-19. However, little is known regarding their gene-specific role in obesity. In this study, we measured body composition, used a comprehensive laboratory-animal monitoring system, and determined the glucose and insulin tolerance in mice fed a high-fat diet. Compared to Sigmar1+/+ mice of the same sex, the male and female Sigmar1-/- mice had lower fat mass (17% and 12% lower, respectively), and elevated lean mass (16% and 10% higher, respectively), but S1R ablation had no effect on their metabolism. The male Tmem97-/- mice exhibited 7% lower fat mass, 8% higher lean mass, increased volumes of O2 and CO2, a decreased respiratory exchange ratio indicating elevated fatty-acid oxidation, and improved insulin tolerance, compared to the male Tmem97+/+ mice. There were no changes in any of these parameters in the female Tmem97-/- mice. Together, these data indicate that the S1R ablation in male and female mice or the S2R ablation in male mice protects against diet-induced adiposity, and that S2R ablation, but not S1R deletion, improves insulin tolerance and enhances fatty-acid oxidation in male mice. Further mechanistic investigations may lead to translational strategies to target differential S1R/S2R regulations and sexual dimorphism for precision treatments of obesity.

Phospho-ablation of cardiac sodium channel Nav1.5 mitigates susceptibility to atrial fibrillation and improves glucose homeostasis under conditions of diet-induced obesity.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia, with growing evidence identifying obesity as an important risk factor for the development of AF. Although defective atrial myocyte excitability due to stress-induced remodeling of ion channels is commonly observed in the setting of AF, little is known about the mechanistic link between obesity and AF. Recent studies have identified increased cardiac late sodium current (INa,L) downstream of calmodulin-dependent kinase II (CaMKII) activation as an important driver of AF susceptibility. METHODS: Here, we investigated a possible role for CaMKII-dependent INa,L in obesity-induced AF using wild-type (WT) and whole-body knock-in mice that ablates phosphorylation of the Nav1.5 sodium channel and prevents augmentation of the late sodium current (S571A; SA mice). RESULTS: A high-fat diet (HFD) increased susceptibility to arrhythmias in WT mice, while SA mice were protected from this effect. Unexpectedly, SA mice had improved glucose homeostasis and decreased body weight compared to WT mice. However, SA mice also had reduced food consumption compared to WT mice. Controlling for food consumption through pair feeding of WT and SA mice abrogated differences in weight gain and AF inducibility, but not atrial fibrosis, premature atrial contractions or metabolic capacity. CONCLUSIONS: These data demonstrate a novel role for CaMKII-dependent regulation of Nav1.5 in mediating susceptibility to arrhythmias and whole-body metabolism under conditions of diet-induced obesity.

Traumatic Endotheliopathy: A Prospective Observational Study of 424 Severely Injured Patients.

OBJECTIVE: Investigate and confirm the association between sympathoadrenal activation, endotheliopathy and poor outcome in trauma patients. BACKGROUND: The association between sympathoadrenal activation, endotheliopathy, and poor outcome in trauma has only been demonstrated in smaller patient cohorts and animal models but needs confirmation in a large independent patient cohort. METHODS: Prospective observational study of 424 trauma patients admitted to a level 1 Trauma Center. Admission plasma levels of catecholamines (adrenaline, noradrenaline) and biomarkers reflecting endothelial damage (syndecan-1, thrombomodulin, and sE-selectin) were measured and demography, injury type and severity, physiology, treatment, and mortality up till 28 days were recorded. RESULTS: Patients had a median ISS of 17 with 72% suffering from blunt injury. Adrenaline and noradrenaline correlated with syndecan-1 (r = 0.38, P < 0.001 and r = 0.23, P < 0.001, respectively) but adrenaline was the only independent predictor of syndecan-1 by multiple linear regression adjusted for age, injury severity score, Glascow Coma Scale, systolic blood pressure, base excess, platelet count, hemoglobin, prehospital plasma, and prehospital fluids (100 pg/mL higher adrenaline predicted 2.75 ng/mL higher syndecan-1, P < 0.001). By Cox analyses adjusted for age, sex, injury severity score, Glascow Coma Scale, base excess, platelet count and hemoglobin, adrenaline, and syndecan-1 were the only independent predictors of both <24-hours, 7-day and 28-day mortality (all P < 0.05). Furthermore, noradrenaline was an independent predictor of <24-hours mortality and thrombomodulin was an independent predictor of 7-day and 28-day mortality (all P < 0.05). CONCLUSIONS: We confirmed that sympathoadrenal activation was strongly and independently associated with endothelial glycocalyx and cell damage (ie, endotheliopathy) and furthermore that sympathoadrenal activation and endotheliopathy were independent predictors of mortality in trauma patients.

Impact of blood products on platelet function in patients with traumatic injuries: a translational study.

BACKGROUND: Reductions in platelet (PLT) count and function are associated with poor outcomes in trauma patients. We proposed to determine if patients expected to receive blood products have a decrease in PLT function higher than expected based on the reduction in PLT count, and if the reduction in function could be associated with the donor plasma/supernatant received. METHODS: PLT count and function were measured on admission to the emergency department and intensive care unit in severely injured patients expected to receive a transfusion. PLT function was measured by Multiplate aggregometry in response to five agonists. Function was corrected for alterations in count. In vitro studies were conducted in the blood of normal subjects to assess the effect of dilutions with AB donor plasma on PLT function. RESULTS: Forty-six patients were enrolled, with 87% requiring a transfusion. Median Injury Severity Score was 23 (13, 29) and mortality 15%. PLT count and function were decreased from emergency department to intensive care unit admission by 25% and 58%, respectively. Decreases in function persisted after adjustment for count. Patients requiring large volumes of blood products had reductions in function that were disproportionately greater. Reductions in PLT function were greatest after transfusion of PLTs. In in vitro studies with a 30% dilution by autologous plasma caused a relational reduction in function, whereas allogenic plasma resulted in greater decreases that were highly variable between donors. CONCLUSIONS: Within hours of injury a decrease in both PLT count and function occurs, that is aggravated with the administration of blood products, with transfusion of PLTs showing the greatest effect. The effect on PLT function of allogenic transfused plasma appears to be highly donor related.

Effects of exercise on soleus in severe burn and muscle disuse atrophy.

BACKGROUND: Muscle loss is a sequela of severe burn and critical illness with bed rest contributing significantly to atrophy. We hypothesize that exercise will mitigate muscle loss after burn with bed rest. MATERIALS AND METHODS: Male rats were assigned to sham ambulatory (S/A), burn ambulatory (B/A), sham hindlimb unloading (S/H), or burn hindlimb unloading (B/H). Rats received a 40% scald burn or sham and were ambulatory or placed in hindlimb unloading, a model of bed rest. Half from each group performed twice daily resistance climbing. Hindlimb isometric forces were measured on day 14. RESULTS: Soleus mass and muscle function were not affected by burn alone. Mass was significantly lower in hindlimb unloading (79 versus 139 mg, P < 0.001) and no exercise (103 versus 115 mg, P < 0.01). Exercise significantly increased soleus mass in B/H (86 versus 77 mg, P < 0.01). Hindlimb unloading significantly decreased muscle force in the twitch (12 versus 31 g, P < 0.001), tetanic (55 versus 148 g, P < 0.001), and specific tetanic measurements (12 versus 22 N/cm(2), P < 0.001). Effects of exercise on force depended on other factors. In B/H, exercise significantly increased twitch (14 versus 8 g, P < 0.05) and specific tetanic force (14 versus 7 N/cm(2), P < 0.01). Fatigue index was lower in ambulatory (55%) and exercise (52%) versus hindlimb (69%, P = 0.03) and no exercise (73%, P = 0.002). CONCLUSIONS: Hindlimb unloading is a significant factor in muscle atrophy. Exercise increased the soleus muscle mass, twitch, and specific force in this model. However, the fatigue index decreased with exercise in all groups. This suggests exercise contributes to functional muscle change in this model of disuse and critical illness.

Insulin effects on glucose tolerance, hypermetabolic response, and circadian-metabolic protein expression in a rat burn and disuse model.

Insulin controls hyperglycemia after severe burns, and its use opposes the hypermetabolic response. The underlying molecular mechanisms are poorly understood, and previous research in this area has been limited because of the inadequacy of animal models to mimic the physiological effects seen in humans with burns. Using a recently published rat model that combines both burn and disuse components, we compare the effects of insulin treatment vs. vehicle on glucose tolerance, hypermetabolic response, muscle loss, and circadian-metabolic protein expression after burns. Male Sprague-Dawley rats were assigned to three groups: cage controls (n = 6); vehicle-treated burn and hindlimb unloading (VBH; n = 11), and insulin-treated burn and hindlimb unloading (IBH; n = 9). With the exception of cage controls, rats underwent a 40% total body surface area burn with hindlimb unloading, then IBH rats received 12 days of subcutaneous insulin injections (5 units·kg(-1)·day(-1)), and VBH rats received an equivalent dose of vehicle. Glucose tolerance testing was performed on day 14, after which blood and tissues were collected for analysis. Body mass loss was attenuated by insulin treatment (VBH = 265 ± 17 g vs. IBH = 283 ± 14 g, P = 0.016), and glucose clearance capacity was increased. Soleus and gastrocnemius muscle loss was decreased in the IBH group. Insulin receptor substrate-1, AKT, FOXO-1, caspase-3, and PER1 phosphorylation was altered by injury and disuse, with levels restored by insulin treatment in almost all cases. Insulin treatment after burn and during disuse attenuated the hypermetabolic response, increased glucose clearance, and normalized circadian-metabolic protein expression patterns. Therapies aimed at targeting downstream effectors may provide the beneficial effects of insulin without hypoglycemic risk.

Maternal exercise preserves offspring cardiovascular health via oxidative regulation of the ryanodine receptor.

OBJECTIVE: The intrauterine environment during pregnancy is a critical factor in the development of obesity, diabetes, and cardiovascular disease in offspring. Maternal exercise prevents the detrimental effects of a maternal high fat diet on the metabolic health in adult offspring, but the effects of maternal exercise on offspring cardiovascular health have not been thoroughly investigated. METHODS: To determine the effects of maternal exercise on offspring cardiovascular health, female mice were fed a chow (C; 21% kcal from fat) or high-fat (H; 60% kcal from fat) diet and further subdivided into sedentary (CS, HS) or wheel exercised (CW, HW) prior to pregnancy and throughout gestation. Offspring were maintained in a sedentary state and chow-fed throughout 52 weeks of age and subjected to serial echocardiography and cardiomyocyte isolation for functional and mechanistic studies. RESULTS: High-fat fed sedentary dams (HS) produced female offspring with reduced ejection fraction (EF) compared to offspring from chow-fed dams (CS), but EF was preserved in offspring from high-fat fed exercised dams (HW) throughout 52 weeks of age. Cardiomyocytes from HW female offspring had increased kinetics, calcium cycling, and respiration compared to CS and HS offspring. HS offspring had increased oxidation of the RyR2 in cardiomyocytes coupled with increased baseline sarcomere length, resulting in RyR2 overactivity, which was negated in female HW offspring. CONCLUSIONS: These data suggest a role for maternal exercise to protect against the detrimental effects of a maternal high-fat diet on female offspring cardiac health. Maternal exercise improved female offspring cardiomyocyte contraction, calcium cycling, respiration, RyR2 oxidation, and RyR2 activity. These data present an important, translatable role for maternal exercise to preserve cardiac health of female offspring and provide insight on mechanisms to prevent the transmission of cardiovascular diseases to subsequent generations.

Transplantation of committed pre-adipocytes from brown adipose tissue improves whole-body glucose homeostasis.

Obesity and its co-morbidities including type 2 diabetes are increasing at epidemic rates in the U.S. and worldwide. Brown adipose tissue (BAT) is a potential therapeutic to combat obesity and type 2 diabetes. Increasing BAT mass by transplantation improves metabolic health in rodents, but its clinical translation remains a challenge. Here, we investigated if transplantation of 2-4 million differentiated brown pre-adipocytes from mouse BAT stromal fraction (SVF) or human pluripotent stem cells (hPSCs) could improve metabolic health. Transplantation of differentiated brown pre-adipocytes, termed "committed pre-adipocytes" from BAT SVF from mice or derived from hPSCs improves glucose homeostasis and insulin sensitivity in recipient mice under conditions of diet-induced obesity, and this improvement is mediated through the collaborative actions of the liver transcriptome, tissue AKT signaling, and FGF21. These data demonstrate that transplantation of a small number of brown adipocytes has significant long-term translational and therapeutic potential to improve glucose metabolism.

Chronic exercise improves hepatic acylcarnitine handling.

Exercise mediates tissue metabolic function through direct and indirect adaptations to acylcarnitine (AC) metabolism, but the exact mechanisms are unclear. We found that circulating medium-chain acylcarnitines (AC) (C12-C16) are lower in active/endurance trained human subjects compared to sedentary controls, and this is correlated with elevated cardiorespiratory fitness and reduced adiposity. In mice, exercise reduced serum AC and increased liver AC, and this was accompanied by a marked increase in expression of genes involved in hepatic AC metabolism and mitochondrial ß-oxidation. Primary hepatocytes from high-fat fed, exercise trained mice had increased basal respiration compared to hepatocytes from high-fat fed sedentary mice, which may be attributed to increased Ca2+ cycling and lipid uptake into mitochondria. The addition of specific medium- and long-chain AC to sedentary hepatocytes increased mitochondrial respiration, mirroring the exercise phenotype. These data indicate that AC redistribution is an exercise-induced mechanism to improve hepatic function and metabolism.

Signals from fat after injury: plasma adipokines and ghrelin concentrations in the severely burned.

INTRODUCTION: Hypermetabolism is universal in the severely burned and is characterized by catabolism of lean mass and body fat with associated insulin resistance. Adipokines are likely to play a role in these changes but have not been identified to date in burn patients. METHODS: From a single burn ICU, 17 burn patients with an expected stay>14 days were studied. Study period began within 14 days of admission. Over 7 days, plasma samples were collected for measurement of leptin, adiponectin, resistin, ghrelin, insulin, and cortisol by ELISA. For comparison, samples from 15 healthy controls of similar age, BMI, and blood glucose were obtained. RESULTS: Mean age was 33±17 years and BMI 26±3.4. Average burn size was 45±20% TBSA and ISS 32±10 with 72% having inhalation injury; in-hospital mortality was 29%. Estimated energy needs were 3626±710 kcal, of which 84±21% were met by enteral feeding with intensive insulin treatment (glucose 80-110 mg/ml). Using the homeostasis model assessment of insulin resistance, burned subjects were more resistant than controls (17±11.3 and 8±10.0). Insulin levels were elevated (57±35.6 µU/ml in burned subject vs. 26±31.1 µU/ml in controls), and cortisol concentrations increased (50±41.2 µg/dl vs. 12±3.9 µg/dl). These traditional hormone changes were associated with increased resistin (16.6±5.5 ng/ml vs. 3.8±0.9 ng/ml) and decreased leptin (8.8±8.9 ng/ml vs. 19.4±23.5 ng/ml), adiponectin (9±3.5 ng/ml vs. 17±10.2 ng/ml), and ghrelin (0.37±0.14 ng/ml vs.0.56±0.26 ng/ml). CONCLUSION: Patients with burns, who are characteristically hypermetabolic with hypercortisolism and insulin resistant, have significant changes in adipokine levels that appear independent of the magnitude of initial injury or metabolic derangement. In addition, suppression of ghrelin in the presence of decreased leptin and adiponectin levels in combination with increased insulin and resistin levels represent unexpected changes in the metabolic milieu of the injured patient possibly due to dramatic activation of inflammatory pathways, indicating strategies for treatment.

Association of hemodilution and blood pressure in uncontrolled bleeding.

BACKGROUND: Hemodynamic status and coagulation capacity affect blood loss after injury. The most advantageous fluid and blood pressure to optimize resuscitation and minimize perturbation of coagulation are unclear. We investigated interactions of isovolumic hemodilution on hemodynamics, coagulation, and blood loss after injury. METHODS: Twenty-five male rats were randomized into three groups (Whole Blood Uncontrolled Blood Pressure [WBU], n = 7; Lactated Ringers Uncontrolled Blood Pressure [LRU], n = 10; Whole Blood Controlled Blood Pressure [WBC], n = 8) with isovolumic hemodilution of 50% blood volume, with and without control of pre-injury blood pressure. All rats underwent uniform grade IV liver injury 30 min after serial exchanges. Post-injury blood loss and coagulation function were measured. RESULTS: Dilution occurred, determined by hematocrit, with LRU having a greater reduction. Pre-injury mean arterial pressure (MAP) decreased compared with baseline (98 ± 7 mmHg) with LRU (62 ± 14 mmHg) and WBC (61 ± 10 mmHg), resulting in WBU (101 ± 13 mmHg) being significantly higher and not changed from baseline. Post-injury, MAP decreased from pre-injury, with LRU significantly lower than the other two groups. No differences were observed in prothrombin time/international normalized ratio or thromboelastography. Bleed volume was significantly different between groups: WBU < WBC < LRU and associated with the pre-injury MAP. Controlling baseline MAP, dilution with Lactated Ringers (LR) resulted in greater blood loss than whole blood (3.0 ± 0.4 versus 1.9 ± 0.3 mL). CONCLUSIONS: In this rat model of liver injury, blood loss was associated with baseline MAP and type of fluid used for dilution. Hemodilution with LR did not produce coagulopathy based on laboratory values. When controlling baseline MAP, dilution with LR increased bleeding, confirming a functional coagulopathic state.

Severe burn and disuse in the rat independently adversely impact body composition and adipokines.

INTRODUCTION: Severe trauma is accompanied by a period of hypermetabolism and disuse. In this study, a rat model was used to determine the effects of burn and disuse independently and in combination on body composition, food intake and adipokines. METHODS: Male rats were assigned to four groups 1) sham ambulatory (SA), 2) sham hindlimb unloaded (SH), 3) 40% total body surface area full thickness scald burn ambulatory (BA) and 4) burn and hindlimb unloaded (BH). Animals designated to the SH and BH groups were placed in a tail traction system and their hindlimbs unloaded. Animals were followed for 14 days. Plasma, urine, fecal and tissue samples were analyzed. RESULTS: SA had a progressive increase in body mass (BM), SH and BA no change and BH a reduction. Compared to SA, BM was reduced by 10% in both SH and BA and by 17% when combined in BH. Compared to SA, all groups had reductions in lean and fat body mass with BH being greater. The decrease in lean mass was associated with the rate of urinary corticosterone excretion. The loss in fat mass was associated with decreases in plasma leptin and adiponectin and an increase in ghrelin. Following the acute response to injury, BH had a greater food intake per 100 g BM. Food intake was associated with the levels of leptin, adiponectin and ghrelin. CONCLUSIONS: The effects of the combination of burn and disuse in this animal model were additive, therefore in assessing metabolic changes with severe trauma both injury and disuse should be considered. Furthermore, the observed changes in adipokines, corticosterone and ghrelin provide insights for interventions to attenuate the hypermetabolic state following injury, possibly reducing catabolism and muscle loss and subsequent adverse effects on recovery and function.

Distinct Effects of High-Fat and High-Phosphate Diet on Glucose Metabolism and the Response to Voluntary Exercise in Male Mice.

The prevalence of metabolic diseases is rapidly increasing and a principal contributor to this is diet, including increased consumption of energy-rich foods and foods with added phosphates. Exercise is an effective therapeutic approach to combat metabolic disease. While exercise is effective to combat the detrimental effects of a high-fat diet on metabolic health, the effects of exercise on a high-phosphate diet have not been thoroughly investigated. Here, we investigated the effects of a high-fat or high-phosphate diet in the presence or absence of voluntary exercise on metabolic function in male mice. To do this, mice were fed a low-fat, normal-phosphate diet (LFPD), a high-phosphate diet (HPD) or a high-fat diet (HFD) for 6 weeks and then subdivided into either sedentary or exercised (housed with running wheels) for an additional 8 weeks. An HFD severely impaired metabolic function in mice, increasing total fat mass and worsening whole-body glucose tolerance, while HPD did not induce any notable effects on glucose metabolism. Exercise reverted most of the detrimental metabolic adaptations induced by HFD, decreasing total fat mass and restoring whole-body glucose tolerance and insulin sensitivity. Interestingly, voluntary exercise had a similar effect on LFPD and HPD mice. These data suggest that a high-phosphate diet does not significantly impair glucose metabolism in sedentary or voluntary exercised conditions.

Maternal Exercise and Paternal Exercise Induce Distinct Metabolite Signatures in Offspring Tissues.

That maternal and paternal exercise improve the metabolic health of adult offspring is well established. Tissue and serum metabolites play a fundamental role in the health of an organism, but how parental exercise affects offspring tissue and serum metabolites has not yet been investigated. Here, male and female breeders were fed a high-fat diet and housed with or without running wheels before breeding (males) and before and during gestation (females). Offspring were sedentary and chow fed, with parents as follows: sedentary (Sed), maternal exercise (MatEx), paternal exercise (PatEx), or maternal+paternal exercise (Mat+PatEx). Adult offspring from all parental exercise groups had similar improvement in glucose tolerance and hepatic glucose production. Targeted metabolomics was performed in offspring serum, liver, and triceps muscle. Offspring from MatEx, PatEx, and Mat+PatEx each had a unique tissue metabolite signature, but Mat+PatEx offspring had an additive phenotype relative to MatEx or PatEx alone in a subset of liver and muscle metabolites. Tissue metabolites consistently indicated that the metabolites altered with parental exercise contribute to enhanced fatty acid oxidation. These data identify distinct tissue-specific adaptations and mechanisms for parental exercise-induced improvement in offspring metabolic health. Further mining of this data set could aid the development of novel therapeutic targets to combat metabolic diseases.

Exercise training after myocardial infarction increases survival but does not prevent adverse left ventricle remodeling and dysfunction in high-fat diet fed mice.

AIMS: Aerobic exercise is an important component of rehabilitation after cardiovascular injuries including myocardial infarction (MI). In human studies, the beneficial effects of exercise after an MI are blunted in patients who are obese or glucose intolerant. Here, we investigated the effects of exercise on MI-induced cardiac dysfunction and remodeling in mice chronically fed a high-fat diet (HFD). MAIN METHODS: C57Bl/6 male mice were fed either a standard (Chow; 21% kcal/fat) or HFD (60% kcal/fat) for 36 weeks. After 24 weeks of diet, the HFD mice were randomly subjected to an MI (MI) or a sham surgery (Sham). Following the MI or sham surgery, a subset of mice were subjected to treadmill exercise. KEY FINDINGS: HFD resulted in obesity and glucose intolerance, and this was not altered by exercise or MI. MI resulted in decreased ejection fraction, increased left ventricle mass, increased end systolic and diastolic diameters, increased cardiac fibrosis, and increased expression of genes involved in cardiac hypertrophy and heart failure in the MI-Sed and MI-Exe mice. Exercise prevented HFD-induced cardiac fibrosis in Sham mice (Sham-Exe) but not in MI-Exe mice. Exercise did, however, reduce post-MI mortality. SIGNIFICANCE: These data indicate that exercise significantly increased survival after MI in a model of diet-induced obesity independent of effects on cardiac function. These data have important translational ramifications because they demonstrate that environmental interventions, including diet, need to be carefully evaluated and taken into consideration to support the effects of exercise in the cardiac rehabilitation of patients who are obese.