RESUMEN
Severe burn injuries are defined by a prolonged hypermetabolic response characterized by increases in resting energy expenditure, systemic catabolism, and multi-organ dysfunction. The sustained elevation of catecholamines following a burn injury is thought to significantly contribute to this hypermetabolic response, leading to changes in adipose tissue such as increased lipolysis and the browning of subcutaneous white adipose tissue (WAT). Failure to mitigate these adverse changes within the adipose tissue has been shown to exacerbate the post-burn hypermetabolic response and lead to negative outcomes. Propranolol, a non-selective ß-blocker, has been clinically administered to improve outcomes of pediatric and adult burn patients, but there is inadequate knowledge of its effects on the distinct adipose tissue depots. In this study, we investigated the adipose depot-specific alterations that occur in response to burn injury. Moreover, we explored the therapeutic effects of ß-adrenoceptor blockade via the drug propranolol in attenuating these burn-induced pathophysiological changes within the different fat depots. Using a murine model of thermal injury, we show that burn injury induces endoplasmic reticulum (ER) stress in the epididymal (eWAT) but not in the inguinal (iWAT) WAT depot. Conversely, burn injury induces the activation of key lipolytic pathways in both eWAT and iWAT depots. Treatment of burn mice with propranolol effectively mitigated adverse burn-induced alterations in the adipose by alleviating ER stress in the eWAT and reducing lipolysis in both depots. Furthermore, propranolol treatment in post-burn mice attenuated UCP1-mediated subcutaneous WAT browning following injury. Overall, our findings suggest that propranolol serves as an effective therapeutic intervention to mitigate the adverse changes induced by burn injury, including ER stress, lipotoxicity, and WAT browning, in both adipose tissue depots. KEY MESSAGES: Burn injury adversely affects adipose tissue metabolism via distinct changes in both visceral and subcutaneous adipose depots. Propranolol, a non-selective ß-adrenergic blocker, attenuates many of the adverse adipose tissue changes mediated by burn injury.
Asunto(s)
Tejido Adiposo , Antagonistas Adrenérgicos beta , Quemaduras , Estrés del Retículo Endoplásmico , Propranolol , Animales , Quemaduras/tratamiento farmacológico , Quemaduras/metabolismo , Antagonistas Adrenérgicos beta/farmacología , Antagonistas Adrenérgicos beta/uso terapéutico , Masculino , Ratones , Estrés del Retículo Endoplásmico/efectos de los fármacos , Propranolol/farmacología , Propranolol/uso terapéutico , Tejido Adiposo/metabolismo , Tejido Adiposo/efectos de los fármacos , Lipólisis/efectos de los fármacos , Ratones Endogámicos C57BL , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/efectos de los fármacos , Modelos Animales de Enfermedad , Metabolismo Energético/efectos de los fármacosAsunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Quemaduras/patología , Sepsis/patología , Proteína Amiloide A Sérica/metabolismo , Quemaduras/tratamiento farmacológico , Quemaduras/metabolismo , Estudios de Casos y Controles , Humanos , Pronóstico , Sepsis/tratamiento farmacológico , Sepsis/metabolismo , Proteína Amiloide A Sérica/genéticaRESUMEN
Burn patients experiencing hypermetabolism develop hepatic steatosis, which is associated with liver failure and poor outcomes after the injury. These same patients also undergo white adipose tissue (WAT) browning, which has been implicated in mediating post-burn cachexia and sustained hypermetabolism. Despite the clinical presentation of hepatic steatosis and WAT browning in burns, whether or not these two pathological responses are linked remains poorly understood. Here, we show that the burn-induced WAT browning and its associated increased lipolysis leads to the accelerated development of hepatic steatosis in mice. Deletion of interleukin 6 (IL-6) and the uncoupling protein 1 (UCP1), regulators of burn-induced WAT browning completely protected mice from hepatic steatosis after the injury. Treatment of post-burn mice with propranolol or IL-6 receptor blocker attenuated burn-induced WAT browning and its associated hepatic steatosis pathology. Lipidomic profiling in the plasma of post-burn mice and burn patients revealed elevated levels of damage-inducing lipids (palmitic and stearic acids), which induced hepatic endoplasmic reticulum (ER) stress and compromised hepatic fat oxidation. Mechanistically, we show that hepatic ER stress after a burn injury leads to a greater ER-mitochondria interaction, hepatocyte apoptosis, oxidative stress, and impaired fat oxidation. Collectively, our findings uncover an adverse "cross-talk" between the adipose and liver tissue in the context of burn injury, which is critically mediated by WAT browning.
Asunto(s)
Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Quemaduras/complicaciones , Hígado Graso/patología , Animales , Humanos , RatonesRESUMEN
OBJECTIVE: Browning, the conversion of white adipose tissue (WAT) to a beige phenotype, has gained interest as a strategy to induce weight loss and improve insulin resistance in metabolic disorders. However, for hypermetabolic conditions stemming from burn trauma or cancer cachexia, browning is thought to contribute to energy wasting and supraphysiological nutritional requirements. Metformin's impact on this phenomenon and underlying mechanisms have not been explored. METHODS: We used both a murine burn model and human ex vivo adipose explants to assess metformin and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)'s effects on the development of subcutaneous beige adipose. Enzymes involved in fat homeostasis and browning, as well as mitochondrial dynamics, were assessed to determine metformin's effects. RESULTS: Treatment with the biguanide metformin lowers lipolysis in beige fat by inducing protein phosphatase 2A (PP2A) independently of adenosine monophosphate kinase (AMPK) activation. Increased PP2A activity catalyzes the dephosphorylation of acetyl-CoA carboxylase (Ser 79) and hormone sensitive lipase (Ser 660), thus promoting fat storage and the "whitening" of otherwise lipolytic beige adipocytes. Moreover, co-incubation of metformin with the PP2A inhibitor okadaic acid countered the anti-lipolytic effects of this biguanide in human adipose. Additionally, we show that metformin does not activate this pathway in the WAT of control mice and that AICAR sustains the browning of white adipose, offering further evidence that metformin acts independently of this cellular energy sensor. CONCLUSIONS: This work provides novel insights into the mechanistic underpinnings of metformin's therapeutic benefits and potential as an agent to reduce the lipotoxicity associated with hypermetabolism and adipose browning.
Asunto(s)
Tejido Adiposo Blanco/efectos de los fármacos , Quemaduras/patología , Metformina/farmacología , Grasa Subcutánea/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Acetil-CoA Carboxilasa/metabolismo , Adipocitos Beige/metabolismo , Tejido Adiposo Blanco/citología , Tejido Adiposo Blanco/metabolismo , Adulto , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacología , Animales , Quemaduras/metabolismo , Modelos Animales de Enfermedad , Humanos , Lipólisis/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Ácido Ocadaico/farmacología , Fosforilación Oxidativa/efectos de los fármacos , Proteína Fosfatasa 2/metabolismo , Ribonucleósidos/farmacología , Esterol Esterasa/metabolismo , Grasa Subcutánea/citología , Grasa Subcutánea/efectos de los fármacosRESUMEN
PURPOSE: To evaluate the ability of a multimodal patient education initiative to improve adherence to healthy bone behaviors (HBBs) in men with prostate cancer receiving androgen deprivation therapy (ADT). METHODS: This was a pilot prospective, single-site, before-and-after clinical trial. The control arm (n = 51) received routine care. The intervention arm (n = 52) received multimodal HBB education which included a healthy bones prescription (BoneRx), focused face-to-face education with an oncology nurse or physician, and customized educational materials. The primary endpoints were feasibility of study methods and self-reported adherence to HBBs (vitamin D intake ≥ 1000 IU/day, calcium intake 1000-1500 mg/day, and exercise ≥ 150 min/week) at 3-month follow-up. Secondary endpoints included receipt of bone mineral density (BMD) testing. RESULTS: Patients were satisfied with the study intervention, found educational materials easy to understand, and felt that it increased their knowledge about osteoporosis. Although the intervention appeared to be associated with trends toward improved levels of vitamin D intake (adjusted odds ratio [OR] 1.8, 95% confidence interval [CI] 0.74-4.5), calcium intake (OR 1.5, 95% CI 0.63-3.4), and exercise (OR 1.7, 0.75-3.9) as compared to the control arm, none of these were statistically significant. Patients who received the study intervention were more likely to receive BMD testing (OR 3.3, 95% CI 1.3-8.8). CONCLUSIONS: Although a brief, tailored educational intervention was feasible to implement and improve BMD test utilization, it did not increase HBB participation. Larger, well-designed trials are needed to clarify the effect of patient education interventions on HBB adherence. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT01973673 ).
Asunto(s)
Antagonistas de Andrógenos/uso terapéutico , Huesos/efectos de los fármacos , Osteoporosis/tratamiento farmacológico , Educación del Paciente como Asunto/métodos , Anciano , Anciano de 80 o más Años , Antagonistas de Andrógenos/farmacología , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estudios ProspectivosRESUMEN
BACKGROUND: Strategies to improve bone health care in men receiving androgen deprivation therapy (ADT) are not consistently implemented. The authors conducted a phase 2 randomized controlled trial of 2 education-based models-of-care interventions to determine their feasibility and ability to improve bone health care. METHODS: A single-center parallel-group randomized controlled trial of men with prostate cancer who were receiving ADT was performed. Participants were randomized 1:1:1 to 1) a patient bone health pamphlet and brief recommendations for their family physician (BHP+FP); 2) a BHP and support from a bone health care coordinator (BHP+BHCC); or 3) usual care. The primary efficacy outcome was receipt of a bone mineral density (BMD) test within 6 months. Secondary efficacy outcomes included guideline-appropriate calcium and vitamin D use and bisphosphonate prescriptions for men at high fracture risk. Feasibility endpoints included recruitment, retention, satisfaction, contamination, and outcome capture. The main analysis used logistic regression with a 1-sided P of .10. The trial is registered at ClinicalTrials.gov (identifier NCT02043236). RESULTS: A total of 119 men were recruited. The BHP+BHCC strategy was associated with a greater percentage of men undergoing a BMD test compared with the usual-care group (78% vs 36%; P<.001). BMD ordering also was found to be increased with the BHP+FP strategy (58% vs 36%; P = .047). Both strategies were associated with higher percentages of patients using calcium and vitamin D, but only the BHP+FP arm was statistically significant (P = .039). No men were detected to be at high fracture risk. All but one feasibility endpoint was met. CONCLUSIONS: Educational strategies to improve bone health care appear feasible and are associated with improved BMD ordering in men receiving ADT. Cancer 2018;124:1132-40. © 2017 American Cancer Society.
Asunto(s)
Antagonistas de Andrógenos/efectos adversos , Antineoplásicos Hormonales/efectos adversos , Osteoporosis/prevención & control , Educación del Paciente como Asunto , Neoplasias de la Próstata/tratamiento farmacológico , Antagonistas de Andrógenos/administración & dosificación , Antineoplásicos Hormonales/administración & dosificación , Densidad Ósea/efectos de los fármacos , Conservadores de la Densidad Ósea/administración & dosificación , Difosfonatos/administración & dosificación , Estudios de Factibilidad , Humanos , Masculino , Persona de Mediana Edad , Osteoporosis/inducido químicamente , Osteoporosis/diagnóstico , Resultado del Tratamiento , Vitamina D/administración & dosificaciónRESUMEN
Acute myeloid leukemia (AML) is an aggressive, acute-onset hematological malignancy. Greater use of intensive chemotherapy (IC), supportive care, and stem cell transplantation have led to an increasing number of long-term survivors. Few studies have examined employment issues among AML survivors and to our knowledge, no study has examined the long-term effects of treatment on return to work. This study is the first to utilize a validated measure of work-related limitation and productivity (WLQ-16) to assess the long-term effects of AML treatment on employment rates, work-related limitations, and overall productivity. We examined RTW issues in 111 adult AML 1-year survivors after conventional IC. We found that, over time, the number of employed survivors increased (to 54% by 36 months) while the number of unemployed, retired, and sick leave patients decreased. Among those employed, the majority were employed full time. Employed individuals reported few work-related limitations and productivity loss scores were low, ranging from 3.47% at 18 months to 2.34% at 36 months. These data suggest that, over time, over half of AML survivors who underwent IC regain social, emotional, cognitive, and physical function sufficient to RTW with few limitations.
Asunto(s)
Supervivientes de Cáncer , Leucemia Mieloide Aguda , Reinserción al Trabajo , Adulto , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
The nucleus accumbens (NAc) is thought to be a site of integration of positively and negatively valenced information and action selection. Functional differentiation in valence processing has previously been found along the rostrocaudal axis of the shell region of the NAc in assessments of unconditioned motivation. Given that the core region of the NAc has been implicated in the elicitation of motivated behavior in response to conditioned cues, we sought to assess the role of caudal, intermediate, and rostral sites within this subregion in cue-elicited approach-avoidance decisions. Rats were trained to associate visuo-tactile cues with appetitive, aversive, and neutral outcomes. Following the successful acquisition of the cue-outcome associations, rats received microinfusions of GABAA and GABAB receptor agonists (muscimol/baclofen) or saline into the caudal, intermediate, or rostral NAc core and were then exposed to a superimposition of appetitively and aversively valenced cues versus neutral cues in a "conflict test," as well as to the appetitive versus neutral cues, and aversive cues versus neutral cues, in separate conditioned preference/avoidance tests. Disruption of activity in the intermediate to caudal parts of the NAc core resulted in a robust avoidance bias in response to motivationally conflicting cues, as well as a potentiated avoidance of aversive cues as compared with control animals, coupled with an attenuated conditioned preference for the appetitive cue. These results suggest that the caudal NAc core may have the capacity to exert bidirectional control over appetitively and aversively motivated responses to valence signals.
Asunto(s)
Reacción de Prevención/fisiología , Conducta de Elección/fisiología , Señales (Psicología) , Núcleo Accumbens/fisiología , Animales , Aprendizaje por Asociación/efectos de los fármacos , Aprendizaje por Asociación/fisiología , Reacción de Prevención/efectos de los fármacos , Baclofeno/farmacología , Conducta de Elección/efectos de los fármacos , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiología , Conflicto Psicológico , Agonistas del GABA/farmacología , Masculino , Motivación/efectos de los fármacos , Motivación/fisiología , Muscimol/farmacología , Núcleo Accumbens/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas Long-Evans , Receptores de GABA-A/metabolismo , Receptores de GABA-B/metabolismo , Percepción del Tacto/efectos de los fármacos , Percepción del Tacto/fisiología , Percepción Visual/efectos de los fármacos , Percepción Visual/fisiologíaRESUMEN
A severe burn can trigger a hypermetabolic state which lasts for years following the injury, to the detriment of the patient. The drastic increase in metabolic demands during this phase renders it difficult to meet the body's nutritional requirements, thus increasing muscle, bone and adipose catabolism and predisposing the patient to a host of disorders such as multi-organ dysfunction and sepsis, or even death. Despite advances in burn care over the last 50 years, due to the multifactorial nature of the hypermetabolic phenomenon it is difficult if not impossible to precisely identify and pharmacologically modulate the biological mediators contributing to this substantial metabolic derangement. Here, we discuss biomarkers and molecules which play a role in the induction and mediation of the hypercatabolic condition post-thermal injury. Furthermore, this thorough review covers the development of the factors released after burns, how they induce cellular and metabolic dysfunction, and how these factors can be targeted for therapeutic interventions to restore a more physiological metabolic phenotype after severe thermal injuries. This article is part of a Special Issue entitled: Immune and Metabolic Alterations in Trauma and Sepsis edited by Dr. Raghavan Raju.