Activity-Based Anorexia Induces Browning of Adipose Tissue Independent of Hypothalamic AMPK.

Anorexia nervosa (AN) is an eating disorder leading to malnutrition and, ultimately, to energy wasting and cachexia. Rodents develop activity-based anorexia (ABA) when simultaneously exposed to a restricted feeding schedule and allowed free access to running wheels. These conditions lead to a life-threatening reduction in body weight, resembling AN in human patients. Here, we investigate the effect of ABA on whole body energy homeostasis at different housing temperatures. Our data show that ABA rats develop hyperactivity and hypophagia, which account for a massive body weight loss and muscle cachexia, as well as reduced uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT), but increased browning of white adipose tissue (WAT). Increased housing temperature reverses not only the hyperactivity and weight loss of animals exposed to the ABA model, but also hypothermia and loss of body and muscle mass. Notably, despite the major metabolic impact of ABA, none of the changes observed are associated to changes in key hypothalamic pathways modulating energy metabolism, such as AMP-activated protein kinase (AMPK) or endoplasmic reticulum (ER) stress. Overall, this evidence indicates that although temperature control may account for an improvement of AN, key hypothalamic pathways regulating thermogenesis, such as AMPK and ER stress, are unlikely involved in later stages of the pathophysiology of this devastating disease.

Differential effects of heat in the phases of the light-dark cycle in the activity-based anorexia model.

BACKGROUND: This research builds on the studies on ambient temperature as a key influence in the recovery of rodents exposed to the activity-based anorexia (ABA) model. The ABA model is an experimental paradigm in which rodents under a restricted feeding schedule and with free access to an activity wheel show signs that parallel those of anorexia nervosa in humans. OBJECTIVE: The present study focuses on the effects of applying heat during the different phases of the dark-light cycle in the activity levels, body weight, food intake, body temperature, and recovery rates of 30 male rats submitted to ABA. METHOD: After reaching a 20% weight loss criterion, animals were randomly assigned to three experimental conditions: (a) continuous warming, (b) warming exclusively during the light phase, or (c) warming exclusively during the dark phase. RESULTS: Differential effects were found depending on the modalities of warming: in comparison with either light or dark warming, continuous warming significatively decreased activity, facilitated weight gain, and maintained body temperature. Transient effects of warming were found both in the groups warmed either during light or dark periods exclusively. DISCUSSION: The results suggest that both light and dark warming did not promote recovery in animals exposed to ABA. Evidence about the beneficial effects of continuous warming are in line with previous research and reinforces adding external heat as a useful tool in the treatment of anorexia nervosa.

Temperature but not leptin prevents semi-starvation induced hyperactivity in rats: implications for anorexia nervosa treatment.

The hypothesis linking hyperactivity with weight loss associated hypoleptinemia in anorexia nervosa gained momentum after a study showing that leptin suppressed semi-starvation induced hyperactivity in rats. Alternatively, ambient temperature is a key modulating factor of activity in semi-starved rats. The aim of the study is to compare the efficacy of leptin with increased ambient temperature in the prevention of hyperactivity in semi-starved rats. 74 Sprague-Dawley male rats were employed in two experiments with the difference residing in the length of baseline. After an extended (28 days), or shorter (14 days) baseline with free access to food and the running wheel, housed at 21 °C, animals were either ad-lib feed or food restricted (60% of food ingested during previous week) and infused with same amount of leptin at 21 °C, 25 °C, or vehicle at 21 °C, 25 °C and 32 °C for a week. Animals housed at 32 °C significantly reduced wheel running and weight loss during food restriction while animals given leptin did not yield no differences in activity or weight loss. Moreover, unlike animals housed at 32 °C, body temperature of leptin infused animals housed at 21 °C was significantly reduced during food restriction. Furthermore, leptin treated rats without a preceding stable pattern of activity displayed a severe dysregulation of circadian rhythm in activity and a collapse of body temperature. Housing temperature plays a more critical role than leptin in the regulation of semi-starvation induced hyperactivity in rats, which may be of relevance for the management of hyperactivity in anorexia nervosa.

Seasonal BMI differences between restrictive and purging anorexia nervosa subtypes.

OBJECTIVE: Seasonal differences in anorexia nervosa is an area of research which has received scarce attention in the literature. The aim of this study was to explore patterns of seasonal variation in body weight in anorexia nervosa patients admitted to an eating disorders unit from January 2007 to December 2011. METHOD: Anorexia nervosa restrictive (ANR) and binge eating/purging (ANBP) subtypes were compared with respect to BMI on admission during the Warm and Cold Semester, and in terms of lenght of hospital stay. RESULTS: The main result was that BMI differences between ANBP and ANR patients were due to bodyweight differences during the colder months of the year (p < 0.01) whereas no difference in bodyweight on admission was observed between both subtypes during the Warm Semester months. Furthermore, ANR patients' bodyweight was lower when admitted during the Cold compared to the Warm Semester (p < 0.05). Length of stay was significantly associated with reduced BMI in ANR patients (p < 0.01), but not so for ANBP patients. DISCUSSION: To our knowledge, this is the first study in the literature providing data on seasonal variations in the BMI on admission of anorexia nervosa patients, and in the length of hospitalization.

Rodent model of activity-based anorexia.

Activity-based anorexia (ABA) consists of a procedure that involves the simultaneous exposure of animals to a restricted feeding schedule, while free access is allowed to an activity wheel. Under these conditions, animals show a progressive increase in wheel running, a reduced efficiency in food intake to compensate for their increased activity, and a severe progression of weight loss. Due to the parallelism with the clinical manifestations of anorexia nervosa including increased activity, reduced food intake and severe weight loss, the ABA procedure has been proposed as the best analog of human anorexia nervosa (AN). Thus, ABA research could both allow a better understanding of the mechanisms underlying AN and generate useful leads for treatment development in AN.

Ozone oxidative postconditioning ameliorates joint damage and decreases pro-inflammatory cytokine levels and oxidative stress in PG/PS-induced arthritis in rats.

Rheumatoid Arthritis (RA) is the most prevalent chronic condition present in ~1% of the adult population. Many pro-inflammatory mediators are increased in RA, including Reactive Oxygen Species such as nitric oxide NO, pro-inflammatory cytokines as tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1ß) and other molecules. Ozone oxidative postconditioning has regulatory effects on some pathological targets associated with RA. Thus, the aim of this study was to investigate the efficacy of ozone therapy in PG/PS-induced arthritis in rats in point of joints inflammation and morphology. Moreover, cytokines, nitric oxide and oxidative stress levels in spleen homogenates were evaluated. Ozone treatment ameliorated joint damage, reduced TNF-α concentrations as well as TNF-α and IL-1ß mRNA levels. Besides, cellular redox balance, nitric oxide and fructolysine levels were reestablished after ozone oxidative postconditioning. It was concluded that pleiotropic ozone's effects clarify its therapeutic efficacy in RA. Decreasing inflammation and joint injury, reduction of pro-inflammatory cytokines, TNF-α and IL-1ß transcripts and re-establishment of cellular redox balance after ozone treatment were demonstrated.

Effect of auditory isolation on activity-based anorexia / Efecto del aislamiento auditivo en la anorexia basada en la actividad

The objective was to study male and female rats exposed to Activity-Based Anorexia (ABA; simultaneous exposition to food restriction and free access to an activity wheel) under two conditions of sound attenuation, by means of different arrangements of wheels (standard versus isolation) in the laboratory room. Regardless of the sound attenuation condition, all but one male and one female with access to wheels had to be removed from the experiment, but extended ABA endurance was found in rats in the sound attenuation condition. Furthermore, significantly lower levels of running were observed in both males and females under the sound attenuation arrangement in the isolation condition. The results suggest that external stimulation plays a role in the activity displayed by rats exposed to ABA, and that the reduction of external stimulation diminishes running but does not protect rats from developing ABA (AU)

El objetivo fue el estudio de ratas macho y hembra expuestas al procedimiento experimental de Anorexia basada en la Actividad (ABA, exposición simultánea a restricción de alimento y acceso libre a una rueda de actividad) bajo dos condiciones de atenuación acústica por medio de un arreglo experimental diferente de las ruedas de actividad (estándar versus aislamiento) en el laboratorio. Independientemente de la condición de la atenuación del sonido, todos los animales con acceso a las ruedas de actividad menos una rata macho y otra hembra tuvieron que ser retirados del experimento, mientras que la condición de atenuación del sonido aumentó la resistencia a ABA. Además, los niveles de actividad de machos y hembras fueron significativamente inferiores en la condición de atenuación del sonido en la condición de aislamiento. Los resultados sugieren que la estimulación externa desempeña un papel en la actividad desplegada por las ratas expuestas a ABA, y que aunque la reducción de la estimulación externa disminuye la actividad no protege a los animales del desarrollo de ABA (AU)

Effect of auditory isolation on activity-based anorexia.

The objective was to study male and female rats exposed to Activity-Based Anorexia (ABA; simultaneous exposition to food restriction and free access to an activity wheel) under two conditions of sound attenuation, by means of different arrangements of wheels (standard versus isolation) in the laboratory room. Regardless of the sound attenuation condition, all but one male and one female with access to wheels had to be removed from the experiment, but extended ABA endurance was found in rats in the sound attenuation condition. Furthermore, significantly lower levels of running were observed in both males and females under the sound attenuation arrangement in the isolation condition. The results suggest that external stimulation plays a role in the activity displayed by rats exposed to ABA, and that the reduction of external stimulation diminishes running but does not protect rats from developing ABA.

Antiatherosclerotic effect of an antibody that binds to extracellular matrix glycosaminoglycans.

OBJECTIVE: Subendothelial retention of proatherogenic lipoproteins by proteoglycans is critical in atherosclerosis. The aim of this study was to characterize the recognition and antiatherogenic properties of a chimeric monoclonal antibody (mAb) that reacts with sulfated molecules. METHODS AND RESULTS: chP3R99 mAb recognized sulfated glycosaminoglycans, mainly chondroitin sulfate (CS), by ELISA. This mAb blocked ≈70% of low-density lipoprotein (LDL)-CS association and ≈80% of LDL oxidation in vitro, and when intravenously injected to Sprague-Dawley rats (n=6, 1 mg/animal), it inhibited LDL (4 mg/kg intraperitoneally, 1 hour later) retention and oxidation in the artery wall. Moreover, subcutaneous immunization of New Zealand White rabbits (n=19) with chP3R99 mAb (100 µg, 3 doses at weekly intervals) prevented Lipofundin-induced atherosclerosis (2 mL/kg, 8 days) with a 22-fold reduction in the intima-media ratio (P<0.01). Histopathologic and ultrastructural studies showed no intimal alterations or slight thickening, with preserved junctions between endothelial cells and scarce collagen fibers and glycosaminoglycans. In addition, immunization with chP3R99 mAb suppressed macrophage infiltration in aorta and preserved redox status. The atheroprotective effect was associated with the induction of anti-CS antibodies in chP3R99-immunized rabbits, capable of blocking CS-LDL binding and LDL oxidation. CONCLUSION: These results support the use of anti-sulfated glycosaminoglycan antibody-based immunotherapy as a potential tool to prevent atherosclerosis.