IUPHAR ECR review: Cancer-related anorexia-cachexia in cancer patients: Pathophysiology and treatment.

Cancer-related anorexia-cachexia (CRAC) comprises one of the most common syndromes of advanced cancer patients. The prevalence of CRAC increases from 50% to 80% before death. CRAC is associated not only with impaired quality of life in patients and family members but also with shorter survival. The management of CRAC is a great challenge in clinical practice. There are no definite practice guidelines yet for the prevention and treatment of CRAC. A multimodal strategy is the most effective way to treat anorexia-cachexia. Numerous medications have been suggested and used in clinical trials, while others are still being studied on experimental animals. These medications include branched-chain amino acids, eicosapentaenoic acid, thalidomide, cytokine inhibitors, steroids, antiserotoninergic medications, and appetite stimulants. The benefits of supportive care interventions and the advancement of exciting new pharmacological medicines for anorexia-cachexia are becoming more widely recognized. Health care professionals need to be aware of the psychosocial and biological effects of anorexia-cachexia, even though knowledge of the underlying molecular causes of the disorder has advanced significantly.

Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation.

Neurons in the arcuate nucleus that produce AgRP, NPY, and GABA (AgRP neurons) promote feeding. Ablation of AgRP neurons in adult mice results in Fos activation in postsynaptic neurons and starvation. Loss of GABA is implicated in starvation because chronic subcutaneous delivery of bretazenil (a GABA(A) receptor partial agonist) suppresses Fos activation and maintains feeding during ablation of AgRP neurons. Moreover, under these conditions, direct delivery of bretazenil into the parabrachial nucleus (PBN), a direct target of AgRP neurons that also relays gustatory and visceral sensory information, is sufficient to maintain feeding. Conversely, inactivation of GABA biosynthesis in the ARC or blockade of GABA(A) receptors in the PBN of mice promote anorexia. We suggest that activation of the PBN by AgRP neuron ablation or gastrointestinal malaise inhibits feeding. Chronic delivery of bretazenil during loss of AgRP neurons provides time to establish compensatory mechanisms that eventually allow mice to eat.

Pilot study on the relationship between oral function or subjective symptoms and appetite.

OBJECTIVE: This pilot study evaluated the relationships between appetite and oral function, and between appetite and the subjective symptoms of decreased oral function. METHODS: Seventy-one adult dental clinic patients (22 males, 66.0 ± 14.0 years) participated in this study. A Council on Nutrition Appetite Questionnaire score of ≤28 indicated anorexia, and the Mini Nutritional Assessment Short-form, body mass index and skeletal muscle mass index were used to define subject characteristics. Seven oral function tests and seven subjective symptoms related to oral function were evaluated. The relationship between subject characteristics, oral function tests, subjective symptoms and anorexia was analysed using the chi-square test and univariate and multivariate logistic regression. RESULT: There were significant differences between the normal appetite group and the anorexia group for the 10-item Eating Assessment Tool (EAT-10) survey and the question 'Food remains in the oral cavity after eating' (p < .05). Univariate logistic regression found significant differences in the items of masticatory function, the EAT-10 survey and the question 'Food remains in the oral cavity after eating'. Multivariate logistic regression revealed significant differences in masticatory function (AOR 4.35; 95% CI: 1.03-18.35; p = .045) and EAT-10 (AOR 6.27; 95% CI: 1.40-24.02; p = .016). CONCLUSION: This pilot study investigated the influence of factors related to oral function on appetite. Relationships were found among poor masticatory function, poor swallowing function and anorexia.

Baseline Dysgeusia in Chemotherapy-Naïve Non-Small Cell Lung Cancer Patients: Association with Nutrition and Quality of Life.

Purpose: Dysgeusia can be found in 50% of cancer patients undergoing chemotherapy. Nonetheless, dysgeusia can be present in treatment-naïve patients, and may negatively impact nutrition and quality of life.Methods: Treatment-naïve non-small cell lung cancer (NSCLC) was assessed for dysgeusia using a self-reporting questionnaire and a rinse stimuli technique. Patients were evaluated in terms of health-related quality of life (HRQL) using the EORTC-QLQ-C30 questionnaire and in terms of nutrition using the subjective global assessment (SGA), energy consumption and body composition.Results: Among 65 treatment-naïve patients, dysgeusia was self-reported in 35%. Using the rinse stimuli technique, most of the patients perceived taste stimuli with a minimal concentration, but could not recognize the taste. Patients with dysgeusia presented significantly less lean-body mass (P = 0.027), and higher fat mass (P = 0.027). Additionally, these patients had significantly more gastrointestinal symptoms including nausea (P = 0.042), anorexia (P = 0.004), and early satiety (P < 0.0001). Dysgeusia was also associated with less food consumption (P = 0.010). Last, patients with dysgeusia had clinically-significant alterations in HRQL scales.Conclusion: Presence of dysgeusia in NSCLC patients before undergoing chemotherapy is associated with worse nutritional outcomes. The routine assessment of dysgeusia in treatment-naïve patients should be encouraged to timely assess and follow nutritional parameters.

Elevated levels of circulating fibroblast growth factor 23 with hypercalcemia following discontinuation of denosumab.

We report a case of a 47-year-old woman with hypercalcemia 6 months after discontinuation of denosumab. She underwent right mastectomy for breast cancer and had received aromatase inhibitor and denosumab therapy for 5 years. Thirst, appetite loss, and bilateral ankle pain began few months after cessation of denosumab. She was admitted to the hospital for hypercalcemia and hyperthyroidism 6 months after the last dose of denosumab. Laboratory investigations revealed hypercalcemia, normophosphatemia, normal renal function, and elevated levels of fibroblast growth factor 23 (FGF-23). Serum tartrate-resistant acid phosphatase 5b and urine N-terminal cross-linked telopeptide of type I collagen were both elevated, and bone scintigraphy revealed increase of whole bone uptake. Radiological examinations showed no recurrence of breast cancer or tumors that secrete intact PTH or FGF-23. Hypercalcemia, which lasted for 1 month, was refractory to discontinuation of the aromatase inhibitor, normalization of thyroid hormone levels, saline hydration, and calcitonin administration, but was effectively treated with zoledronic acid. Abnormal uptake on bone scintigraphy and ankle pain both resolved a few months after treatment, and hypercalcemia has not recurred in the ensuing 2 years. In conclusion, we found elevated levels of circulating FGF-23 with hypercalcemia following the discontinuation of denosumab. FGF-23 might be a surrogate marker for massive bone resorption triggered by discontinuation of long-term denosumab treatment.

Sexually dimorphic behavioral effects of maternal separation in anorexic rats.

Exposure to negative events during the neonatal period is one of the leading factors contributing to the development of psychiatric disorders, including anorexia nervosa. In this study, we investigated the effects of maternal separation (MS) on the development of anorexia in rodents using the mild-stress form of the activity-based anorexia (ABA) model (2 hr of free access to a running wheel and a 1-hr feeding test) in both male and female rats. We assessed anxiety-like and locomotor behavior and hyperactivity with the open field and elevated plus maze tests. Our results showed that ABA rats of both sexes displayed hyperactive behavior associated with reduced anxiety-like behavior when compared to controls. However, a sexually dimorphic effect of MS emerged in anorexic rats: while the females exposed to MS + ABA were hyperactive with diminished anxiety-related behaviors compared to females of the ABA group, MS in males attenuated or did not alter the effects of the ABA protocol. In conclusion, our data reveal that the synergistic effects of MS and ABA on physical activity and anxiety-like behavior act in opposite directions in the two sexes.

Changes in adipose tissue physiology during the first two weeks posthatch in chicks from lines selected for low or high body weight.

Chickens from lines selected for low (LWS) or high (HWS) body weight (BW) differ in appetite and adiposity. Mechanisms associated with the predisposition to becoming obese are unclear. The objective of the experiment was to evaluate developmental changes in depot-specific adipose tissue during the first 2 wk posthatch. Subcutaneous (SQ), clavicular (CL), and abdominal (AB) depots were collected at hatch (DOH) and days 4 (D4) and 14 (D14) posthatch for histological and mRNA measurements. LWS chicks had decreased SQ fat mass on a BW basis with reduced adipocyte size from DOH to D4 and increased BW and fat mass with unchanged adipocyte size from D4 to D14. HWS chicks increased in BW from DOH to D14 and increased in fat mass in all three depots with enlarged adipocytes in the AB depot from D4 to D14. Meanwhile, CCAAT/enhancer-binding protein-α, neuropeptide Y, peroxisome proliferator-activated receptor-γ, and acyl-CoA dehydrogenase mRNAs differed among depots between lines at different ages. Plasma nonesterified fatty acids were greater in LWS than HWS at D4 and D14. From DOH to D4, LWS chicks mobilized SQ fat and replenished the reservoir through hyperplasia, whereas HWS chicks were dependent on hyperplasia and hypertrophy to maintain adipocyte size and depot mass. From D4 to D14, adipose tissue catabolism and adipogenesis slowed. Whereas LWS fat depots and adipocyte sizes remained stable, HWS chicks rapidly accumulated fat in CL and AB depots. Chicks predisposed to be anorexic or obese have different fat development patterns during the first 2 wk posthatch.

Guanfacine decreases symptoms of cannabis withdrawal in daily cannabis smokers.

The α2a-adrenergic agonist, lofexidine, reduced cannabis withdrawal-related sleep disruption in the laboratory, but side effects (e.g. fatigue, hypotension) limit its utility as a treatment for cannabis use disorder. This study tested the potential efficacy and tolerability of a daily bedtime administration of the FDA-approved α2a-adrenergic agonist, guanfacine, in a human laboratory model of cannabis use disorder. Daily, nontreatment-seeking cannabis smokers (13M, 2F) completed a within-subject study comprising two 9-day inpatient study phases. Each phase tested the effects of daily placebo or immediate-release guanfacine (2 mg) on cannabis intoxication (5.6 percent THC; 2 days), withdrawal (4 days of abstinence) and subsequent 'relapse' (3 days of cannabis self-administration). Ratings of mood, sleep, cardiovascular effects, food intake, psychomotor performance and cannabis self-administration were assessed. An outpatient phase preceded each inpatient phase for medication clearance or dose induction. Under placebo medication conditions, cannabis abstinence produced significant withdrawal, including irritability, sleep disruption and anorexia. Guanfacine reduced ratings of irritability and improved objective measures of sleep during cannabis withdrawal relative to placebo but did not reduce cannabis self-administration. Guanfacine was well tolerated with little evidence of fatigue and only small decreases in blood pressure: no dose was held due to hypotension. Thus, a single daily administration of guanfacine at bedtime improved sleep and mood during cannabis withdrawal relative to placebo. This positive signal supports further studies varying the guanfacine dose, formulation or frequency of administration, or combining it with other medications to increase the likelihood of having an impact on cannabis use.

Are the therapeutic strategies in anorexia of ageing effective on nutritional status? A systematic review with meta-analysis.

BACKGROUND: Anorexia of ageing (AA) may be considered as a risk factor for frailty and has an important impact on quality of life, morbidity and mortality. METHODS: A systematic review and a meta-analysis were performed to summarise the results from several trials on the effectiveness of treatments in AA, as associated with depression, sensory impairment of taste and smell, decreased appetite or early satiety, and disability. Eligible studies were required to report baseline and follow-up values, the mean change (∆-change) from baseline, and/or the mean difference among intervention groups versus control group, concerning food intake (kcal/daily) and/or nutritional outcomes, such as body weight, body mass index, albumin and Mini Nutritional Assessment. RESULTS: The systematic review included 20 papers based on different therapeutic approaches concerning food intake and/or nutritional outcomes. The results of the meta-analysis indicate that the interventions for AA have an important impact on body weight [+1.59 kg; 95% confidence interval (CI) = 1.48-+1.71 kg; P < 0.001) and on energy intake (+56.09 kcal; 95% CI = -54.05 to +166.25 kcal; P = 0.32). Regarding secondary outcomes, it was not possible to meta-analyse the limited amount of data availab le. CONCLUSIONS: The different variants of AA need to be defined because diverse therapeutic approaches are available. A more precise definition of the functional impairments associated with AA may allow a more correct decision about the most appropriate therapy to be prescribed. Moreover, this may allow for a more effective performance of the different therapeutic approaches once they are better targeted to the different scenarios of AA.

AgRP Neurons Can Increase Food Intake during Conditions of Appetite Suppression and Inhibit Anorexigenic Parabrachial Neurons.

To maintain energy homeostasis, orexigenic (appetite-inducing) and anorexigenic (appetite suppressing) brain systems functionally interact to regulate food intake. Within the hypothalamus, neurons that express agouti-related protein (AgRP) sense orexigenic factors and orchestrate an increase in food-seeking behavior. In contrast, calcitonin gene-related peptide (CGRP)-expressing neurons in the parabrachial nucleus (PBN) suppress feeding. PBN CGRP neurons become active in response to anorexigenic hormones released following a meal, including amylin, secreted by the pancreas, and cholecystokinin (CCK), secreted by the small intestine. Additionally, exogenous compounds, such as lithium chloride (LiCl), a salt that creates gastric discomfort, and lipopolysaccharide (LPS), a bacterial cell wall component that induces inflammation, exert appetite-suppressing effects and activate PBN CGRP neurons. The effects of increasing the homeostatic drive to eat on feeding behavior during appetite suppressing conditions are unknown. Here, we show in mice that food deprivation or optogenetic activation of AgRP neurons induces feeding to overcome the appetite suppressing effects of amylin, CCK, and LiCl, but not LPS. AgRP neuron photostimulation can also increase feeding during chemogenetic-mediated stimulation of PBN CGRP neurons. AgRP neuron stimulation reduces Fos expression in PBN CGRP neurons across all conditions. Finally, stimulation of projections from AgRP neurons to the PBN increases feeding following administration of amylin, CCK, and LiCl, but not LPS. These results demonstrate that AgRP neurons are sufficient to increase feeding during noninflammatory-based appetite suppression and to decrease activity in anorexigenic PBN CGRP neurons, thereby increasing food intake during homeostatic need.SIGNIFICANCE STATEMENT The motivation to eat depends on the relative balance of activity in distinct brain regions that induce or suppress appetite. An abnormal amount of activity in neurons that induce appetite can cause obesity, whereas an abnormal amount of activity in neurons that suppress appetite can cause malnutrition and a severe reduction in body weight. The purpose of this study was to determine whether a population of neurons known to induce appetite ("AgRP neurons") could induce food intake to overcome appetite-suppression following administration of various appetite-suppressing compounds. We found that stimulating AgRP neurons could overcome various forms of appetite suppression and decrease neural activity in a separate population of appetite-suppressing neurons, providing new insights into how the brain regulates food intake.

Excitatory Hindbrain-Forebrain Communication Is Required for Cisplatin-Induced Anorexia and Weight Loss.

Cisplatin chemotherapy is commonly used to treat cancer despite severe energy balance side effects. In rats, cisplatin activates nucleus tractus solitarius (NTS) projections to the lateral parabrachial nucleus (lPBN) and calcitonin-gene related peptide (CGRP) projections from the lPBN to the central nucleus of the amygdala (CeA). We demonstrated previously that CeA glutamate receptor signaling mediates cisplatin-induced anorexia and body weight loss. Here, we used neuroanatomical tracing, immunofluorescence, and confocal imaging to demonstrate that virtually all NTS→lPBN and lPBN→CeA CGRP projections coexpress vesicular glutamate transporter 2 (VGLUT2), providing evidence that excitatory projections mediate cisplatin-induced energy balance dysregulation. To test whether lPBN→CeA projection neurons are required for cisplatin-induced anorexia and weight loss, we inhibited these neurons chemogenetically using a retrograde Cre-recombinase-expressing canine adenovirus-2 in combination with Cre-dependent inhibitory Designer Receptors Exclusive Activated by Designer Drugs (DREADDs) before cisplatin treatment. Inhibition of lPBN→CeA neurons attenuated cisplatin-induced anorexia and body weight loss significantly. Using a similar approach, we additionally demonstrated that inhibition of NTS→lPBN neurons attenuated cisplatin-induced anorexia and body weight loss significantly. Together, our data support the view that excitatory hindbrain-forebrain projections are necessary for cisplatin's untoward effects on energy intake, elucidating a key neuroanatomical circuit driving pathological anorexia and weight loss that accompanies chemotherapy treatment. SIGNIFICANCE STATEMENT: Chemotherapy treatments are commonly used to treat cancers despite accompanying anorexia and weight loss that may limit treatment adherence and reduce patient quality of life. Strikingly, we lack a neural understanding of, and effective treatments for, chemotherapy-induced anorexia and weight loss. The current data characterize the excitatory nature of neural projections activated by cisplatin in rats and reveal the necessity of specific hindbrain-forebrain projections for cisplatin-induced anorexia and weight loss. Together, these findings help to characterize the neural mechanisms mediating cisplatin-induced anorexia, advancing opportunities to develop better-tolerated chemotherapies and adjuvant therapies to prevent anorexia and concurrent nutritional deficiencies during cancer treatment.

In Vitro and In Vivo Characterization of Novel Stable Peptidic Ghrelin Analogs: Beneficial Effects in the Settings of Lipopolysaccharide-Induced Anorexia in Mice.

Ghrelin, the only known orexigenic gut hormone produced primarily in the stomach, has lately gained attention as a potential treatment of anorexia and cachexia. However, its biologic stability is highly limited; therefore, a number of both peptide and nonpeptide ghrelin analogs have been synthesized. In this study, we provide in vitro and in vivo characterization of a series of novel peptide growth hormone secretagogue receptor (GHS-R1a) agonists, both under nonpathologic conditions and in the context of lipopolysaccharide (LPS)-induced anorexia. These analogs were based on our previous series modified by replacing the Ser3 with diaminopropionic acid (Dpr), the N-terminal Gly with sarcosine, and Phe4 with various noncoded amino acids. New analogs were further modified by replacing the n-octanoyl bound to Dpr3 with longer or unsaturated fatty acid residues, by incorporation of the second fatty acid residue into the molecule, or by shortening the peptide chain. These modifications preserved the ability of ghrelin analogs to bind to the membranes of cells transfected with GHS-R1a, as well as the GHS-R1a signaling activation. The selected analogs exhibited long-lasting and potent orexigenic effects after a single s.c. administration in mice. The stability of new ghrelin analogs in mice after s.c. administration was significantly higher when compared with ghrelin and [Dpr3]ghrelin, with half-lives of approximately 2 hours. A single s.c. injection of the selected ghrelin analogs in mice with LPS-induced anorexia significantly increased food intake via the activation of orexigenic pathways and normalized blood levels of proinflammatory cytokines, demonstrating the anti-inflammatory potential of the analogs.

Physiological response to central and peripheral injection of prostaglandin D2 in chicks.

Prostaglandin D2 (PGD2) is associated with a diverse array of functions in mammals including regulation of appetite, body temperature, sleep, and immune responses. Although much is known about the effects of PGD2 in mammals, there is a lack of information about its effects in birds. Therefore, the purpose of the present study was to determine if intracerebroventricular (ICV) and intraperitoneal (IP) injections of PGD2 affect feeding, voluntary movement, crop-emptying rate, corticosterone release, and cloacal temperature in chicks (Gallus gallus). ICV injection of PGD2 was associated with a reduction in food intake, a reduction in voluntary movement, an increase in the time spent sitting, a decline in crop emptying rate, and also short-term hypothermia. Central injection of PGD2 also decreased the plasma glucose concentration in chicks while it tended to increase the plasma corticosterone concentration. On the other hand, except for crop emptying, such physiological changes are not observed after IP injection of PGD2. In sum, the present study suggests that PGD2 induces anorexia, change in behavior, decline in crop empting rate, hypoglycemia and hypothermia, but most of these effects are exerted via central nervous system in chicks.

Female Athlete Triad/Relative Energy Deficiency in Sport: A Perspective Interview With Professor Barbara Drinkwater.

Barbara Drinkwater has been a lifelong champion of equality for women in many areas of life well before it was widely accepted. Her "walking the walk" of women breaking barriers in traditional male roles in administration and leadership is exemplified by her election as the first woman president of the American College of Sports Medicine in 1988. Some of the controversial areas in which Barbara was vocal in the arena of women in sport, besides triad/relative energy deficiency in sport, include increased opportunity and participation, total equality, acceptance of diversity, intolerance of harassment and abuse, and fairness with transgender athletes. She co-founded the evidence-based advocacy group on the international stage known as Women Sport International. As a physiologist, Barbara has had a major influence on attention to the health of the female athlete, and she produced the original pioneering work in the field. Her impactful study, "Bone mineral density after resumption of menses in amenorrheic athletes," was published in the Journal of the American Medical Association in 1986. Since that time, the female athlete triad has set the stage for research and treatment to enhance women in physical activity at all levels.

Interhemispheric functional connectivity in anorexia and bulimia nervosa.

The functional interplay between hemispheres is fundamental for behavioral, cognitive, and emotional control. Anorexia nervosa (AN) and bulimia nervosa (BN) have been largely studied with brain magnetic resonance imaging (MRI) in relation to the functional mechanisms of high-level processing, but not in terms of possible inter-hemispheric functional connectivity anomalies. Using resting-state functional MRI (fMRI), voxel-mirrored homotopic connectivity (VMHC) and regional inter-hemispheric spectral coherence (IHSC) were studied in 15 AN and 13 BN patients and 16 healthy controls (HC). Using T1-weighted and diffusion tensor imaging MRI scans, regional VMHC values were correlated with the left-right asymmetry of corresponding homotopic gray matter volumes and with the white matter callosal fractional anisotropy (FA). Compared to HC, AN patients exhibited reduced VMHC in cerebellum, insula, and precuneus, while BN patients showed reduced VMHC in dorso-lateral prefrontal and orbito-frontal cortices. The regional IHSC analysis highlighted that the inter-hemispheric functional connectivity was higher in the 'Slow-5' band in all regions except the insula. No group differences in left-right structural asymmetries and in VMHC vs. callosal FA correlations were significant in the comparisons between cohorts. These anomalies, not explained by structural changes, indicate that AN and BN, at least in their acute phase, are associated with a loss of inter-hemispheric connectivity in regions implicated in self-referential, cognitive control and reward processing. These findings may thus gather novel functional markers to explore aberrant features of these eating disorders.

Anorexia of aging and its role for frailty.

PURPOSE OF REVIEW: The purpose of this review is to examine the concept of anorexia of aging, including its complex pathophysiology and the multifaceted interventions required to prevent adverse health consequences from this geriatric syndrome. RECENT FINDINGS: Anorexia of aging is extremely common, occurring in up to 30% of elderly individuals; however, this diagnosis is frequently missed or erroneously attributed to a normal part of the aging process. With aging, impairments in smell and taste can limit the desire to eat. Alterations in stress hormones and inflammatory mediators can lead to excess catabolism, cachexia, and reduced appetite. In addition, mood disorders, such as anxiety and depression, are powerful inhibitors of appetite. Anorexia of aging, with its negative consequences on weight and muscle mass, is a risk factor for the development of frailty and is important to screen for, as early intervention is key to reversing this debilitating condition. SUMMARY: Anorexia of aging is a complex geriatric syndrome and a direct risk factor for frailty and thus should not be accepted as normal consequence of aging. Early diagnosis and formulating a plan for targeted interventions is critical to prevent disability and preserve function in elderly patients.

The role of hypothalamic inflammation, the hypothalamic-pituitary-adrenal axis and serotonin in the cancer anorexia-cachexia syndrome.

PURPOSE OF REVIEW: In cancer patients, the development of cachexia (muscle wasting) is frequently aggravated by anorexia (loss of appetite). Their concurrence is often referred to as anorexia-cachexia syndrome. This review focusses on the recent evidence underlining hypothalamic inflammation as key driver of these processes. Special attention is given to the involvement of hypothalamic serotonin. RECENT FINDINGS: The anorexia-cachexia syndrome is directly associated with higher mortality in cancer patients. Recent reports confirm its severe impact on the quality of life of patients and their families.Hypothalamic inflammation has been shown to contribute to muscle and adipose tissue loss in cancer via central hypothalamic interleukine (IL)1ß-induced activation of the hypothalamic-pituitary-adrenal axis. The resulting release of glucocorticoids directly stimulates catabolic processes in these tissues via activation of the ubiquitin-proteosome pathway. Next to this, hypothalamic inflammation has been shown to reduce food intake in cancer by triggering changes in orexigenic and anorexigenic responses via upregulation of serotonin availability and stimulation of its signalling pathways in hypothalamic tissues. This combination of reduced food intake and stimulation of tissue catabolism represents a dual mechanism by which hypothalamic inflammation contributes to the development and maintenance of anorexia and cachexia in cancer. SUMMARY: Hypothalamic inflammation is a driving force in the development of the anorexia-cachexia syndrome via hypothalamic-pituitary-adrenal axis and serotonin pathway activation.

Enlargement of Axo-Somatic Contacts Formed by GAD-Immunoreactive Axon Terminals onto Layer V Pyramidal Neurons in the Medial Prefrontal Cortex of Adolescent Female Mice Is Associated with Suppression of Food Restriction-Evoked Hyperactivity and Resilience to Activity-Based Anorexia.

Many, but not all, adolescent female mice that are exposed to a running wheel while food restricted (FR) become excessive wheel runners, choosing to run even during the hours of food availability, to the point of death. This phenomenon is called activity-based anorexia (ABA). We used electron microscopic immunocytochemistry to ask whether individual differences in ABA resilience may correlate with the lengths of axo-somatic contacts made by GABAergic axon terminals onto layer 5 pyramidal neurons (L5P) in the prefrontal cortex. Contact lengths were, on average, 40% greater for the ABA-induced mice, relative to controls. Correspondingly, the proportion of L5P perikaryal plasma membrane contacted by GABAergic terminals was 45% greater for the ABA mice. Contact lengths in the anterior cingulate cortex correlated negatively and strongly with the overall wheel activity after FR (R = -0.87, P < 0.01), whereas those in the prelimbic cortex correlated negatively with wheel running specifically during the hours of food availability of the FR days (R = -0.84, P < 0.05). These negative correlations support the idea that increases in the glutamic acid decarboxylase (GAD) terminal contact lengths onto L5P contribute toward ABA resilience through suppression of wheel running, a behavior that is intrinsically rewarding and helpful for foraging but maladaptive within a cage.

Eating in mice with gastric bypass surgery causes exaggerated activation of brainstem anorexia circuit.

BACKGROUND/OBJECTIVE: Obesity and metabolic diseases are at an alarming level globally and increasingly affect children and adolescents. Gastric bypass and other bariatric surgeries have proven remarkably successful and are increasingly performed worldwide. Reduced desire to eat and changes in eating behavior and food choice account for most of the initial weight loss and diabetes remission after surgery, but the underlying mechanisms of altered gut-brain communication are unknown. SUBJECTS/METHODS: To explore the potential involvement of a powerful brainstem anorexia pathway centered around the lateral parabrachial nucleus (lPBN), we measured meal-induced neuronal activation by means of c-Fos immunohistochemistry in a new high-fat diet-induced obese mouse model of Roux-en-Y gastric bypass (RYGB) at 10 and 40 days after RYGB or sham surgery. RESULTS: Voluntary ingestion of a meal 10 days after RYGB, but not after sham surgery, strongly and selectively activates calcitonin gene-related peptide neurons in the external lPBN as well as neurons in the nucleus tractus solitarius, area postrema and medial amygdala. At 40 days after surgery, meal-induced activation in all these areas was greatly diminished and did not reach statistical significance. CONCLUSIONS: The neural activation pattern and dynamics suggest a role of the brainstem anorexia pathway in the early effects of RYGB on meal size and food intake that may lead to adaptive neural and behavioral changes involved in the control of food intake and body weight at a lower level. However, selective inhibition of this pathway will be required for a more causal implication.

Cancer and treatment-related symptoms are associated with mobility disability in women with ovarian cancer: A cross-sectional study.

OBJECTIVE: To examine the prevalence of symptom-related mobility disability and identify specific symptoms and other factors associated with mobility disability among a national sample of ovarian cancer (OC) survivors. METHODS: Descriptive, correlational secondary analysis of a National Ovarian Cancer Coalition mailed survey of women with a history of OC (n=713). We used the Symptom Representation Questionnaire (SRQ), the MD Anderson Symptom Inventory (MDASI) Interference Scale, and medical and demographic information to determine prevalence of symptom-related mobility disability. We constructed a multiple linear regression model to determine the relative contributions of specific symptoms and other factors to mobility disability. RESULTS: A majority of the sample (60.0%) reported symptom-related mobility disability. Independent predictors included: > one comorbidity (ß=0.112, p=0.001), active OC (ß=0.111, p=0.037), abdominal bloating (ß=0.097, p=0.006), fatigue (ß=0.314, p<0.001), lack of appetite (ß=0.072, p=0.045), numbness/tingling (ß=0.134, p<0.001), and pain (ß=0.194, p<0.001). The model explained 41.5% of the variance in symptom-related mobility disability (R2=0.415). Unexpectedly, age (ß=-0.028, p=0.412) and current chemotherapy (ß=0.107, p=0.118) were not significant predictors. CONCLUSIONS: Symptom-related mobility disability is common among women with OC and is associated with medical comorbidities, abdominal bloating, fatigue, lack of appetite, numbness/tingling, and pain. Longitudinal research should clarify the relationship of these symptoms to mobility disability and determine whether effective symptom management minimizes disability.