Development of activity-based anorexia requires PKC-δ neurons in two central extended amygdala nuclei.

Anorexia nervosa (AN) is a serious psychiatric disease, but the neural mechanisms underlying its development are unclear. A subpopulation of amygdala neurons, marked by expression of protein kinase C-delta (PKC-δ), has previously been shown to regulate diverse anorexigenic signals. Here, we demonstrate that these neurons regulate development of activity-based anorexia (ABA), a common animal model for AN. PKC-δ neurons are located in two nuclei of the central extended amygdala (EAc): the central nucleus (CeA) and oval region of the bed nucleus of the stria terminalis (ovBNST). Simultaneous ablation of CeAPKC-δ and ovBNSTPKC-δ neurons prevents ABA, but ablating PKC-δ neurons in the CeA or ovBNST alone is not sufficient. Correspondingly, PKC-δ neurons in both nuclei show increased activity with ABA development. Our study shows how neurons in the amygdala regulate ABA by impacting both feeding and wheel activity behaviors and support a complex heterogeneous etiology of AN.

Orexin-A attenuated motion sickness through modulating neural activity in hypothalamus nuclei.

BACKGROUND AND PURPOSE: We evaluated the hypothesis that central orexin application could counteract motion sickness responses through regulating neural activity in target brain areas. EXPERIMENTAL APPROACH: Thec effects of intracerebroventricular (i.c.v.) injection of orexin-A and SB-334867 (OX1 antagonist) on motion sickness-induced anorexia, nausea-like behaviour (conditioned gaping), hypoactivity and hypothermia were investigated in rats subjected to Ferris wheel-like rotation. Orexin-A responsive brain areas were identified using Fos immunolabelling and were verified via motion sickness responses after intranucleus injection of orexin-A, SB-334867 and TCS-OX2-29 (OX2 antagonist). The efficacy of intranasal application of orexin-A versus scopolamine on motion sickness symptoms in cats was also investigated. KEY RESULTS: Orexin-A (i.c.v.) dose-dependently attenuated motion sickness-related behavioural responses and hypothermia. Fos expression was inhibited in the ventral part of the dorsomedial hypothalamus (DMV) and the paraventricular nucleus (PVN), but was enhanced in the ventral part of the premammillary nucleus ventral part (PMV) by orexin-A (20 µg) in rotated animals. Motion sickness responses were differentially inhibited by orexin-A injection into the DMV (anorexia and hypoactivity), the PVN (conditioned gaping) and the PMV (hypothermia). SB-334867 and TCS-OX2-29 (i.c.v. and intranucleus injection) inhibited behavioural and thermal effects of orexin-A. Orexin-A (60 µg·kg-1) and scopolamine inhibited rotation-induced emesis and non-retching/vomiting symptoms, while orexin-A also attenuated anorexia with mild salivation in motion sickness cats. CONCLUSION AND IMPLICATIONS: Orexin-A might relieve motion sickness through acting on OX1 and OX2 receptors in various hypothalamus nuclei. Intranasal orexin-A could be a potential strategy against motion sickness.

Creation of a Peptide Antagonist of the GFRAL-RET Receptor Complex for the Treatment of GDF15-Induced Malaise.

Growth differentiation factor 15 (GDF15) is a contributor to nausea, emesis, and anorexia following chemotherapy via binding to the GFRAL-RET receptor complex expressed in hindbrain neurons. Therefore, GDF15-mediated GFRAL-RET signaling is a promising target for improving treatment outcomes for chemotherapy patients. We developed peptide-based antagonists of GFRAL that block GDF15-mediated RET recruitment. Our initial library screen led to five novel peptides. Surface plasmon resonance and flow cytometric analyses of the most efficacious of this group, termed GRASP, revealed its capacity to bind to GFRAL. In vivo studies in rats revealed that GRASP could attenuate GDF15-induced nausea and anorexia resulting from cisplatin. Combined with Ondansetron, GRASP led to an even greater attenuation of the anorectic effects of cisplatin compared to either agent alone. Our results highlight the beneficial effects of GRASP as an agent to combat chemotherapy-induced malaise. GRASP may also be effective in other conditions associated with elevated levels of GDF15.

Expanded insights into the neural component of the activity-based anorexia animal model - morphological changes in the enteric nervous system and altered pain perception.

Anorexia nervosa (AN) is an eating disorder characterized by distinct etiopathogenetic concepts that are gradually being linked together to unravel the dominant pathophysiological pathways underlying the disease. Excessive food restrictions, often accompanied by over-exercise and undertaken to lose weight, lead to the development of numerous complications. The biological concept of neurohormonal dysfunction in AN seems incomplete without demonstrating or excluding the role of the enteric nervous system (ENS). Using an animal model of activity-based anorexia (ABA), we conducted the preliminary assessment of the ENS structure. Here we show, in preparations stained by immunohistochemistry with anti- ChAT, anti-NOS, anti-PGP 9.5, anti-c-fos, and anti-TH antibodies, a lower density of cholinergic and nitrergic nerve fibers as well as reduced neuronal activity in myenteric plexus. Such structural and functional damage to the ENS may be responsible for a number of gastrointestinal symptoms that worsen the course of the disease. In addition, we expanded the study to address the unresolved issue of mechanical and thermal pain sensitivity in AN. The Von Frey and hot plate tests revealed, that in ABA animals, the pain threshold for mechanical stimulus decreases while for thermal increases. In this way, we have significantly supplemented the background of AN with potentially observable nervous system changes which may influence the evolution of the therapeutic approach in the future.

CD4+ T cells regulate sickness-induced anorexia and fat wasting during a chronic parasitic infection.

Infections cause catabolism of fat and muscle stores. Traditionally, studies have focused on understanding how the innate immune system contributes to energy stores wasting, while the role of the adaptive immune system remains elusive. In the present study, we examine the role of the adaptive immune response in adipose tissue wasting and cachexia using a murine model of the chronic parasitic infection Trypanosoma brucei, the causative agent of sleeping sickness. We find that the wasting response occurs in two phases, with the first stage involving fat wasting caused by CD4+ T cell-induced anorexia and a second anorexia-independent cachectic stage that is dependent on CD8+ T cells. Fat wasting has no impact on host antibody-mediated resistance defenses or survival, while later-stage muscle wasting contributes to disease-tolerance defenses. Our work reveals a decoupling of adaptive immune-mediated resistance from the catabolic response during infection.

Aging Changes the Efficacy of Central Urocortin 2 to Induce Weight Loss in Rats.

Middle-aged obesity and aging cachexia present healthcare challenges. Central responsiveness to body-weight-reducing mediators, e.g., to leptin, changes during aging in a way, which may promote middle-aged obesity and aging cachexia. Leptin is connected to urocortin 2 (Ucn2), an anorexigenic and hypermetabolic member of the corticotropin family. We aimed to study the role of Ucn2 in middle-aged obesity and aging cachexia. The food intake, body weight and hypermetabolic responses (oxygen consumption, core temperature) of male Wistar rats (3, 6, 12 and 18 months) were tested following intracerebroventricular injections of Ucn2. Following one central injection, Ucn2-induced anorexia lasted for 9 days in the 3-month, 14 days in the 6-month and 2 days in the 18-month group. Middle-aged 12-month rats failed to show anorexia or weight loss. Weight loss was transient (4 days) in the 3-month, 14 days in the 6-month and slight but long-lasting in the 18-month rats. Ucn2-induced hypermetabolism and hyperthermia increased with aging. The age-dependent changes in the mRNA expression of Ucn2 detected by RNAscope in the paraventricular nucleus correlated with the anorexigenic responsiveness. Our results show that age-dependent changes in Ucn2 may contribute to middle-aged obesity and aging cachexia. Ucn2 shows potential in the prevention of middle-aged obesity.

GDNF family receptor alpha-like antagonist antibody alleviates chemotherapy-induced cachexia in melanoma-bearing mice.

BACKGROUND: Patients with cancer undergoing chemotherapy experience cachexia with anorexia, body weight loss, and the depletion of skeletal muscles and adipose tissues. Effective treatment strategies for chemotherapy-induced cachexia are scarce. The growth differentiation factor 15 (GDF15)/GDNF family receptor alpha-like (GFRAL)/rearranged during transfection (RET) axis is a critical signalling pathway in chemotherapy-induced cachexia. In this study, we developed a fully human GFRAL antagonist antibody and investigated whether it inhibits the GDF15/GFRAL/RET axis, thereby alleviating chemotherapy-induced cachexia in tumour-bearing mice. METHODS: Anti-GFRAL antibodies were selected via biopanning, using a human combinatorial antibody phage library. The potent GFRAL antagonist antibody A11 was selected via a reporter cell assay and its inhibitory activity of GDF15-induced signalling was evaluated using western blotting. To investigate the in vivo function of A11, a tumour-bearing mouse model was established by inoculating 8-week-old male C57BL/6 mice with B16F10 cells (n = 10-16 mice per group). A11 was administered subcutaneously (10 mg/kg) 1 day before intraperitoneal treatment with cisplatin (10 mg/kg). Animals were assessed for changes in food intake, body weight, and tumour volume. Plasma and key metabolic tissues such as skeletal muscles and adipose tissues were collected for protein and mRNA expression analysis. RESULTS: A11 reduced serum response element-luciferase reporter activity up to 74% (P < 0.005) in a dose-dependent manner and blocked RET phosphorylation up to 87% (P = 0.0593), AKT phosphorylation up to 28% (P = 0.0593) and extracellular signal regulatory kinase phosphorylation up to 75% (P = 0.0636). A11 inhibited the action of cisplatin-induced GDF15 on the brainstem and decreased GFRAL-positive neuron population expressing c-Fos in the area postrema and nucleus of the solitary tract by 62% in vivo (P < 0.05). In a melanoma mouse model treated with cisplatin, A11 recovered anorexia by 21% (P < 0.05) and tumour-free body weight loss by 13% (P < 0.05). A11 significantly improved the cisplatin-induced loss of skeletal muscles (quadriceps: 21%, gastrocnemius: 9%, soleus: 13%, P < 0.05) and adipose tissues (epididymal white adipose tissue: 37%, inguinal white adipose tissue: 51%, P < 0.05). CONCLUSIONS: Our study suggests that GFRAL antagonist antibody may alleviate chemotherapy-induced cachexia, providing a novel therapeutic approach for patients with cancer experiencing chemotherapy-induced cachexia.

Current advancements in pharmacotherapy for cancer cachexia.

INTRODUCTION: Cancer cachexia is a multifactorial metabolic syndrome associated with a pathophysiology intertwined with increased inflammatory response, anorexia, metabolic dysregulation, insulin resistance, and hormonal alterations, which together generate a negative energy balance in favor of catabolism. The development of therapeutic strategies to treat cancer cachexia has always been related to clinical interventions with increased food intake/supplementation, physical exercise regimens, and/or medication to attenuate catabolism and increase the anabolic response. However, the approval of drugs by regulatory agencies has always been a challenge. AREAS COVERED: This review outlines the main pharmacotherapy findings in cancer cachexia as well as the ongoing clinical trials that have evaluated changes in body composition and muscle function. The National Library of Medicine (PubMed) was used as search tool. EXPERT OPINION: The pharmacological therapy for cachexia should be focused on improving body composition, muscle function, and mortality, although none of the compounds used so far was able to demonstrate positive results beyond increased appetite and improvements in body composition. Ponsegromab (GDF15 inhibitor), a new compound that has just entered a phase II clinical trial, is a promising candidate to treat cancer cachexia and may produce exciting results if the study can be conducted as planned.

Melanocortin-4 receptors on neurons in the parabrachial nucleus mediate inflammation-induced suppression of food-seeking behavior.

Anorexia is a common symptom during infectious and inflammatory disease. Here we examined the role of melanocortin-4 receptors (MC4Rs) in inflammation-induced anorexia. Mice with transcriptional blockage of the MC4Rs displayed the same reduction of food intake following peripheral injection of lipopolysaccharide as wild type mice but were protected against the anorexic effect of the immune challenge in a test in which fasted animals were to use olfactory cues to find a hidden cookie. By using selective virus-mediated receptor re-expression we demonstrate that the suppression of the food-seeking behavior is subserved by MC4Rs in the brain stem parabrachial nucleus, a central hub for interoceptive information involved in the regulation of food intake. Furthermore, the selective expression of MC4R in the parabrachial nucleus also attenuated the body weight increase that characterizes MC4R KO mice. These data extend on the functions of the MC4Rs and show that MC4Rs in the parabrachial nucleus are critically involved in the anorexic response to peripheral inflammation but also contribute to body weight homeostasis during normal conditions.

Individual differences in the positive outcome from adolescent ketamine treatment in a female mouse model of anorexia nervosa involve drebrin A at excitatory synapses of the medial prefrontal cortex.

Anorexia nervosa (AN) is a mental illness with the highest rates of mortality and relapse, and no approved pharmacological treatment. Using an animal model of AN, called activity-based anorexia (ABA), we showed earlier that a single intraperitoneal injection of ketamine at a dose of 30 mg/kg (30mgKET), but not 3 mg/kg (3mgKET), has a long-lasting effect upon adolescent females of ameliorating anorexia-like symptoms through the following changes: enhanced food consumption and body weight; reduced running and anxiety-like behavior. However, there were also individual differences in the drug's efficacy. We hypothesized that individual differences in ketamine's ameliorative effects involve drebrin A, an F-actin-binding protein known to be required for the activity-dependent trafficking of NMDA receptors (NMDARs). We tested this hypothesis by electron microscopic quantifications of drebrin A immunoreactivity at excitatory synapses of pyramidal neurons (PN) and GABAergic interneurons (GABA-IN) in deep layer 1 of prefrontal cortex (PFC) of these mice. Results reveal that (1) the areal density of excitatory synapses on GABA-IN is greater for the 30mgKET group than the 3mgKET group; (2) the proportion of drebrin A+ excitatory synapses is greater for both PN and GABA-IN of 30mgKET than 3mgKET group. Correlation analyses with behavioral measurements revealed that (3) 30mgKET's protection is associated with reduced levels of drebrin A in the cytoplasm of GABA-IN and higher levels at extrasynaptic membranous sites of PN and GABA-IN; (5) altogether pointing to 30mgKET-induced homeostatic plasticity that engages drebrin A at excitatory synapses of both PN and GABA-IN.

AgRP neurons coordinate the mitigation of activity-based anorexia.

Anorexia nervosa (AN) is a debilitating and deadly disease characterized by low body mass index due to diminished food intake, and oftentimes concurrent hyperactivity. A high percentage of AN behavioral and metabolic phenotypes can be replicated in rodents given access to a voluntary running wheel and subject to food restriction, termed activity-based anorexia (ABA). Despite the well-documented bodyweight loss observed in AN human patients and ABA rodents, much less is understood regarding the neurobiological underpinnings of these maladaptive behaviors. Hunger-promoting hypothalamic agouti-related peptide (AgRP) neurons have been well characterized in their ability to regulate appetite, yet much less is known regarding their activity and function in the mediation of food intake during ABA. Here, feeding microstructure analysis revealed ABA mice decreased food intake due to increased interpellet interval retrieval and diminished meal number. Longitudinal activity recordings of AgRP neurons in ABA animals exhibited a maladaptive inhibitory response to food, independent of basal activity changes. We then demonstrated that ABA development or progression can be mitigated by chemogenetic AgRP activation through the reprioritization of food intake (increased meal number) over hyperactivity, but only during periods of food availability. These results elucidate a potential neural target for the amelioration of behavioral maladaptations present in AN patients.

Different Effects of Low Selenite and Selenium-Nanoparticle Supplementation on Adipose Tissue Function and Insulin Secretion in Adolescent Male Rats.

Adolescence is a period of intense growth and endocrine changes, and obesity and insulin-resistance processes during this period have lately been rising. Selenium (Se) homeostasis is related to lipid metabolism depending on the form and dose of Se. This study tests the actions of low-dose selenite and Se nanoparticles (SeNPs) on white (WAT) and brown adipose tissue (BAT) deposition, insulin secretion, and GPx1, IRS-1 and FOXO3a expression in the WAT of adolescent rats as regards oxidative stress, adipocyte length and adipokine secretion. Four groups of male adolescent rats were treated: control (C), low selenite supplementation (S), low SeNP supplementation (NS) and moderate SeNP supplementation (NSS). Supplementation was received orally through water intake; NS and NSS rats received two- and tenfold more Se than C animals, respectively. SeNPs were obtained by reducing Se tetrachloride in the presence of ascorbic acid. For the first time in vivo, it was demonstrated that low selenite supplementation contributed to increased adipogenesis via the insulin signaling pathway and LCN2 modulation, while low SeNP administration prevented fat depots in WAT via the decrease in insulin signaling and FOXO3a autophagy in WAT, lowering inflammation. These effects were independent of GPx1 expression or activity in WAT. These findings provide data for dietary approaches to prevent obesity and/or anorexia during adolescence. These findings may be relevant to future studies looking at a nutritional approach aimed at pre-venting obesity and/or anorexia in adolescence.

Atractylodin alleviates cancer anorexia-cachexia syndrome by regulating NPY through hypothalamic Sirt1/AMPK axis-induced autophagy.

Cancer anorexia-cachexia syndrome (CACS) is a complex syndrome associated with loss of muscle and adipose tissue and weight loss, and is a major lethal factor in the later stages of cancer. The mechanism of action of CACS is not fully understood and there are no drugs specifically approved for its treatment. Atractylodin, the main active component of Atractylodes lancea, is widely used in the treatment of digestive disorders and has the ability to reduce IL-1, IL-6 and TNF-α levels. Our results showed that gavage with Atractylodin increased body weight, muscle and fat weight and reduced tumor weight and volume as well as abnormally high serum concentrations of the muscle atrophy-causing cytokines IL-1ß, IL-6 and TNF-α in CACS model mice. RT-PCR data revealed that Atractylodin promoted the expression of the pro-feeding NPY and suppressed the expression of the anorexia POMC in the hypothalamus. Western blot results showed that Atractylodin promoted the expression of Sirt1 and p-AMPK in the hypothalamus, accompanied by an increase in autophagy. Furthermore, the Sirt1 inhibitor EX527 or AMPK inhibitor Compound C (CC) reversed Atractylodin-induced beneficial effects in CACS model mice. In hypothalamic cells subjected to glucose deprivation, Atractylodin increased NPY mRNA expression by enhancing AMPK-modulated autophagy; while EX527 or Compound C blunted Atractylodin-induced autophagy enhancement effect in vitro. In conclusion, Atractylodin can be used as an anti-cachexia drug and the underlying mechanism may involve the promotion of NPY expression by Sirt1/AMPK-regulated autophagy.

[Development of Therapy for Cancer Cachexia in Pancreatic Cancer].

Cancer cachexia is a metabolic disorder syndrome that causes skeletal muscle loss and progressive physical dysfunction, which is observed in more than half of patients with advanced pancreatic cancer. Cancer cachexia is considered to be associated with poor prognosis, worsening adverse events, decreased treatment compliance, and decreased treatment efficacy. The ghrelin receptor agonist leads skeletal muscle gain, weight gain, and the improvement of anorexia in patients with cancer cachexia, and has been approved as an anti-cachexia treatment in Japan. Cancer cachexia patients who present with cachexia symptoms such as appetite loss as well as weight loss are able to receive the treatment of the ghrelin receptor agonist, but the evidence for patients with advanced pancreatic cancer is limited. Further research is needed to evaluate the efficacy of the ghrelin receptor agonist for cancer cachexia in pancreatic cancer patients. Inhibition of inflammatory cytokine such as interleukin-1α and nutrition and exercise therapy are under development for anti-cachexia therapy.

Tumor cell anabolism and host tissue catabolism-energetic inefficiency during cancer cachexia.

Cancer-associated cachexia (CC) is a pathological condition characterized by sarcopenia, adipose tissue depletion, and progressive weight loss. CC is driven by multiple factors such as anorexia, excessive catabolism, elevated energy expenditure by growing tumor mass, and inflammatory mediators released by cancer cells and surrounding tissues. In addition, endocrine system, systemic metabolism, and central nervous system (CNS) perturbations in combination with cachexia mediators elicit exponential elevation in catabolism and reduced anabolism in skeletal muscle, adipose tissue, and cardiac muscle. At the molecular level, mechanisms of CC include inflammation, reduced protein synthesis, and lipogenesis, elevated proteolysis and lipolysis along with aggravated toxicity and complications of chemotherapy. Furthermore, CC is remarkably associated with intolerance to anti-neoplastic therapy, poor prognosis, and increased mortality with no established standard therapy. In this context, we discuss the spatio-temporal changes occurring in the various stages of CC and highlight the imbalance of host metabolism. We provide how multiple factors such as proteasomal pathways, inflammatory mediators, lipid and protein catabolism, glucocorticoids, and in-depth mechanisms of interplay between inflammatory molecules and CNS can trigger and amplify the cachectic processes. Finally, we highlight current diagnostic approaches and promising therapeutic interventions for CC.

Growth differentiation factor 15 (GDF15) and semaglutide inhibit food intake and body weight through largely distinct, additive mechanisms.

AIMS: To evaluate whether the potent hypophagic and weight-suppressive effects of growth differentiation factor-15 (GDF15) and semaglutide combined would be a more efficacious antiobesity treatment than either treatment alone by examining whether the neural and behavioural mechanisms contributing to their anorectic effects were common or disparate. MATERIALS/METHODS: Three mechanisms were investigated to determine how GDF15 and semaglutide induce anorexia: the potentiation of the intake suppression by gastrointestinal satiation signals; the reduction in motivation to feed; and the induction of visceral malaise. We then compared the effects of short-term, combined GDF15 and semaglutide treatment on weight loss to the individual treatments. Rat pharmaco-behavioural experiments assessed whether GDF15 or semaglutide added to the satiating effects of orally gavaged food and exogenous cholecystokinin (CCK). A progressive ratio operant paradigm was used to examine whether GDF15 or semaglutide reduced feeding motivation. Pica behaviour (ie, kaolin intake) and conditioned affective food aversion testing were used to evaluate visceral malaise. Additionally, fibre photometry studies were conducted in agouti-related protein (AgRP)-Cre mice to examine whether GDF15 or semaglutide, alone or in combination with CCK, modulate calcium signalling in hypothalamic AgRP neurons. RESULTS: Semaglutide reduced food intake by amplifying the feeding-inhibitory effect of CCK or ingested food, inhibited the activity of AgRP neurons when combined with CCK, reduced feeding motivation and induced malaise. GDF15 induced visceral malaise but, strikingly, did not affect feeding motivation, the satiating effect of ingested food or CCK signal processing. Combined GDF15 and semaglutide treatment produced greater food intake and body weight suppression than did either treatment alone, without enhancing malaise. CONCLUSIONS: GDF15 and semaglutide reduce food intake and body weight through largely distinct processes that produce greater weight loss and feeding suppression when combined.

Body weight regulation via MT1-MMP-mediated cleavage of GFRAL.

GDNF-family receptor a-like (GFRAL) has been identified as the cognate receptor of growth/differentiation factor 15 (GDF15/MIC-1), considered a key signaling axis in energy homeostasis and body weight regulation. Currently, little is known about the physiological regulation of the GDF15-GFRAL signaling pathway. Here we show that membrane-bound matrix metalloproteinase 14 (MT1-MMP/MMP14) is an endogenous negative regulator of GFRAL in the context of obesity. Overnutrition-induced obesity increased MT1-MMP activation, which proteolytically inactivated GFRAL to suppress GDF15-GFRAL signaling, thus modulating the anorectic effects of the GDF15-GFRAL axis in vivo. Genetic ablation of MT1-MMP specifically in GFRAL+ neurons restored GFRAL expression, resulting in reduced weight gain, along with decreased food intake in obese mice. Conversely, depletion of GFRAL abolished the anti-obesity effects of MT1-MMP inhibition. MT1-MMP inhibition also potentiated GDF15 activity specifically in obese phenotypes. Our findings identify a negative regulator of GFRAL for the control of non-homeostatic body weight regulation, provide mechanistic insights into the regulation of GDF15 sensitivity, highlight negative regulators of the GDF15-GFRAL pathway as a therapeutic avenue against obesity and identify MT1-MMP as a promising target.

Inhibition of POMC neurons in mice undergoing activity-based anorexia selectively blunts food anticipatory activity without affecting body weight or food intake.

Anorexia nervosa (AN) is a debilitating eating disorder characterized by severely restricted eating and significant body weight loss. In addition, many individuals also report engaging in excessive exercise. Previous research using the activity-based anorexia (ABA) model has implicated the hypothalamic proopiomelanocortin (POMC) system. Using the ABA model, Pomc mRNA has been shown to be transiently elevated in both male and female rodents undergoing ABA. In addition, the POMC peptide ß-endorphin appears to contribute to food anticipatory activity (FAA), a characteristic of ABA, as both deletion and antagonism of the µ opioid receptor (MOR) that ß-endorphin targets, results in decreased FAA. The role of ß-endorphin in reduced food intake in ABA is unknown and POMC neurons release multiple transmitters in addition to ß-endorphin. In the current study, we set out to determine whether targeted inhibition of POMC neurons themselves rather than their peptide products would lessen the severity of ABA. Inhibition of POMC neurons during ABA via chemogenetic Designer Receptors Exclusively Activated by Designer Drugs (DREADD) technology resulted in reduced FAA in both male and female mice with no significant changes in body weight or food intake. The selective reduction in FAA persisted even in the face of concurrent chemogenetic inhibition of additional cell types in the hypothalamic arcuate nucleus. The results suggest that POMC neurons could be contributing preferentially to excessive exercise habits in patients with AN. Furthermore, the results also suggest that metabolic control during ABA appears to take place via a POMC neuron-independent mechanism.

Anorexia disrupts glutamate-glutamine homeostasis associated with astroglia in the prefrontal cortex of young female rats.

Anorexia nervosa (AN) is an eating disorder characterized by self-starvation and excessive weight loss with a notorious prevalence in young women. The neurobiology of AN is unknown but murine models, like dehydration induced anorexia (DIA), reproduce weight loss and avoidance of food despite its availability. Astrocytes are known to provide homeostatic support to neurons, but it is little explored if anorexia affects this function. In this study, we tested if DIA disrupts glutamate-glutamine homeostasis associated with astrocytes in the prefrontal cortex (PFC) of young female rats. Our results showed that anorexia reduced the redox state, as well as endogenous glutamate and glutamine. These effects correlated with a reduced expression of the glutamate transporters (GLT-1 and GLAST) and glutamine synthetase, all of them are preferentially expressed by astrocytes. Accordingly, the expression of GFAP was reduced. Anorexia reduced the astrocyte density, promoted a de-ramified morphology, and augmented the de-ramified/ramified astrocyte ratio in the medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC), but not in the motor cortex (M2). The increase of a de-ramified phenotype correlated with increased expression of vimentin and nestin. Based on these results, we conclude that anorexia disrupts glutamate-glutamine homeostasis and the redox state associated with astrocyte dysfunction.

LPS induces rapid increase in GDF15 levels in mice, rats, and humans but is not required for anorexia in mice.

Growth differentiation factor 15 (GDF15), a TGFß superfamily cytokine, acts through its receptor, cell line-derived neurotrophic factorfamily receptor α-like (GFRAL), to suppress food intake and promote nausea. GDF15 is broadly expressed at low levels but increases in states of disease such as cancer, cachexia, and sepsis. Whether GDF15 is necessary for inducing sepsis-associated anorexia and body weight loss is currently unclear. To test this we used a model of moderate systemic infection in GDF15KO and GFRALKO mice with lipopolysaccharide (LPS) treatment to define the role of GDF15 signaling in infection-mediated physiologic responses. Since physiological responses to LPS depend on housing temperature, we tested the effects of subthermoneutral and thermoneutral conditions on eliciting anorexia and inducing GDF15. Our data demonstrate a conserved LPS-mediated increase in circulating GDF15 levels in mouse, rat, and human. However, we did not detect differences in LPS-induced anorexia between WT and GDF15KO or GFRALKO mice. Furthermore, there were no differences in anorexia or circulating GDF15 levels at either thermoneutral or subthermoneutral housing conditions in LPS-treated mice. These data demonstrate that GDF15 is not necessary to drive food intake suppression in response to moderate doses of LPS.NEW & NOTEWORTHY Although many responses to LPS depend on housing temperature, the anorexic response to LPS does not. LPS results in a potent and rapid increase in circulating levels of GDF15 in mice, rats, and humans. Nevertheless, GDF15 and its receptor (GFRAL) are not required for the anorexic response to systemic LPS administration. The anorexic response to LPS likely involves a myriad of complex physiological alterations.