Activation of the hypothalamic-pituitary-adrenal axis by exogenous and endogenous GDF15.

An acute increase in the circulating concentration of glucocorticoid hormones is essential for the survival of severe somatic stresses. Circulating concentrations of GDF15, a hormone that acts in the brain to reduce food intake, are frequently elevated in stressful states. We now report that GDF15 potently activates the hypothalamic-pituitary-adrenal (HPA) axis in mice and rats. A blocking antibody to the GDNF-family receptor α-like receptor completely prevented the corticosterone response to GDF15 administration. In wild-type mice exposed to a range of stressful stimuli, circulating levels of both corticosterone and GDF15 rose acutely. In the case of Escherichia coli or lipopolysaccharide injections, the vigorous proinflammatory cytokine response elicited was sufficient to produce a near-maximal HPA response, regardless of the presence or absence of GDF15. In contrast, the activation of the HPA axis seen in wild-type mice in response to the administration of genotoxic or endoplasmic reticulum toxins, which do not provoke a marked rise in cytokines, was absent in Gdf15-/- mice. In conclusion, consistent with its proposed role as a sentinel hormone, endogenous GDF15 is required for the activation of the protective HPA response to toxins that do not induce a substantial cytokine response. In the context of efforts to develop GDF15 as an antiobesity therapeutic, these findings identify a biomarker of target engagement and a previously unrecognized pharmacodynamic effect, which will require monitoring in human studies.

The cytokine GDF15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signalling.

The cytokine, GDF15, is produced in pathological states which cause cellular stress, including cancer. When over expressed, it causes dramatic weight reduction, suggesting a role in disease-related anorexia. Here, we demonstrate that the GDF15 receptor, GFRAL, is located in a subset of cholecystokinin neurons which span the area postrema and the nucleus of the tractus solitarius of the mouse. GDF15 activates GFRALAP/NTS neurons and supports conditioned taste and place aversions, while the anorexia it causes can be blocked by a monoclonal antibody directed at GFRAL or by disrupting CCK neuronal signalling. The cancer-therapeutic drug, cisplatin, induces the release of GDF15 and activates GFRALAP/NTS neurons, as well as causing significant reductions in food intake and body weight in mice. These metabolic effects of cisplatin are abolished by pre-treatment with the GFRAL monoclonal antibody. Our results suggest that GFRAL neutralising antibodies or antagonists may provide a co-treatment opportunity for patients undergoing chemotherapy.

GDF15 Induces an Aversive Visceral Malaise State that Drives Anorexia and Weight Loss.

The anorectic and weight-suppressive effects of growth differentiation factor-15 (GDF15) are attracting considerable attention for treating obesity. Current experiments in rats investigate whether GDF15 induces an aversive visceral malaise-based state that mediates its acute anorectic effect and, through aversion conditioning, exerts longer-term anorexia. Visceral malaise, conditioned affective food responses (taste reactivity), gastric emptying (GE), food intake, and body weight are evaluated after acute and chronic systemic dosing of GDF15 or long-acting Fc-GDF15. Pica, a marker of visceral malaise, is present at all anorectic GDF15 doses. Moreover, malaise induced by GDF15 does not decline over time, suggesting the lack of an improved tolerance after prolonged exposure. One association between GDF15 and novel food conditions a disgust/aversive response that persists beyond GDF15 acute action. Delayed GE is not a requirement for GDF15-induced anorexia. Clinical studies are required to evaluate whether GDF15's aversive-state-based anorexia will be contraindicated as an obesity treatment.

GDF15 Induces Anorexia through Nausea and Emesis.

Growth differentiation factor 15 (GDF15) is a cytokine that reduces food intake through activation of hindbrain GFRAL-RET receptors and has become a keen target of interest for anti-obesity therapies. Elevated endogenous GDF15 is associated with energy balance disturbances, cancer progression, chemotherapy-induced anorexia, and morning sickness. We hypothesized that GDF15 causes emesis and that its anorectic effects are related to this function. Here, we examined feeding and emesis and/or emetic-like behaviors in three different mammalian laboratory species to help elucidate the role of GDF15 in these behaviors. Data show that GDF15 causes emesis in Suncus murinus (musk shrews) and induces behaviors indicative of nausea/malaise (e.g., anorexia and pica) in non-emetic species, including mice and lean or obese rats. We also present data in mice suggesting that GDF15 contributes to chemotherapy-induced malaise. Together, these results indicate that GDF15 triggers anorexia through the induction of nausea and/or by engaging emetic neurocircuitry.

The value of macrophage inhibitory cytokine-1 level in differentiating benign from malignant solitary pulmonary nodules.

INTRODUCTION: Macrophage inhibitory cytokine-1 (MIC-1), a transforming growth factor-ß superfamily cytokine, is involved in tumor pathogenesis, and its measurement can be used as a clinical tool for the diagnosis of a wide range of cancers. OBJECTIVES: The aim of this study was to explore the diagnostic value of serum MIC-1 in patients with solitary pulmonary nodules (SPNs). METHODS: Serum specimens from 158 malignant SPN patients, 110 benign SPN patients, along with 120 healthy volunteers. The levels of serum MIC-1 were measured by sandwich enzyme-linked immunosorbent assay. RESULTS: Serum levels of MIC-1 in malignant SPN patients were significantly higher than those in benign SPN patients (P < .01), or those in healthy volunteers (P < .01). With a cutoff of 685.8 pg/ml, the sensitivity and specificity of MIC-1 in differentiating between malignant SPN patients and benign SPN patients, and between malignant SPN patients and healthy volunteers was, 56.3% and 92.7%, and 65.8% and 96.7%, respectively. An area under the curve (AUC) for malignant SPN resulting from MIC-1, which was significantly better than any other tumor markers tested including carbohydrate antigens 12-5 (CA125), and carcinoembryonic antigen (CEA). CONCLUSIONS: In conclusion, measurement of serum MIC-1 levels could be considered as a diagnostic biomarker for malignant SPN patients.

The Use of Recombinant nAG Protein in Spinal Cord Crush Injury in a Rat Model.

OBJECTIVE: To evaluate the therapeutic properties of nAG protein during the recovery following acute spinal cord injuries in the rat. STUDY DESIGN: An experimental study. PLACE AND DURATION OF STUDY: King Saud University, Riyadh, Saudi Arabia, from September 2014 to September 2015. METHODOLOGY: Eight rats were studied (4 control rats and 4 experimental rats; and hence 50% were controls and 50% were experimental). All rats were subjected to an acute spinal cord injury using the aneurysmal clip injury model. Immediately after the injury, a single intra-dural injection of either normal saline (in the control group) or the nAG protein (in the experimental group) was done. Assessment of both groups was done over a 6-week period with regard to weight maintenance, motor recovery scores, MRI and histopathology of the injury site. RESULTS: Weight maintenance was seen in the experimental and not in the control rats. Starting at 3 weeks after injury, the motor recovery was significantly (p<0.05) better in the experimental group. MRI assessment at 6 weeks showed better maintenance of cord continuity and less fluid accumulation at the injury site in the nAG-treated group. Just proximal to the injury site, there was less gliosis in the experimental group compared to the control group. At the crush injury site, there was less tissue architecture distortion, less vacuole formation, and less granulation tissue formation in the experimental group. CONCLUSION: The local injection nAG protein enhances neuro-restoration, reduces gliosis, and reduces vacuole/ granulation tissue formation following acute spinal cord crush injury in the rat aneurysmal clip animal model.

The anorectic actions of the TGFß cytokine MIC-1/GDF15 require an intact brainstem area postrema and nucleus of the solitary tract.

Macrophage inhibitory cytokine-1 (MIC-1/GDF15) modulates food intake and body weight under physiological and pathological conditions by acting on the hypothalamus and brainstem. When overexpressed in disease, such as in advanced cancer, elevated serum MIC-1/GDF15 levels lead to an anorexia/cachexia syndrome. To gain a better understanding of its actions in the brainstem we studied MIC-1/GDF15 induced neuronal activation identified by induction of Fos protein. Intraperitoneal injection of human MIC-1/GDF15 in mice activated brainstem neurons in the area postrema (AP) and the medial (m) portion of the nucleus of the solitary tract (NTS), which did not stain with tyrosine hydroxylase (TH). To determine the importance of these brainstem nuclei in the anorexigenic effect of MIC-1/GDF15, we ablated the AP alone or the AP and the NTS. The latter combined lesion completely reversed the anorexigenic effects of MIC-1/GDF15. Altogether, this study identified neurons in the AP and/or NTS, as being critical for the regulation of food intake and body weight by MIC-1/GDF15.