👤 Ádám Ferenczi

Fasting triggers complex physiological and neuroimmune adaptations, yet its impact on hypothalamic microglia and the underlying regulatory role of glucocorticoids remains incompletely understood. The present study focused on fasting-induced systemic changes and cellular adaptations seen in the hypothalamus where components of metabolic- hormonal- and immune regulations are integrated. Adult male microglia reporter (CX3CR1 Overnight fasting resulted in a decrease in energy expenditure and respiratory exchange ratio (RER) indicating conservation of energy and a metabolic shift towards utilization of fatty acids as alternative energy source. Fasting increased hypothalamic expression of orexigenic neuropeptides and mRNA levels of Pdk4, Glut1, and Mct2 genes, in line with metabolic compensation. Upregulation of hypothalamic Crh and increased plasma concentration of corticosterone indicated sustained activation of the HPA axis. Importantly, fasting promoted an anti-inflammatory milieu in the hypothalamus characterized by elevated Il-4, Il-10 and IkBα genes without significant activation of pro-inflammatory cytokines (e.g., Il-1β, Il-6, Tnfα). Morphological analysis revealed region-specific changes in microglia number and branching complexity, particularly in hypothalamic regions directly exposed to blood-borne signals. Functional profiling showed increased microglial expression of IkBα and decreased pIkBα, indicating suppressed NFkB signaling. Adrenalectomy (1 week) and acute pharmacological inhibition of corticosterone synthesis (methyrapone) revealed that fasting-induced anti-inflammatory and metabolic gene expression, as well as microglial plasticity were largely glucocorticoid dependent. Hypothalamic expression of fasting-related neuropeptides (Npy, Agrp) and genes, related to the metabolic shift (Pdk4, Glut-1, Mct2, Angptl4) as well as some immune-related genes (Il10, Iba1) was dependent on presence of the adrenal gland or fasting-induced elevation of corticosterone. These findings highlight short term fasting as a potent modulator of hypothalamic immune-metabolic crosstalk and reveal critical role of adrenal glucocorticoids in orchestrating microglial responses to energetic challenges. The results have potential implications for therapeutic interventions targeting metabolic and inflammatory disorders. Show less

Gastric adenocarcinoma with enteroblastic differentiation (GAED) is a rare entity with worse prognosis compared to conventional gastric adenocarcinomas. Its histological characteristics are fetal gut-like architecture and tumor cells with cytoplasmic clearing, as well as positive immunohistochemical reaction to at least one of the enteroblastic markers. Hereby, we present a case of GAED with neuroendocrine marker positivity, with whole-exome sequencing (WES), and an updated literature review. A 68-year-old woman presented at the general practitioner with abdominal pain. Abdominal ultrasound described gastric wall thickening raising suspicion of gastric cancer; thus, gastroscopy was performed, and biopsy samples were taken, which confirmed malignancy. Neoadjuvant systemic chemotherapy was initiated, and total gastrectomy was performed. Microscopically, pleomorphic polygonal cells were visible with clear cytoplasm and high-grade cellular atypia. Alcian blue and PAS stains demonstrated positivity for acidic and neutral mucins. P53 IHC was negative, indicative of null-phenotype, while Syntaxin-1 and Chromogranin showed focal positivity. SALL4 and Glypican 3 were positive; however, AFP displayed only minimal, uncertain positivity. The Ki67 labeling index was 70%. Due to the morphological and immunohistochemical characteristics, the tumor was concluded as GAED with neuroendocrine marker positivity. WES was carried out revealing 4 pathogenic, including TP53, KLHL7, RAPSN, and ACTA1, and 3 likely pathogenic mutations, encompassing PNKP, HNF1A, and ADNP. GAED is a rare subtype of gastric adenocarcinomas, representing 0.3-5.4% of all cases, and has an unclarified etiology. Our WES results identified new pathogenic and likely pathogenic mutations. From a differential diagnostic point of view, hepatoid adenocarcinoma and the possibility of metastatic origin have to be excluded. Show less