The mammalian target of rapamycin (mTOR) signaling pathway is one of the key regulators of cellular energy metabolism. It senses diverse alterations in the extracellular environment such as availability of nutrients and growth factors, and mediates the corresponding intracellular response. In the brain, astrocytes crucially contribute to energy and neurotransmitter metabolism, and numerous other functions. However, the relevance of physiological, astrocytic mTOR signaling in maintaining brain homeostasis and function is not well understood. Pathophysiological mTOR signaling is involved in manifold diseases in the central nervous system and most of the knowledge about astrocytic mTOR signaling has been derived from observations on these disorders. Dysregulation of the mTOR signaling pathway impairs important functions of astrocytes including neurotransmitter uptake and -signaling as well as energy metabolism. Some of these alterations could trigger neuropathological conditions such as epilepsy. This review focuses on how mTOR signaling regulates properties of astrocytes, and how these signaling events might contribute to the physiological function of the brain.

The liver is one of the most sexually dimorphic organs. The hepatic metabolic pathways that are subject to sexual dimorphism include xenobiotic, amino acid and lipid metabolism. Non-alcoholic fatty liver disease and hepatocellular carcinoma are among diseases with sex-dependent prevalence, progression and outcome. Although male and female livers differ in their abilities to metabolize foreign compounds, including drugs, sex-dependent treatment and pharmacological dynamics are rarely applied in all relevant cases. Therefore, it is important to consider hepatic sexual dimorphism when developing new treatment strategies and to understand the underlying mechanisms in model systems. We isolated primary hepatocytes from male and female C57BL6/N mice and examined the sex-dependent transcriptome, proteome and extracellular metabolome parameters in the course of culturing them for 96 h. The sex-specific gene expression of the general xenobiotic pathway altered and the female-specific expression of Cyp2b13 and Cyp2b9 was significantly reduced during culture. Sex-dependent differences of several signaling pathways increased, including genes related to serotonin and melatonin degradation. Furthermore, the ratios of male and female gene expression were inversed for other pathways, such as amino acid degradation, beta-oxidation, androgen signaling and hepatic steatosis. Because the primary hepatocytes were cultivated without the influence of known regulators of sexual dimorphism, these results suggest currently unknown modulatory mechanisms of sexual dimorphism in vitro. The large sex-dependent differences in the regulation and dynamics of drug metabolism observed during cultivation can have an immense influence on the evaluation of pharmacodynamic processes when conducting initial preclinical trials to investigate potential new drugs.

The Hedgehog (Hh) and Wnt/β-Catenin (Wnt) cascades are morphogen pathways whose pronounced influence on adult liver metabolism has been identified in recent years. How both pathways communicate and control liver metabolic functions are largely unknown. Detecting core components of Wnt and Hh signaling and mathematical modeling showed that both pathways in healthy liver act largely complementary to each other in the pericentral (Wnt) and the periportal zone (Hh) and communicate mainly by mutual repression. The Wnt/Hh module inversely controls the spatiotemporal operation of various liver metabolic pathways, as revealed by transcriptome, proteome, and metabolome analyses. Shifting the balance to Wnt (activation) or Hh (inhibition) causes pericentralization and periportalization of liver functions, respectively. Thus, homeostasis of the Wnt/Hh module is essential for maintaining proper liver metabolism and to avoid the development of certain metabolic diseases. With caution due to minor species-specific differences, these conclusions may hold for human liver as well.

In the liver, energy homeostasis is mainly regulated by mechanistic target of rapamycin (mTOR) signalling, which influences relevant metabolic pathways, including lipid metabolism. However, the Hedgehog (Hh) pathway is one of the newly identified drivers of hepatic lipid metabolism. Although the link between mTOR and Hh signalling was previously demonstrated in cancer development and progression, knowledge of their molecular crosstalk in healthy liver is lacking. To close this information gap, we used a transgenic mouse model, which allows hepatocyte-specific deletion of the Hh pathway, and in vitro studies to reveal interactions between Hh and mTOR signalling. The study was conducted in male and female mice to investigate sexual differences in the crosstalk of these signalling pathways. Our results reveal that the conditional Hh knockout reduces mitochondrial adenosine triphosphate (ATP) production in primary hepatocytes from female mice and inhibits autophagy in hepatocytes from both sexes. Furthermore, in vitro studies show a synergistic effect of cyclopamine and rapamycin on the inhibition of mTor signalling and oxidative respiration in primary hepatocytes from male and female C57BL/6N mice. Overall, our results demonstrate that the impairment of Hh signalling influences mTOR signalling and therefore represses oxidative phosphorylation and autophagy.

Astrocytes constitute a heterogeneous cell population within the brain, contributing crucially to brain homeostasis and playing an important role in overall brain function. Their function and metabolism are not only regulated by local signals, for example, from nearby neurons, but also by long‐range signals such as hormones. Thus, two prominent hormones primarily known for regulating the energy balance of the whole organism, insulin, and leptin, have been reported to also impact astrocytes within the brain. In this study, we investigated the acute regulation of astrocytic metabolism by these hormones in cultured astrocytes prepared from the mouse cortex and hypothalamus, a pivotal region in the context of nutritional regulation. Utilizing genetically encoded, fluorescent nanosensors, the cytosolic concentrations of glucose, lactate, and ATP, along with glycolytic rate and the NADH/NAD⁺ redox state were measured. Under basal conditions, differences between the two populations of astrocytes were observed for glucose and lactate concentrations as well as the glycolytic rate. Additionally, astrocytic metabolism responded to insulin and leptin in both brain regions, with some unique characteristics for each cell population. Finally, both hormones influenced how cells responded to elevated extracellular levels of potassium ions, a common indicator of neuronal activity. In summary, our study provides evidence that insulin and leptin acutely regulate astrocytic metabolism within minutes. Additionally, while astrocytes from the hypothalamus and cortex share similarities in their metabolism, they also exhibit distinct properties, further underscoring the growing recognition of astrocyte heterogeneity. image