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The type of nutrient utilized by the organism at any given time—substrate utilization—is a critical component of energy metabolism. The neuronal mechanisms involved in the regulation of substrate utilization in mammals are largely unknown. Here, we found that activation of hypothalamic Agrp neurons rapidly altered whole-body substrate utilization, increasing carbohydrate utilization, while decreasing fat utilization. These metabolic changes occurred even in the absence of caloric ingestion and were coupled to increased lipogenesis. Accordingly, inhibition of fatty acid synthase—a key enzyme that mediates lipogenesis—blunted the effects of Agrp neuron activation on substrate utilization. In pair-fed conditions during positive energy balance, activation of Agrp neurons improved metabolic efficiency, and increased weight gain and adiposity. Conversely, ablation of Agrp neurons impaired fat mass accumulation. These results suggest Agrp neurons regulate substrate utilization, contributing to lipogenesis and fat mass accumulation during positive energy balance. Agouti-related peptide (AgRP) producing neurons regulate food intake and metabolic processes in peripheral organs. Here, the authors show that hypothalamic AgRP neurons alter whole body substrate utilization to favour carbohydrate usage and lipid storage.

In this study, the authors show that conditional deletion of leptin receptors from astrocytes alters their morphology and results in an increase in the number of synapses on POMC and AgRP neurons of the arcuate nucleus. In addition, they find that loss of leptin response in astrocytes modified leptin- and ghrelin-controlled food intake. We found that leptin receptors were expressed in hypothalamic astrocytes and that their conditional deletion led to altered glial morphology and synaptic inputs onto hypothalamic neurons involved in feeding control. Leptin-regulated feeding was diminished, whereas feeding after fasting or ghrelin administration was elevated in mice with astrocyte-specific leptin receptor deficiency. These data reveal an active role of glial cells in hypothalamic synaptic remodeling and control of feeding by leptin.

In addition to its canonical function of protection from pathogens, the immune system can also alter behaviour 1 , 2 . The scope and mechanisms of behavioural modifications by the immune system are not yet well understood. Here, using mouse models of food allergy, we show that allergic sensitization drives antigen-specific avoidance behaviour. Allergen ingestion activates brain areas involved in the response to aversive stimuli, including the nucleus of tractus solitarius, parabrachial nucleus and central amygdala. Allergen avoidance requires immunoglobulin E (IgE) antibodies and mast cells but precedes the development of gut allergic inflammation. The ability of allergen-specific IgE and mast cells to promote avoidance requires cysteinyl leukotrienes and growth and differentiation factor 15. Finally, a comparison of C57BL/6 and BALB/c mouse strains revealed a strong effect of the genetic background on the avoidance behaviour. These findings thus point to antigen-specific behavioural modifications that probably evolved to promote niche selection to avoid unfavourable environments. A study using mouse models of food allergy shows that allergic sensitization drives antigen-specific avoidance behaviour mediated by immunoglobulin E antibodies and mast cells.

Social isolation enhances sociability, suggesting that social behavior is maintained through a homeostatic mechanism. Further, mammalian social needs shift dramatically from infancy through adolescence into adulthood, raising the question of whether the neural mechanisms governing this homeostatic regulation evolve across developmental stages. Here, we show that agouti-related peptide (Agrp) neurons, which regulate hunger in adults, are activated by social isolation from weaning through adolescence but not in adulthood. Importantly, the activity of these neurons is critical for social behavior during adolescence: inhibiting Agrp neurons reduced isolation-induced sociability in juveniles but not in adults, and Agrp neuron activation promoted sociability only in young mice. After isolation, reunion with siblings or other conspecifics, but not unfamiliar adult males, rapidly decreased neuronal activity in juveniles, an effect requiring intact olfaction. These findings identify Agrp neurons as a key component of the circuitry governing age-specific social homeostasis.

We have shown that synaptic re-organization of hypothalamic feeding circuits in response to metabolic shifts involves astrocytes, cells that can directly respond to the metabolic hormone, leptin, in vitro. It is not known whether the role of glia cells in hypothalamic synaptic adaptions is active or passive. Here we show that leptin receptors are expressed in hypothalamic astrocytes and that conditional, adult deletion of leptin receptors in astrocytes leads to altered glial morphology, decreased glial coverage and elevated synaptic inputs onto pro-opiomelanocortin (POMC)- and Agouti-related protein (AgRP)-producing neurons. Leptin-induced suppression of feeding was diminished, while rebound feeding after fasting or ghrelin administration was elevated in mice with astrocyte-specific leptin receptor deficiency. These data unmask an active role of glial cells in the initiation of hypothalamic synaptic plasticity and neuroendocrine control of feeding by leptin.

Agrp neurons drive feeding. To what extend these neurons participate in the regulation of other homeostatic processes is not well understood. We investigated the role of Agrp neurons in substrate utilization in mice. Activation of Agrp neurons was sufficient to rapidly increase RER and carbohydrate utilization, while decreasing fat utilization. These metabolic changes were linearly correlated with carbohydrates ingested, but not protein or fat ingestion. However, even in the absence of ingestive behaviors, activation of Agrp neurons led to changes in substrate utilization in well-fed mice. These effects were coupled to metabolic shifts towards lipogenesis. Inhibition of fatty acid synthetase (FAS) blunted the effects of Agrp neurons on substrate utilization. Finally, Agrp neurons controlled peripheral metabolism, but not food intake, via 3-adrenergic receptor signaling in fat tissues. These results reveal a novel component of Agrp neuron-mediate metabolism regulation that involves sympathetic activity on fat compartments to shift metabolism towards lipogenesis.

Glutaminyl-peptide cyclotransferase (QPCT) catalyzes the formation of pyroglutamate-modified amyloid-beta (pGlu-Aβ). pGlu-Aβ is a neurotoxic and aggregation-prone form of Aβ that accelerates plaque formation and contributes to Alzheimer's Disease (AD). While QPCT's role in promoting Aβ aggregation is well established, little is known about how its expression differs between sexes and associates with AD biomarkers. Given that women are more affected by AD, investigating sex-specific associations between cerebrospinal fluid (CSF) QPCT levels and AD biomarkers could provide valuable insights into disease mechanisms. Data were obtained from 405 individuals from the ADNI cohort at baseline, stratified by sex, CSF Aβ (AC) and Aβ-PET (AP) positivity, which was defined based on the ratio p -Tau181/CSF Aβ42>0.028 and Aβ-PET>1.11, respectively (Table 1). Generalized linear-mixed models were applied to examine the association between CSF QPCT levels and AD biomarkers across groups (AC-AP- women, AC-AP- men, AC+AP+ women, AC+AP+ men), adjusting for age, clinical diagnosis and APOE phenotype. Additionally, voxel-wise analyses investigated the association of CSF QPCT levels with FDG-PET and Aβ-PET. CSF QPCT levels did not differ between AC-AP- and AC+AP+. However, AC+AP+ women had higher CSF QPCT than AC+AP+ men. In AC-AP-, CSF QPCT correlated positively with CSF Aβ, Total-Tau, and CSF sTREM2 in both sexes, while MoCA score only in women (Figure 1). In AC+AP+, CSF QPCT also correlated positively with Aβ42, Total-Tau, and sTREM2 in both sexes; with hippocampal volume only in men and FDG-PET only in women, primarily in temporal lobes as demonstrated in voxel-wise analysis. In SUVr analysis, no associations were found between CSF QPCT and Aβ-PET in either group. However, a negative association with Aβ-PET was observed in the cortex of women at the voxel level (Figure 2). Our study demonstrates that AC+AP+ positive women had higher QPCT levels than AC+AP+ men. Additionally, stronger correlations between QPCT and imaging biomarkers, particularly FDG and Aβ-PET, were found in women whereas men exhibited associations with hippocampal volume. These preliminary results suggest that, in AC+AP+ women, CSF QPCT protein levels are increased and associated with Aβ-PET and FDG-PET biomarkers.

Background Glutaminyl‐peptide cyclotransferase (QPCT) catalyzes the formation of pyroglutamate‐modified amyloid‐beta (pGlu‐Aβ). pGlu‐Aβ is a neurotoxic and aggregation‐prone form of Aβ that accelerates plaque formation and contributes to Alzheimer's Disease (AD). While QPCT's role in promoting Aβ aggregation is well established, little is known about how its expression differs between sexes and associates with AD biomarkers. Given that women are more affected by AD, investigating sex‐specific associations between cerebrospinal fluid (CSF) QPCT levels and AD biomarkers could provide valuable insights into disease mechanisms. Method Data were obtained from 405 individuals from the ADNI cohort at baseline, stratified by sex, CSF Aβ (AC) and Aβ‐PET (AP) positivity, which was defined based on the ratio p ‐Tau181/CSF Aβ42>0.028 and Aβ‐PET>1.11, respectively (Table 1). Generalized linear‐mixed models were applied to examine the association between CSF QPCT levels and AD biomarkers across groups (AC‐AP‐ women, AC‐AP‐ men, AC+AP+ women, AC+AP+ men), adjusting for age, clinical diagnosis and APOE phenotype. Additionally, voxel‐wise analyses investigated the association of CSF QPCT levels with FDG‐PET and Aβ‐PET. Results CSF QPCT levels did not differ between AC‐AP‐ and AC+AP+. However, AC+AP+ women had higher CSF QPCT than AC+AP+ men. In AC‐AP‐, CSF QPCT correlated positively with CSF Aβ, Total‐Tau, and CSF sTREM2 in both sexes, while MoCA score only in women (Figure 1). In AC+AP+, CSF QPCT also correlated positively with Aβ42, Total‐Tau, and sTREM2 in both sexes; with hippocampal volume only in men and FDG‐PET only in women, primarily in temporal lobes as demonstrated in voxel‐wise analysis. In SUVr analysis, no associations were found between CSF QPCT and Aβ‐PET in either group. However, a negative association with Aβ‐PET was observed in the cortex of women at the voxel level (Figure 2). Conclusion Our study demonstrates that AC+AP+ positive women had higher QPCT levels than AC+AP+ men. Additionally, stronger correlations between QPCT and imaging biomarkers, particularly FDG and Aβ‐PET, were found in women whereas men exhibited associations with hippocampal volume. These preliminary results suggest that, in AC+AP+ women, CSF QPCT protein levels are increased and associated with Aβ‐PET and FDG‐PET biomarkers.

The APOEε4 allele is a well-known genetic risk factor for sporadic Alzheimer's disease (AD). However, its influence on gene expression in peripheral blood remains underexplored. This study aimed to investigate the influence of the ε4 allele on blood gene expression in cognitively unimpaired (CU) and impaired (CI) individuals. We selected 423 individuals from the ADNI database with available APOE status, clinical diagnosis, and blood microarray data. CU and CI individuals were divided into ε4 carriers (n = 184) and non-carriers (n = 239) (Table.1). Differentially expressed genes (DEGs) between CU and CI individuals stratified by APOEε4 carriership were analyzed in R using the Limma package. Linear models were performed to associate DEGs with CSF Aβ42, pTau181, total-Tau, and FDG-PET (p <0.05). In addition, pathway enrichment analysis using Gene Ontology (GO) and KEGG was performed for up and downregulated genes across groups. The CU vs. CI comparison identified 607 upregulated and 593 downregulated genes in carriers, while non-carriers showed 501 upregulated and 390 downregulated genes (Figure 1A-B). In the enrichment analyses, carriers revealed upregulated pathways related to innate immunity, neutrophil degranulation, MAPK cascade, and GTPase signaling, while downregulated pathways were associated with ribosome biogenesis, mitochondrial function, cell cycle regulation, and RNA metabolism. For non-carriers, only upregulated pathways showed significant enrichment, primarily in ubiquitin-related processes and Golgi vesicle transport and organization (Figure 1B-C). Linear regressions identified 106 upregulated genes (70 carriers, 36 non-carriers) and 79 downregulated genes (55 carriers, 24 non-carriers) influencing at least one biomarker (CSF Aβ42, pTau181, total-Tau, or FDG-PET). Among carriers, FDG-PET emerged as a notable biomarker, showing a negative association with most upregulated genes (60) and a positive association with most downregulated genes (39). Conversely, Aβ42 was the most altered biomarker in non-carriers, following a similar pattern to FDG-PET in carriers, being negatively associated with 31 upregulated genes and positively associated with 15 downregulated genes (Figure 2A-B). Our findings suggest the APOEε4 allele influences blood gene expression in CI individuals, leading to distinct transcriptomic signatures and pathophysiological pathways. Additionally, distinct gene expression patterns in carriers and non-carriers impact biomarker variability, notably FDG-PET and Aβ42.

The APOEε4 allele is a well-known genetic risk factor for sporadic Alzheimer's disease (AD). However, its influence on gene expression in peripheral blood remains underexplored. This study aimed to investigate the influence of the ε4 allele on blood gene expression in cognitively unimpaired (CU) and impaired (CI) individuals. We selected 423 individuals from the ADNI database with available APOE status, clinical diagnosis, and blood microarray data. CU and CI individuals were divided into ε4 carriers (n = 184) and non-carriers (n = 239) (Table 1). Differentially expressed genes (DEGs) between CU and CI individuals stratified by APOEε4 carriership were analyzed in R using the Limma package. Linear models were performed to associate DEGs with CSF Aβ42, pTau181, total-Tau, and FDG-PET (p <0.05). In addition, pathway enrichment analysis using Gene Ontology (GO) and KEGG was performed for up and downregulated genes across groups. The CU vs. CI comparison identified 607 upregulated and 593 downregulated genes in carriers, while non-carriers showed 501 upregulated and 390 downregulated genes (Figure 1A-B). In the enrichment analyses, carriers revealed upregulated pathways related to innate immunity, neutrophil degranulation, MAPK cascade, and GTPase signaling, while downregulated pathways were associated with ribosome biogenesis, mitochondrial function, cell cycle regulation, and RNA metabolism. For non-carriers, only upregulated pathways showed significant enrichment, primarily in ubiquitin-related processes and Golgi vesicle transport and organization (Figure 1B-C). Linear regressions identified 106 upregulated genes (70 carriers, 36 non-carriers) and 79 downregulated genes (55 carriers, 24 non-carriers) influencing at least one biomarker (CSF Aβ42, pTau181, total-Tau, or FDG-PET). Among carriers, FDG-PET emerged as a notable biomarker, showing a negative association with most upregulated genes (60) and a positive association with most downregulated genes (39). Conversely, Aβ42 was the most altered biomarker in non-carriers, following a similar pattern to FDG-PET in carriers, being negatively associated with 31 upregulated genes and positively associated with 15 downregulated genes (Figure 2A-B). Our findings suggest the APOEε4 allele influences blood gene expression in CI individuals, leading to distinct transcriptomic signatures and pathophysiological pathways. Additionally, distinct gene expression patterns in carriers and non-carriers impact biomarker variability, notably FDG-PET and Aβ42.