Maternal obesity disrupts fetal hypothalamic development by inducing structural changes in feeding circuits, such as reduced hypothalamic precursor proliferation, blunted energy-status sensing, and aberrant wiring of melanocortin pathways, ultimately promoting long-term obesity risk in offspring. Although this hypothalamic reprogramming has dominated research, emerging evidence supports a broader, distributed model involving both brainstem interoceptive circuits and mesocorticolimbic reward-control systems. Maternal obesity is associated with impaired white matter development in offspring, as well as compromised functional connectivity, abnormal orexigenic and anorexigenic signaling, hypothalamic inflammation, and epigenetic alterations in neurodevelopmental genes. Human neuroimaging studies demonstrate altered network connectivity in neonates associated with maternal adiposity. However, the mechanism through which dysregulated maternal signals ultimately reach and reprogram the developing brain remains largely elusive. The present review aims to elucidate the mechanisms by which maternal overnutrition drives the embryonic rewiring of feeding circuits beyond the hypothalamus, highlighting the susceptibility of these extra-hypothalamic neural networks to obesogenic programming. Future research should prioritize investigating the effects of maternal obesity on fetal cytoarchitecture and function in feeding-related neuroanatomical circuits, including brainstem interoceptive nuclei and mesocorticolimbic reward–control pathways. Elucidating these developmental neuro-metabolic changes may offer the opportunity to establish early intervention measures for preserving offspring metabolic health.

Cancer cells dynamically reprogram their metabolism to adapt to changing microenvironmental conditions during tumor growth and metastatic dissemination. Metastasis of solid tumors—the principal cause of cancer-related mortality—is often driven through activation of epithelial–mesenchymal transition (EMT), regulated by the transcription factor ZEB1, which is frequently upregulated during tumor progression. To investigate the role of metabolic plasticity in metastasis, we employed murine pancreatic ductal adenocarcinoma (PDAC) cell lines with distinct EMT states, ZEB1 expression and lung colonization capacities. Highly plastic epithelial-type cancer cells (KPCepi) efficiently colonize the lung, whereas Zeb1-deficient cancer cells (KPCZ) with compromised metabolic plasticity show markedly reduced colonization, correlated with absent glycolytic reserve, mitochondrial dysfunction, and reduced anti-oxidant metabolite levels. Interestingly, mesenchymal-type cancer cells (KPCmes) also exhibit poor lung colonization despite retaining normal glycolytic capacity and a high proportion of functional mitochondria; however, similar to KPCZ cells, they display diminished levels of detoxifying metabolites. Low metastatic capacity correlates with increased susceptibility to ferroptosis even in epithelial-type KPCZ cells, indicating a limited ability to counteract reactive oxygen species under stress. Together, these findings demonstrate that metabolic plasticity and redox homeostasis are essential prerequisites for efficient lung colonization. Thus, concurrent targeting of metabolic adaptability and redox buffering may represent a promising strategy to prevent metastasis in aggressive PDAC tumors.

Mental stress serves as a major contributor to a spectrum of esophageal motility disorders, including distal esophageal spasm (DES), a condition marked by premature contractile activity of the lower esophageal sphincter (LES). These spasms are often exacerbated by psychiatric conditions such as distress, anxiety, and depression. This study investigates the impact of mental stress on LES contractile function in mice. Chronic unpredictable mild stress (CUMS) was observed to reduce food intake, prolong esophageal emptying time, and increase LESP, along with elevated levels of inflammatory factors, IL-1β and TNFα in mice. Retrograde viral tracing identified a neuronal projection from the hypothalamus paraventricular nucleus (PVN) to the LES via the dorsal motor nucleus of the vagus (DMV) and the vagus nerve. Optogenetic activation of the PVN-DMV-vagus pathway increased the frequency and amplitude of LES electromyogram signals in mice, an effect negated by vagotomy or acetylcholine receptor antagonists. Conversely, chemogenetic inhibition of the PVN-DMV-vagus pathway alleviated CUMS-induced LES contraction abnormalities. High-throughput RNA sequencing revealed an upregulation of myosin binding protein C2 (MYBPC2) in the gastroesophageal junction (GEJ) following sustained activation of the PVN-DMV-vagus pathway. Similarly, cultured GEJ cells exposed to acetylcholine exhibited increased MYBPC2 levels. Notably, downregulation of MYBPC2 expression in the GEJ restored normal function in mice with PVN-DMV-vagus-acetylcholine pathway activation. In summary, this study demonstrates that mental stress induces LES contraction disorders through a PVN-DMV-vagus dependent pathway, which drives an increase in MYBPC2 expression in the GEJ.

Background

Glutamate decarboxylase-like 1 (GADL1) decarboxylates aspartic acid to β-alanine in several mammalian tissues, particularly in the brain and skeletal muscle. β-alanine is a precursor to the antioxidant and osmoregulatory dipeptide carnosine (β-alanyl-l-histidine), as well as pantothenic acid and coenzyme A. Deletion of GADL1 reduces carnosine and anserine levels in multiple tissues, but the consequences for brain metabolism remain unclear. This study aimed to explore sex-specific metabolic and cellular effects of GADL1 and β-alanine depletion in different areas of the brain.

Methods and results

We conducted a metabolomic screening of seven mouse tissues, followed by a detailed transcriptomic, proteomic, and metabolomic analysis of cerebrum, cerebellum, and olfactory bulb tissues from male and female GADL1 knockout and wild-type mice to explore sex-, age-, and region-specific molecular alterations. Loss of GADL1 induced distinct, sex-dependent metabolic responses across brain regions. Metabolomic data showed increased oxidative stress and possible synaptic remodeling in the cerebrum of mature females, whereas males exhibited massive lipid accumulation in multiple tissues. A similar pattern appeared in the developing olfactory bulb, where both sexes displayed lipid accumulation, but only males showed signs of inflammatory activation and altered energy metabolism, as supported by transcriptomic and proteomic analyses.

Conclusions

GADL1 loss and consequent β-alanine depletion trigger widespread metabolic remodeling in brain tissue. Even modest β-alanine reduction leads to region, age, and sex-specific perturbations of energy metabolism and cellular homeostasis. These findings highlight the multifaceted biochemical roles of β-alanine and suggest that its physiological and therapeutic effects may differ by tissue, sex, and developmental stage.

Objectives

Phosphomannomutase 1 (PMM1) is an evolutionarily conserved metabolic enzyme classically linked to mannose metabolism, but its physiological role in adipose tissue remains unknown. This study aimed to define the function of PMM1 in thermogenic regulation and systemic metabolism.

Methods

An unbiased, integrative transcriptomic analysis of human subcutaneous adipose tissue was performed to relate PMM1 expression to clinical measures. Functional studies in mice and in primary murine and human adipocytes with PMM1 loss- and gain-of-function were conducted to investigate PMM1's role in the thermogenic program, assessed by metabolic phenotyping, RNA sequencing, targeted metabolomics, and signaling assays.

Results

PMM1 expression was inversely associated with obesity-related anthropometric and biochemical measures and was markedly induced by thermogenic stimulation. Adipocyte-specific Pmm1 knockdown promoted adipose thermogenic remodeling, increased energy expenditure, and protected mice from diet-induced obesity and insulin resistance. Mechanistically, PMM1 deficiency rerouted glucose metabolism into the pentose phosphate pathway, increasing inosine monophosphate and extracellular inosine. The elevated inosine engaged adenosine A_2A/A_2B receptors, activated the PKA–CREB signaling cascade, and enhanced a thermogenic program in both murine and human adipocytes. Pharmacologic blockade of A_2A/A_2B receptors or PKA abrogated these effects, confirming the requirement of inosine signaling. In contrast, PMM1 overexpression in primary adipocytes blunted thermogenic activation.

Conclusions

PMM1 functions as a key metabolic brake on the adipose thermogenic program by limiting inosine production and downstream A_2A/A_2B–PKA signaling. These findings reveal a previously unrecognized PMM1–inosine regulatory pathway linking purine metabolism to energy homeostasis and identify PMM1 as a potential therapeutic target for obesity and related metabolic disorders.

Exposure to certain pesticides appears to be involved in type 2 diabetes and Parkinson's disease onset which are reported to be epidemiologically associated. While the exact causes of this association and the deleterious mechanisms linking these aging-associated diseases are not fully known, it seems important to assess the extent to which environmental factors such as pesticides could be involved. Our aim was to evaluate the consequences of chronic dietary exposure to a mixture of pesticides at levels below the Acceptable Daily Intake in transgenic mice predisposed to develop motor disorders. Male mice expressing mutated A53T human α-synuclein (M83) and wild-type mice were fed either a control or a diet enriched with 6 pesticides (captan, boscalid, chlorpyrifos, thiachloprid, thiofanate, ziram) for 50 weeks. Exposure to pesticides led to body weight gain and insulin resistance in wild-type and M83 mice, caused, at least in part, by a reduction in insulin receptor levels in liver, skeletal muscle and adipose tissue. However, only M83 mice exposed to pesticides showed early motor deficits associated with decreased insulin receptor levels in midbrain and striatum. While pesticides promoted glucose intolerance in wild-type mice, M83 mice surprisingly showed improved glucose tolerance accompanied by a significant increase in pancreatic beta-cell mass and function. Transcriptomic analysis further revealed an enrichment of genes involved in amino-acid metabolism in M83 mouse islets with abundant α-synuclein expression. Overall, exposure to pesticides led to insulin resistance, which can be overcome thanks to a previously unrecognized role of α-synuclein in beta-cell adaptation.

Background

Diabetic osteoporosis is characterized by disrupted bone remodeling involving impaired osteogenesis and excessive osteoclastic activity. Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) have hypoglycemic benefits, their effects on bone metabolism remain unclear. This study investigates the osteoprotective potential of polyethylene glycol loxenatide (PEG-Loxe), a GLP-1RA hypoglycemic drug.

Methods

In vitro studies involved MC3T3-E1 osteoblasts and RANKL-stimulated RAW264.7 osteoclasts, both treated with 100 nM PEG-Loxe. Osteogenic markers (ALP, Col-1, and Runx2) and osteoclast differentiation were assessed, and HMGB-1 overexpression was used to validate pathway involvement. For in vivo studies, type 2 diabetic ApoE^−/− mice were treated with PEG-Loxe. We examined serum markers (CTX, HMGB-1, TNF-α, and IL-1β) and performed micro-CT and histomorphometric analyses. In clinical research, serum markers and BMD were analysed.

Results

PEG-Loxe has dual regulatory effects. PEG-Loxe can significantly enhance osteoblast differentiation (increased ALP, Col-1 and Runx2 activities, p < 0.001) and suppressing osteoclastogenesis by inhibiting HMGB-1/RAGE/TLR4/NF-κB pathway (p < 0.001). In ApoE^−/− mice, PEG-Loxe increased osteoblasts and reduced osteoclasts. RAGE, HMGB-1, TNF-α, and IL-1β were reduced to varying degrees (p < 0.05; p < 0.01; p < 0.01; p < 0.01). Micro CT scanning of 3D images of mouse femurs showed that PEG-Loxe can increase femoral tissue and reduce porosity. In clinical research,CTX, HMGB-1, TNF-α, and IL-1β were significantly reduced in the PEG-Loxe group compared to the Non-PEG-Loxe group (p < 0.05). There was no significant difference in BMD between the two groups.

Conclusions

PEG-Loxe exerts comprehensive osteoprotective effects in type 2 diabetes by simultaneously promoting osteogenesis and suppressing osteoclastogenesis, through modulation of HMGB-1 signaling. PEG-Loxe can significantly improve bone turnover status and reduce bone resorption levels, with potential osteoprotective effects.