Volume 109, Current Issue
Vol 28, October 2019
Vol 27, September 2019
Vol 26, August 2019
Vol 25, July 2019
Vol 24, June 2019
Vol 23, May 2019
Vol 22, April 2019
Vol 21, March 2019
Vol 20, February 2019
Vol 19, January 2019
Vol 18, December 2018
Vol 17, November 2018
Vol 16, October 2018
Vol 15, September 2018
Vol 14, August 2018
Vol 13, July 2018
Vol 12, June 2018
Vol 11, May 2018
Vol 10, April 2018
Vol 9, March 2018
Vol 8, February 2018
Vol 7, January 2018
Vol 6 No 12, December 2017
Vol 6 No 11, November 2017
Vol 6 No 10, October 2017
Vol 6 No 9, September 2017
Vol 6 No 8, August 2017
Vol 6 No 7, July 2017
Vol 6 No 6, June 2017
Vol 6 No 5, May 2017
Vol 6 No 4, April 2017
Vol 6 No 3, March 2017
Vol 6 No 2, February 2017
Vol 6 No 1, January 2017
Vol 5 No 12, December 2016
Vol 5 No 11, November 2016
Vol 5 No 10, October 2016
Vol 5 No 9, September 2016
Vol 5 No 8, August 2016
Vol 5 No 7, July 2016
Vol 5 No 6, June 2016
Vol 5 No 5, May 2016
Vol 5 No 4, April 2016
Vol 5 No 3, March 2016
Vol 5 No 2, February 2016
Vol 5 No 1, January 2016
Vol 4 No 12, December 2015
Vol 4 No 11, November 2015
Vol 4 No 10, October 2015
Cover Story Current Issue

Epidemiological evidences provide proof of concept that certain pesticides are involved in metabolic disorders, but also in the pathophysiology of Parkinson's disease (PD). In addition, large prospective cohort studies reported that type 2 diabetes (T2D) and PD are epidemiologically associated, including an elevated risk of developing PD in patients with T2D.
Current Issue
- Abstract
Maternal obesity and the embryonic rewiring of feeding circuits: Beyond the hypothalamus
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.
- Abstract
Metabolic plasticity and optimal redox homeostasis are essential for efficient metastatic colonization
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.
- Abstract
Vagal control of the brain-esophagus axis ameliorates stress-induced esophageal motility dysfunction in male mice
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.
- Abstract
Blocking β-alanine synthesis triggers widespread perturbations of energy and lipid metabolism in the brain
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.
- Abstract
Phosphomannomutase 1 restrains adipose thermogenic programming via inosine signaling
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 A2A/A2B receptors, activated the PKA–CREB signaling cascade, and enhanced a thermogenic program in both murine and human adipocytes. Pharmacologic blockade of A2A/A2B 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 A2A/A2B–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.
- Abstract
Insulin resistance induced by pesticides is overcome by pancreatic islet adaptation in a mouse model of Parkinson's disease
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.
- Abstract
Effects of the glucagon-like peptide-1 receptor agonist PEG-Loxe on diabetic osteoporosis: A mechanistic study
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.
Articles in Press
- Abstract
Glucagon-like peptide-1 receptor (GLP-1R) agonists such as semaglutide are highly effective treatments for obesity, yet the mechanisms by which they reduce food intake remain incompletely understood. Because taste plays a critical role in guiding food intake, several clinical studies have investigated whether GLP-1R agonists alter taste function, but these reports have yielded conflicting results. Here, we systematically tested the effects of chronic semaglutide treatment on taste responsivity in diet-induced obese mice. Mice were evaluated using brief-access gustometer tests to assess responses to sweet, bitter, sour, salty, and fatty tastants. Chronic semaglutide treatment produced robust weight loss but did not alter lick rates for any tastant, indicating intact taste-driven orosensory evaluation across modalities. Psychophysical analysis using a broad range of sucrose concentrations revealed similar concentration-response functions and comparable EC50 values between vehicle- and semaglutide-treated mice, demonstrating unchanged sweet taste sensitivity. However, semaglutide modestly increased total licking and trial initiation for sucrose, suggesting enhanced behavioral engagement rather than altered taste perception. Consistent with the behavioral findings on taste, semaglutide did not affect the abundance of taste receptor cell subtypes in the circumvallate papilla or the expression of genes involved in taste receptor signaling and neurotransmission. Together, these results indicate that chronic semaglutide does not detectably impair peripheral taste function in mice under our experimental conditions. Instead, GLP-1R agonists likely influence ingestive behavior through mechanisms independent of taste signaling, potentially involving alterations in motivational processes.
- Abstract
Abstract/objective
RNASET2 is a lysosomal RNase whose enzymatic function is required for early events in lipotoxicity. However, the endogenous RNA substrates of RNASET2 that modulate lipid-induced cell death are not known. The purpose of this study was to identify RNASET2 substrates that impact lipotoxic stress.
Methods
RNA sequencing was used to identify RNAs that increase in abundance in human cells upon RNASET2 knockdown, and actinomycin D assays were used to show that RNASET2 impacted decay rates of these RNAs. We tested for the presence of these RNAs in immunoisolated lysosomes and determined the contribution of the lysosomal membrane transporter SIDT2 in delivery of these RNAs to the lysosome. A role for these RNAs in lipotoxic cell death was directly tested in loss- and gain of function analysis.
Results
RNASET2 knockdown increased steady-state abundance of UCHL3, PFN2 and PRDX3 mRNAs and prolonged their decay rate, leading to increased protein expression. These mRNAs were delivered to the lysosomal lumen by the lysosomal membrane transporter SIDT2 that mediates RNautophagy. While UCHL3 and PFN2 have not previously been implicated in lipotoxic responses, expression of these proteins protected against lipid-induced cell death.
Conclusions
Our study identified specific mRNA substrates of RNASET2 and uncovered a previously unexplored function for lysosomes and RNautophagy in regulation of the response to metabolic stress. Moreover, we demonstrated that RNautophagy selectively regulates turnover of specific endogenous RNAs and thereby impacts regulation of gene expression.
- Abstract
The β cells in the pancreatic endocrine islets preferentially secrete insulin in specific subdomains of the plasma membrane adjacent to the vasculature (i.e., hot spots). Impaired insulin secretion and β -cell dysfunction are central features of Type-2 Diabetes, yet the cytoskeletal machinery that supports directional secretion and secretory hot spots remains incompletely defined. KIF21A is a plus-end-directed kinesin-4 motor protein that anchors microtubule plus ends to the cell cortex. Our work introduces KIF21A as a disease-linked, mechanistically relevant motor whose distribution suggests a role in organizing secretion-competent cortical microtubule architecture in islet endocrine cells. We show that KIF21A is downregulated in T2D human islets at both the mRNA (RNA-seq) and protein (quantitative proteomics) levels. We also demonstrate cell-type-specific enrichment of Kif21a protein (δ > α > β) in intact islets, confirming the hierarchy suggested by single-cell transcriptomics. We also show that within each endocrine lineage, Kif21a protein shows pronounced cell-to-cell heterogeneity, consistent with endocrine sub-states and functional specialization. And most importantly, we show that implicating Kif21a is spatially enriched at the rosettes and laminin-rich interfaces at vasculature-oriented secretion sites (hot spots), where microtubule anchoring is expected to shape targeted granule delivery. These findings establish KIF21A as a T2D-associated gene in pancreatic endocrine cells and suggest that it may have a cortical microtubule-anchoring function and may contribute to the directed granule delivery to the vasculature for regulated hormone secretion.
- Abstract
Objective
Statins (HMG-CoA reductase inhibitors) are associated with myopathy, yet the precise in vivo mechanisms underlying this association remain unclear. Emerging evidence implicates a deficiency of geranylgeranyl pyrophosphate (GGPP), a key downstream isoprenoid metabolite of the mevalonate pathway. We employed novel muscle-specific genetic mouse models to elucidate the roles of GGPP and Rab geranylgeranyl transferase β (RabGGT-β) in the development of myopathy.
Methods
Using doxycycline-inducible Cre-LoxP technology, we generated three skeletal muscle-specific knockout (KO) models: Hmgcr-DimKO, Rabggtb-DimKO, and combined Hmgcr/Rabggtb-DimKO mice. The severity of myopathy was evaluated based on serum creatine kinase levels and histological examination. Mitochondrial mass and function were rigorously quantified. Prenylation deficit in Rabggtb-DimKO mice was confirmed via subcellular fractionation. To validate GGPP’s involvement, rescue experiments were conducted using its precursor, geranylgeraniol (GGOH).
Results
Hmgcr KO resulted in pronounced myopathy, marked by an early reduction in mitochondria-rich myosin heavy chain (MyHC) type I and IIa muscle fibers, followed by a later reduction in mitochondria-poor glycolytic MyHC type IIb muscle fibers, and these changes were reversed by GGOH administration. Rabggtb-DimKO mice developed myopathy later than Hmgcr-DimKO mice; however, in Hmgcr/Rabggtb-DimKO mice, myopathy was dramatically accelerated and more severe. Across all models, mitochondrial dysfunction emerged early—preceding clinical signs of myopathy—consistent with a causal relationship.
Conclusion
Our findings demonstrate that myopathy induced by HMGCR deficiency is primarily driven by GGPP depletion in a mouse model. Furthermore, impaired RabGGT-β-mediated protein geranylgeranylation represents a critical downstream mechanism that aggravates the myopathic phenotype. Early mitochondrial abnormalities may contribute to the pathogenesis of myopathy due to disruption of the mevalonate pathway.
- Abstract
Prenatal metabolic adversity, including fetal growth restriction (FR), programs long-term alterations in systemic and neural insulin sensitivity, yet its impact on insulin signaling within reward-circuit plasticity across development remains poorly understood. Using a rodent model of gestational FR, we examined how early metabolic stress alters insulin regulation of mesolimbic reward circuits using in vivo chronoamperometry to measure nucleus accumbens (NAc) dopamine (DA) release during palatable food exposure, with and without peripheral insulin. We assessed longitudinal consumption behavior and conducted transcriptomic profiling (RNA-Seq) at birth (P0), weaning (P21), and adulthood (P90) following saline or insulin administration. FR blunted immediate NAc DA release in response to palatable food, a deficit specifically reversed by peripheral insulin, indicating altered insulin sensitivity of mesolimbic reward circuits. FR animals also display accelerated initial palatable food consumption. Transcriptomic analysis revealed that FR reprograms the NAc’s molecular response to insulin. Across development and sex, only 2-9% of insulin-responsive genes overlap between FR and controls. FR generated condition-specific and frequently inverted transcriptional signatures, affecting genes linked to synaptic plasticity (Cplx3, Rab3b) and neurodevelopment (Ccn3). These findings demonstrate that prenatal adversity reconfigures the NAc by altering its molecular and neurochemical responsiveness to insulin. This developmental reprogramming reveals how early metabolic stress reshapes insulin sensitivity within reward circuitry, a mechanism that may contribute to both metabolic and psychiatric disease vulnerability.
- Abstract
Objective
Glucokinase Regulatory Protein (GKRP) controls the activity of Glucokinase (GCK) to regulate liver glucose uptake and storage. Coding variants in GCKR, the gene encoding GKRP, strongly associate with fatty liver disease, hypertriglyceridemia, and hypercholesterolemia. Here, we sought to investigate the mechanisms by which a common GKRP variant affects hepatic lipid and cholesterol metabolism.
Methods
We developed mouse models to examine how the human GKRP P446L variant influences liver and systemic metabolism. Endogenous Gckr expression was ablated in adult mouse hepatocytes, together with re-expression of either human GKRP P446L or the reference GKRP protein. We assessed body weight, adiposity, systemic glucose homeostasis, and hepatic metabolites in mice expressing reference GKRP or GKRP P446L under multiple metabolic conditions. To determine whether the effects of GKRP P446L may result from reduced GCK activity, we analyzed mice with liver-specific deletion of Gck.
Results
Hepatic expression of GKRP P446L resulted in reduced GKRP and GCK protein levels and elevated serum cholesterol. Hepatic deletion of Gck in mice recapitulated several effects of GKRP P446L, including increased hepatic cholesterol and triglyceride content. The elevated cholesterol was associated with increased cholesterogenic gene expression and cholesterol synthesis. Hepatic expression of an alternative hexokinase (HKII) normalized the effects of GCK-deficiency, suggesting that impaired glucose phosphorylation underlies the phenotype.
Conclusions
The GKRP P446L variant reduced GKRP protein abundance, and diminished GCK activity while increasing cholesterol levels. Loss of GCK elevated cholesterol and hepatic triglyceride levels. Collectively, these findings demonstrate that GCK suppresses hepatic cholesterol synthesis and lipid accumulation, suggesting that reduced GCK activity underlies the metabolic abnormalities associated with the GKRP P446L variant.
- Abstract
Nuclei within the limbic system like the central amygdala (CeA) play a critical role in mediating fear, motivation, reward, and appetitive behavior. Although previous reports demonstrate the presence of the glucagon-like peptide-1 receptor (GLP-1R) in limbic nuclei, how limbic neurons mediate the actions of systemically administrated GLP-1R agonists is unclear. In this study, we investigated the CeA’s response to peripherally administered GLP-1R agonist Exendin-4 (Ex-4) in vivo, and determined the functional requirement of select CeA neuron populations in acute Ex-4 induced hypophagia. Using fiber photometry, we observed that Ex-4 promoted a rapid and lasting activation of CeA neurons that was blocked by pretreatment with the GLP-1R antagonist Exendin-9. We then tested the functional requirement of CeA neuron activation in mediating Ex-4 induced hypophagia of standard grain chow using inhibitory chemogenetics. Chemogenetic inhibition of all CeA neurons significantly suppressed the hypophagic actions of Ex-4. Then using selective mouse Cre-drivers, we found that chemogenetic inhibition of protein kinase c delta (PrkcdCeA) and GLP-1R (Glp1rCeA), but not somatostatin (SstCeA), neurons also attenuates the full hypophagic effect of Ex-4. Having observed that inhibition of Glp1rCeA modestly attenuated Ex-4 induced hypophagia of standard chow, we then tested whether these neurons might mediate Ex-4 suppression of energy-dense, palatable diet. We used intermittent high-fat diet (HFD) access and found that inhibition of Glp1rCeA neurons significantly rescued the reduction of HFD consumption by Ex-4. Collectively, these data demonstrate that the CeA responds to peripherally administered GLP-1R agonists and that multiple CeA neuron populations are required for the complete effect of GLP-1R agonist mediated hypophagia.
- Abstract
Glycosylation encompasses a broad spectrum of post-translational modifications (PTMs) that shape protein stability, spatial organization, and function. Traditionally, it is classified into two major categories: complex glycosylation within the secretory pathway — including N-glycosylation, mucin-type O-glycosylation, glycosaminoglycans (GAGs), and glycolipids — which generate structurally stable and long-lived modifications; and O-GlcNAcylation, a highly dynamic modification of nucleocytoplasmic and mitochondrial proteins that rapidly responds to metabolic and environmental cues. While this dichotomous framework has guided our understanding of glycan biology, emerging evidence now reveals that glycosylations are functionally interconnected through shared metabolic substrates, and regulatory circuits.
Here, we revisit this classical classification and integrate it into a modern, systems-level view of glycosylation. We highlight the nucleotide sugar UDP-N-acetylglucosamine (UDP-GlcNAc) as a metabolic node reflecting cellular nutrient status and fuelling both complex glycan synthesis and O-GlcNAcylation. UDP-GlcNAc pool fluctuations drive coordinated remodeling across glycosylation pathways, and dysregulation of this hub is associated with diverse human diseases. We discuss how O-GlcNAcylation functions as a supplementary regulatory PTM, modulating glycosylation-related enzymes and proteins through both direct effects on their interactions, stability, localisation and activity, and via broader transcriptional and epigenetic programs, thereby dynamically controlling otherwise stable glycosylation processes. Examples from metabolic, cardiovascular, neurological diseases, cancer and congenital disorders of glycosylation (CDGs) illustrate how perturbations in one glycosylation pathway propagate through the glycosylation network, reshaping cellular identity and disease trajectories. We support a paradigm in which glycosylation operates as an integrated regulatory framework linking metabolism, signaling, and extracellular architecture, providing new perspectives for disease stratification and therapeutic intervention.
Registration & Abstract Submission are open!

13th
Helmholtz Diabetes Conference
Munich, 21-23. Sep 2026
2024 impact factor: 6.6
You are what you eat
Here is a video of Vimeo. When the iframes is activated, a connection to Vimeo is established and, if necessary, cookies from Vimeo are also used. For further information on cookies policy click here.






































































