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/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.

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.

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.

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.

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.

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 (Prkcd^CeA) and GLP-1R (Glp1r^CeA), but not somatostatin (Sst^CeA), neurons also attenuates the full hypophagic effect of Ex-4. Having observed that inhibition of Glp1r^CeA 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 Glp1r^CeA 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.

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.