Molecular Metabolism最新文献

C3 is highly expressed in human and rodent pancreatic islets, which secrete insulin to regulate blood glucose homeostasis. We have previously shown that cytosolic C3 protects pancreatic beta-cells from stress, by allowing cytoprotective autophagy, and that the same intracellular pool also protects them from cytokine-induced apoptosis. We now generated a beta-cell specific C3 knockout mouse (beta-C3-KO) to test whether cell-intrinsic C3 is required for beta-cell function in a whole animal model. While no differences were found between baseline metabolic performance when comparing floxed controls and beta-C3KO mice, significant differences were found when mice were put on high-fat diet (HFD). Beta-C3-KO mice gained more weight, exhibited higher fasting blood glucose and insulin levels, and showed signs of adipose tissue inflammation and insulin resistance. Consistent with previous results showing that C3 alleviates beta-cell stress, increased amounts of unprocessed pro-insulin were found in the circulation of HFD-fed beta-C3-KO mice, as well as in islets from these mice. Beta-C3-KO HFD mouse islets also had a higher proportion of insulin staining, and isolated islets released more insulin in vitro. The interaction of increased insulin secretion and HFD may lead to enhanced weight gain. Cell-intrinsic expression of C3 is therefore important for optimal function of mouse pancreatic beta-cells under metabolic pressure in vivo.

Hypothalamic neurons expressing either POMC or AGRP sense nutritional state directly and indirectly and transmit these neuropeptide signals to other brain centres through the melanocortin 3 and 4 receptors. MC4R is primarily concerned with the control of appetite and energy expenditure while MC3R is more closely related to the control of linear growth and the timing of puberty. The role of MC3R in the long-term control of energy balance and body composition is less clear, particularly in humans. We have undertaken studies in humans, domestic dogs and mice with the goal of clarifying the relative impact of MC3R deficiency on energy balance, growth and sexual development. By studying three large consanguineously enriched cohorts, totalling approximately 300K people, we identified nine individuals who are homozygous for functionally null MC3R variants. The body mass index (BMI) of the homozygous MC3R variant carriers was not significantly different from that of age, sex and demographically matched controls, with six of the nine homozygotes having a BMI < 30kg/m². We detected a canine MC3R missense variant (p.M320I) which is common in labrador retrievers and showed that this significantly impairs receptor signalling. Dogs homozygous for p.M320I were lighter and showed delayed pubertal development but were not significantly more obese than wild-type or heterozygous dogs. We also established that the lack of Mc3r delayed pubertal development in both male and female mice. Finally, we studied growth and pubertal trajectories of individuals carrying rare loss-of-function MC3R variants and found that male carriers had delayed peak weight velocity and genital development but had no evidence for excess body fat compared to non-carriers. Our results support MC3R having a conserved role across mammals in controlling growth and pubertal timing. While MC3R deficiency may influence linear growth and body composition, complete loss of MC3R does not result in a penetrant human obesity syndrome.

Brown adipose tissue (BAT) dissipates energy as heat in response to β-adrenergic signaling induced by the sympathetic nervous system (SNS). While this pathway is essential for the cold-induced remodeling and metabolic activity of BAT, its role in developmental programming is unclear. Here, we show that brown adipocytes acquire thermogenic identity during embryogenesis independently of sympathetic innervation and β-adrenergic signaling. Genetic sympathectomy or disrupted β-adrenergic signaling had minimal effects on thermogenic gene expression or tissue morphology during either embryonic or postnatal BAT development in the absence of cold stress. Functional analyses revealed that the SNS is likely required for circulatory support of BAT activity during β-adrenergic stimulation but not for the development of the thermogenic capacity of BAT itself. These findings demonstrate that developmental and cold-responsive BAT remodeling are mechanistically distinct processes. Defining the molecular programs that drive BAT development may reveal new strategies to enhance BAT formation and function without relying on β-adrenergic stimulation.

In rodent models of type 2 diabetes, a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) induces sustained remission of hyperglycemia. Overactive agouti-related peptide (AgRP) neurons, located in the hypothalamic arcuate nucleus, are a hallmark of diabetic states, and their long-term inhibition has been linked to FGF1's antidiabetic effects. To investigate the underlying mechanism(s), we performed single-nucleus RNA sequencing of the mediobasal hypothalamus at Days 5 and 14 post-injection in wild-type and diabetic (Lep^ob/ob) mice treated with FGF1 or vehicle. We found that AgRP neurons from Lep^ob/ob mice form a transcriptionally distinct, hyperactive subpopulation. By Day 5, icv FGF1 induced a subset of these neurons to shift toward a less active, wild-type-like state, characterized by reduced activity-linked gene expression that persisted through Day 14. Spatial transcriptomics revealed that this FGF1-responsive AgRP subset is positioned dorsally within the arcuate nucleus. The transcriptional shift was accompanied by increased transcriptional processes indicative of GABAergic signaling, axonogenesis, and astrocyte-AgRP and oligodendrocyte-AgRP interactions. These glial inputs involve astrocytic neurexins and the perineuronal net (PNN) component phosphacan, suggesting both intrinsic and extrinsic mechanisms underlie FGF1-induced AgRP silencing. Combined with evidence that FGF1 increases assembly in the arcuate nucleus, our findings reveal a cell-type-specific model for how FGF1 elicits long-term reprogramming of hypothalamic circuits to achieve diabetes remission.

Electrogenic Na⁺/K⁺ ATPases (NKAs) control β-cell Ca²⁺ influx and insulin secretion by integrating the signal strength of stimulatory G protein (G_s)-coupled ligands (e.g., GLP-1, glucagon) and inhibitory G protein (G_i)-coupled ligands (e.g., somatostatin, epinephrine). However, there is a significant gap in our understanding of how specific NKA subunits contribute to β-cell function. Here, we demonstrate that the NKA β1-subunit (NKAβ1) is highly expressed and functional at the plasma membrane of mouse and human β-cells. β-cell-specific NKAβ1 knockout improves glucose tolerance and hepatic insulin sensitivity, coinciding with enhanced first- and second-phase glucose-stimulated insulin secretion (GSIS). Electrophysiological studies reveal that β-cell NKAβ1 enhances somatostatin-induced NKA currents, increases action potential afterhyperpolarization amplitude, and accelerates action potential frequency. Loss of NKAβ1 delays glucose-stimulated Ca²⁺ entry by impairing glycolysis-dependent NKA activation and reduces Na⁺ clearance efficiency during Ca²⁺ oscillations, resulting in prolonged silent phases. Thus, glycolytic stimulation of Na⁺ influx dictates silent phase duration via the kinetics of Na⁺ clearance by NKA, which is diminished in β-cells without NKAβ1. Furthermore, NKAβ1 differentially modulates β-cell G protein-coupled receptor (GPCR) signaling by attenuating G_i-GPCR effects and augmenting G_s-coupled GLP-1 receptor-mediated cAMP production and Ca²⁺ entry. NKAβ1^βKD in human pseudoislets led to tonically elevated intracellular Ca²⁺ and increased insulin secretion. These findings establish NKAβ1-containing NKA complexes as critical regulators of β-cell electrical activity, Ca²⁺ oscillations, and secretory patterns, with direct consequences for systemic glucose homeostasis.

Insulin secretion from pancreatic β-cells is essential for maintaining glucose homeostasis and preventing type 2 diabetes, a condition closely associated with aging. Although previous studies in mice have shown that both basal and glucose-stimulated insulin secretion increase with age, the underlying mechanisms remained poorly understood. In this study, we identify protein kinase D (PKD) as a critical regulator of β-cell function during aging through its control of cellular senescence. Using β-cell-specific expression of dominant-negative PKDkd-EGFP and the selective PKD inhibitor CRT0066101, we demonstrate that inhibition of PKD activity in mature adult mice induced a senescent-like β-cell phenotype characterized by enlarged cell size and elevated β-galactosidase activity. These changes were associated with decreased expression of the antioxidant enzyme superoxide dismutase 2 and increased levels of reactive oxygen species. Surprisingly, despite promoting a senescent-like phenotype, PKD inhibition significantly improved glucose tolerance, enhanced glucose-stimulated insulin secretion, and protected against high-fat diet-induced glucose and insulin intolerance. These findings highlight the importance of PKD in preserving β-cell function under aging and metabolic stress conditions.

Pancreatitis is a common cause of hospitalization that necessitates attentive clinical management. Affected individuals are at risk for pancreatic cancer due to aberrant signaling and empowered cell plasticity. Yet, molecular and cellular dynamics that govern epithelial cell behavior in response to inflammation remain largely elusive. Here we found that inflammation induces Endoplasmic Reticulum-Associated Degradation protein (ERAD)-mediated downregulation of Niemann-Pick type C protein 1 (NPC1), which leads to the sequestration of free cholesterol within acinar cells' lysosomes. Reducing intra-pancreatic cholesterol levels through genetic ablation of Acly ameliorates cerulein-induced pancreatitis, while pharmacological targeting of NPC1 exacerbates tissue damage. Mechanistically, the accumulation of lysosomal cholesterol is sensed by the mechanistic Target of Rapamycin Complex 1 (mTORC1) that promotes metaplasia of pancreatic acinar cells, an event commonly associated to pancreatitis and tissue regeneration. Indeed, cholesterol supplementation or NPC1 inhibition facilitate acinar-to-ductal metaplasia (ADM) both ex vivo and in vivo, in an mTORC1-dependent manner. These results identify a metabolic/signaling axis driving the reprogramming of pancreatic epithelial cells in response to inflammation. This hinges on a nutrient sensing paradigm, previously documented exclusively in pathological conditions.

The current understanding of interactions and crosstalk among essential organs remains incomplete, mainly due to the limitations of studies on the systemic mechanisms at play. The gut and the liver are essential for the functioning of the entire body, and their derived mediators circulate through blood or lymph, impacting other organs like the brain, heart, and kidneys. This publication reviews gut-liver-derived mediators, which were tested and validated in vivo in humans and rodents, together with the current knowledge of their systemic effects on key vital organs. Original articles published up to February 2025, based on clinical trials or in vivo experimental models, were retrieved from PubMed and Web of Science. During this systematic analysis, 28 gut-liver-derived mediators were identified from 52 publications and classified into five distinct groups based on their molecular characteristics: (a) low molecular weight metabolites, (b) endotoxins, (c) hormones, (d) lipids and (e) proteins. Additionally, the mechanism of action for each of these molecules was specified, aimed at providing a mechanistic overview of their effects on the brain, heart, and kidneys. The diverse and occasionally conflicting impact of the identified mediators on comorbidities necessitates further investigations pinpointing key mechanisms influencing disease genesis and progression. Our research shows the necessity of a thorough examination of these mediators, exploring their diagnostic and therapeutic potential in a holistic multi-organ setting, to elucidate inter-organ crosstalk.