Christophe Magnan

Anorexia nervosa is a metabolic-psychiatric disorder characterized by severe food restriction, often accompanied by hyperactivity, associated with high mortality and the lack of specific pharmacological treatment. Despite a marked energy deficit, patients paradoxically maintain euglycemia, suggesting adaptations in energy homeostasis. This study aims to characterize the interactions between food restriction, the gut microbiota and peripheral organs in a mouse model mimicking anorexia nervosa. Our results show that food-restricted mice exhibit improved glucose tolerance and increased expression of the gluconeogenic genes G6pc and Pck1 in the intestine, suggesting an adaptation in endogenous glucose production. Gut microbiota analysis reveals a marked shift in composition in food-restricted mice, with an increase in the Lachnospiraceae and Marinifilaceae families and a decrease in Lactobacillaceae . These changes are associated with metabolic parameters such as glycemia, body weight, and GLP-1 levels. Transfer of microbiota from food-restricted mice into control mice improves glucose tolerance and increases the gluconeogenic gene expression. Furthermore, the improvement in glucose tolerance is abolished in mice lacking intestinal gluconeogenesis, suggesting that intestinal gluconeogenesis is required for the effects of the FR microbiota on glucose homeostasis. Overall, these findings highlight a complex metabolic adaptation in a mouse model of anorexia nervosa, involving interactions between the gut microbiota, intestinal gluconeogenesis and maintenance of energy homeostasis.

This study discovered that medications mimicking GLP-1, like exendin-4, improve bone strength and structure in mice, including better bone volume and collagen quality. Interestingly, exendin-4’s effects were observed when delivered to the brain but not when prevented from reaching it. This suggests GLP-1 influences bones through brain signals rather than acting directly on bone. Although GLP-1 treatments show promise for preventing bone weakness, more research is needed to understand this brain-bone connection.

Aims/Hypothesis: The importance for normal insulin secretion of ceramide synthesis is unclear. De novo ceramide synthesis requires serine palmitoyl transferase, SPT2, encoded by Sptl2 . Methods: We generated β-cell-selective Sptl2 null mice by crossing animals with floxed alleles to mice expressing Cre recombinase from the Ins1 locus. Metabolic phenotyping, transcriptomic, functional analyses and histology were performed using standard approaches. Results: Islets from Sptlc2 ^{Δ Ins1} mice displayed marked alterations in ceramide and sphingomyelin levels: ceramide content: p=0.016 and p=0.109; sphingomyelin content: p=0.016 and p=0.004 in Sptlc2 ^{Δ Ins1} vs Sptlc2 ^CTL mice under regular and high fat diet, respectively, despite compensatory increases in the expression of enzymes in the salvage and sphingomyelinase pathways. Correspondingly, profound abnormalities were observed in glucose-regulated insulin secretion and glucose tolerance in vivo , both on a regular chow and high fat diet. These changes were associated with a drastic (∼80%) lowering in β-cell numbers, and a more minor increase in delta cell numbers. They were also preserved in animals maintained on a ketogenic diet, consistent with a cell autonomous effect on the β-cell. Despite normal glucose-regulated intracellular calcium dynamics and insulin secretion, marked transcriptomic changes were observed in Sptlc2 ^{Δ Ins1} mouse islets, with affected GO terms including lysosome organisation and regulation of autophagy. Consistent with roles for compromised SPT2 function in diseased β-cells, Sptl2 expression in Balbc and DBA2J mouse islets was lowered by a high fat-diet. Moreover, SPTLC2 mRNA tended to be lower, and SPTLC1 mRNA was significantly decreased, in islets from human subjects with type 2 diabetes versus normoglycemic individuals. Conclusions: Preserved de novo ceramide synthesis is required to maintain normal β-cell mass and thus insulin secretion in mice. Therapeutic approaches which seek to target this process systemically using pharmacological SPT2 inhibitors should thus be treated with caution. Research in context: - What is already known about this subject?: Ceramides are key components of sphingolipid metabolism. Excess ceramide levels contribute to lipotoxicity and β-cell apoptosis. α-cell-restricted deletion of Cers2 , which is responsible for the synthesis of very long ceramide chains, alters the insulin content of pancreatic islets and modifies glucose tolerance. Deletion of Cers 5 or 6 , responsible for the synthesis of the long chains, has no effect. - What is the key question?: What is the importance of de novo ceramide synthesis in β-cells for the normal regulation of insulin production and glucose homeostasis? - What are the new findings?: Inhibition of the de novo ceramide synthesis pathway in β-cells, achieved by selective deletion of Sptlc2 , encoding subunit 2 of the serine palmitoyltransferase (SPT) enzyme, induces a major alteration of glucose tolerance and insulin secretion. This is accompanied by a drastic reduction in β-cell mass and islet insulin content. The remaining islets of Sptlc2 ^{Δ Ins1} display normal glucose-regulated intracellular calcium dynamics and insulin secretion despite imbalances in ceramide and sphingomyelin levels and substantial transcriptomic changes. Expression of SPTLC1 , which encodes the other subunit of the SPT heterodimer, is reduced in islets from humans with type 2 diabetes, and a trend is observed towards lowered SPTLC2 expression. Taken together, these findings highlight the importance of de novo ceramide synthesis for normal β-cell survival and function - How might this impact on clinical practice in the foreseeable future?: By suppressing insulin production, global blockade or inhibition of SPT2, achieved with pharmacological approaches which seek to rescue insulin sensitivity in T2D, may be deleterious for glucose tolerance.

The mechanisms governing adipose tissue macrophage (ATM) metabolic adaptation during diet-induced obesity (DIO) are poorly understood. In obese adipose tissue, ATMs are exposed to lipid fluxes, which can influence the activation of specific inflammatory and metabolic programs and contribute to the development of obesity-associated insulin resistance and other metabolic disorders. In the present study, we demonstrate that the membrane ATP-binding cassette g1 (Abcg1) transporter controls the ATM functional response to fatty acids (FAs) carried by triglyceride-rich lipoproteins, which are abundant in high-energy diets. Mice genetically lacking Abcg1 in the myeloid lineage presented an ameliorated inflammatory status in adipose tissue and reduced insulin resistance. Abcg1-deficient ATMs exhibited a less inflammatory phenotype accompanied by a low bioenergetic profile and modified FA metabolism. A closer look at the ATM lipidome revealed a shift in the handling of FA pools, including a redirection of saturated FAs from membrane phospholipids to lipid droplets, leading to a reduction in membrane rigidity and neutralization of proinflammatory FAs. ATMs from human individuals with obesity presented the same reciprocal relationship between ABCG1 expression and this inflammatory and metabolic status. Abolition of this protective, anti-inflammatory phenotype in Abcg1-deficient ATMs was achieved through restoration of lipoprotein lipase (Lpl) activity, thus delineating the importance of the Abcg1/Lpl axis in controlling ATM metabolic inflammation. Overall, our study identifies the rewiring of FA pools by Abcg1 as a major pathway orchestrating ATM plasticity and insulin resistance in DIO.

Preclinical mouse models are extensively used in biomedical research to gain insight into disease mechanisms and to test new drug treatments. Glucose and insulin tolerance tests are simple experimental tests frequently used worldwide to assess glucose metabolism in mice. Various guidelines and methodological considerations have been published to help researchers standardize procedures and optimize research outcomes. Yet, there is still important experimental heterogeneity in the way these simple procedures are performed, with no real consensus on what the best practices are to achieve high-quality research and reproducible results. Here we critically examine several published guidelines and recent technical reports on how to perform these metabolic tests in laboratory mice and discuss the influence of various confounding factors on test results. We hope this work will help scientists establish more consensual guidelines for maximizing the relevance and clinical translation of studies using mouse models in metabolic research.

Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and holds significant pharmacological potential. Nevertheless, the regulation of energy homeostasis by centrally-produced GLP-1 remains partially understood. Preproglucagon cells, known to release GLP-1, are found in the olfactory bulb (OB). We show that activating GLP-1 receptors (GLP-1R) in the OB stimulates insulin secretion in response to oral glucose in lean and diet-induced obese male mice. This is associated with reduced noradrenaline content in the pancreas and blocked by an α₂-adrenergic receptor agonist, implicating functional involvement of the sympathetic nervous system (SNS). Inhibiting GABA_A receptors in the paraventricular nucleus of the hypothalamus (PVN), the control centre of the SNS, abolishes the enhancing effect on insulin secretion induced by OB GLP-1R. Therefore, OB GLP-1-dependent regulation of insulin secretion relies on a relay within the PVN. This study provides evidence that OB GLP-1 signalling engages a top-down neural mechanism to control insulin secretion via the SNS.

Around 1 of every 10 babies is born preterm, and the incidence of preterm birth has been rising. The long-term consequences of preterm survivors are not fully understood. Preterm birth is proven to be associated with metabolic diseases and related disorders later in life. Preterm newborns are susceptible to perinatal inflammatory events such as chorioamnionitis, hypoxia-ischemia, and sepsis. We hypothesized that perinatal inflammation has a role in the developmental programming of metabolic diseases and related disorders. In the present study, perinatal inflammation was modeled by systemic administration of IL-1β in mice. We observed a pronounced sexual dimorphism where only the males presented significant insulin resistance and glucose intolerance accompanied by leptin resistance in the long term following perinatal inflammation exposure. Adiposity and energy homeostasis were intact. It showed that perinatal inflammation selectively contributes to the long-term dysregulation of glucose metabolism in a sex-dependent manner. The underlying mechanism might be linked with hypothalamic inflammation and upregulated circulating CCL5. Metformin treatment might be optional to treat insulin resistance resulting from perinatal inflammation. Highlights Perinatal inflammation is common in preterm infants, often leading to perinatal brain injuries. However, the long-term metabolic outcomes of these infants are not fully revealed. We explored the long-term metabolic outcomes in mice with perinatal IL-1β exposure and sought its association with inflammation. Perinatal inflammation has a profound and deleterious role in glucose metabolism in a sex-dependent and time-dependent manner. Perinatal inflammation might be a risk factor for metabolic disorders in preterm survivors.