This review highlights the crucial role of olfaction in regulating energy homeostasis. Neurons in the olfactory system stimulate the limbic and hedonic pathways involved in food-related behaviors. These neurons are modulated by the body's energy metabolism status, which they, in turn, help to regulate. Olfactory sensitivity is reduced in obesity, while bariatric surgery restores olfactory function. In type 2 diabetes, the onset of olfactory dysfunction is predictive of cognitive decline. Finally, in a mouse model of obesity, local activation of glucagon-like peptide 1 (GLP-1) and its receptors in the olfactory bulb -the main brain structure responsible for encoding odorsleads to improved glycemic control and regulation of food intake. Activation of this new neurometabolic pathway connecting the olfactory system to the pancreas leads to increased insulin secretion and sensitivity to this hormone.

Cette synthèse présente le rôle crucial de l’olfaction dans la régulation de l’homéostasie énergétique. Les neurones du système olfactif stimulent les aires cérébrales impliquées dans les émotions, la mémoire et le plaisir, et qui sont liées à l’alimentation. Ils sont modulés par le niveau du métabolisme énergétique corporel, qu’ils régulent en retour. La sensibilité olfactive diminue dans l’obésité et la chirurgie bariatrique la rétablit. Dans le diabète de type 2, l’apparition de troubles olfactifs peut prédire les troubles cognitifs. Enfin, dans un modèle murin de l’obésité, l’activation locale du système glucagon-like peptide-1 (GLP-1) dans le bulbe olfactif, première structure cérébrale codant les odeurs, induit une meilleure régulation de la glycémie et de la prise alimentaire. Le recrutement de cette nouvelle voie neurométabolique menant jusqu’au pancréas provoque une augmentation de la libération d’insuline et de la sensibilité à cette hormone.

Brain regions drive multiple physiological functions through specific gene expression patterns that adapt to environmental influences, drug treatments and disease conditions. To generate a detailed atlas of the brain transcriptome in the context of diabetes, we carried out RNA sequencing in hypothalamus, hippocampus, brainstem and striatum of the Goto-Kakizaki (GK) rat model of spontaneous type 2 diabetes, which was applied to identify gene transcription adaptation to improved glycemic control following vertical sleeve gastrectomy (VSG) in the GK. Over 19,000 distinct transcripts were detected in the rat brain, including 2794 which were consistently expressed in the four brain regions. Region-specific gene expression was identified in hypothalamus (n = 477), hippocampus (n = 468), brainstem (n = 1173) and striatum (n = 791), resulting in differential regulation of biological processes between regions. Differentially expressed genes between VSG and sham operated rats were only found in the hypothalamus and were predominantly involved in the regulation of endothelium and extracellular matrix. These results provide a detailed atlas of regional gene expression in the diabetic rat brain and suggest that the long term effects of gastrectomy-promoted diabetes remission involve functional changes in the hypothalamus endothelium.

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 ΔInsl 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 ΔInsl 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 ΔInsl 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.

Obesity is a devastating worldwide metabolic disease, with the highest prevalence in children and adolescents. Obesity impacts neuronal function but the fate of functional hyperemia, a vital mechanism making possible cerebral blood supply to active brain areas, is unknown in organisms fed a high-caloric Western Diet (WD) since adolescence. We mapped changes in cerebral blood volume (CBV) in the somatosensory cortex in response to whisker stimulation in adolescent, adult, and middle-aged mice fed a WD since adolescence. To this aim, we used non-invasive and high-resolution functional ultrasound imaging (fUS). We efficiently mimicked the metabolic syndrome of adolescents in young mice with early weight gain, dysfunctional glucose homeostasis, and insulinemia. Functional hyperemia is compromised as early as 3 weeks of WD and remains impaired after that in adolescent mice. These findings highlight the cerebrovascular vulnerability to WD during adolescence. In WD, ω-6:ω-3 polyunsaturated fatty acids (PUFAs) ratio is unbalanced towards proinflammatory ω-6. A balanced ω-6:ω-3 PUFAs ratio in WD achieved by docosahexaenoic acid supplementation efficiently restores glucose homeostasis and functional hyperemia in adults. WD triggers a rapid impairment in cerebrovascular activity in adolescence, which is maintained at older ages, and can be rescued by a PUFA-based nutraceutical approach.

Bariatric surgery results in type 2 diabetes (T2D) improvement. To identify mechanisms associated with gastrectomy-promoted T2D remission in lean individuals, we performed pathophysiological, behavioural and molecular (liver transcriptome, metabolome and lipidome) investigations in the Goto-Kakizaki (GK) model of spontaneously-occurring non-obese T2D following vertical sleeve gastrectomy (VSG) or sham operation. VSG resulted in sustained reduction in hyperglycemia and changes in nycthemeral feeding patterns and activity. Liver transcriptome and lipidome profiling pointed to changes in the expression of genes involved in inflammation, PPAR signalling and fatty acid metabolism, and in the regulation of phosphatidylcholine and lysophosphatidylethanolamine classes. Deeper analysis revealed altered expression of genes involved in histone methylation and co-ordinately differential transcription of key regulators of the molecular clock (Clock, Arntl/Bmal1, Per1, Per2, Per3). In addition to previously reported changes in bile acid metabolism and gut microbiome in this model of VSG, our findings underline the multiple biological mechanisms associated with diabetes remission following VSG and suggest a contribution of chronobiology and epigenetic processes in the long-term therapeutic consequences of VSG in the context of polygenic non-obese T2D.

Glucagon-like peptide-1 (GLP-1) has previously been shown to be indispensable for optimal bone strength by acting at the bone material level. However, it was not fully clear whether the effects of GLP-1 were mediated by direct or indirect actions on bone cells. In the present study, we were unable to demonstrate the expression of the GLP-1 receptor (GLP-1r) in bone tissue at the gene expression level using qPCR and in situ hybridization, or at the protein level. Furthermore, the peripheral administration of exendin-4, a specific GLP-1r agonist, in ovariectomized BALB/c mice enhanced postyield displacement (18%) and energy-to-fracture (24%), as well as bone volume/total volume (BV/TV) (11%), trabecular number (Tb.N) (6%), and collagen maturity (18%). These bone effects were still observed when exendin-4 was centrally administered into the lateral cerebral ventricle. On the contrary, the peripheral administration of exendin-4 coupled to bovine serum albumin, a GLP-1r agonist that cannot penetrate the brain, failed to replicate the positive effects on bone despite increased calcitonin secretion. Altogether, these data confirm that GLP-1r agonists represent an interesting approach for managing bone fragility due to ovariectomy but also suggest that GLP-1r agonists require a central relay-yet to be identified-to exert positive effects on bone physiology. Further studies are needed to decipher the mechanisms of action of GLP-1 and GLP-1r agonists on bone physiology.NEW & NOTEWORTHY 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.

The central nervous system is a key regulator of energy and glucose homeostasis, integrating peripheral signals such as hormones and nutrients to maintain metabolic balance. Among its regions, the hypothalamus plays a central role in monitoring energy status and orchestrating physiological responses via neuronal and glial circuits. Recent research highlights the influence of de novo ceramide synthesis on central nervous system regulation of metabolism. Indeed, ceramides have emerged as critical signalling molecules linking fatty acid sensing to hypothalamic control of feeding, energy expenditure, and glucose regulation. This review details the mechanisms of de novo ceramide synthesis and explores how dysregulation of this pathway in the hypothalamus contributes to obesity and type 2 diabetes. Serine palmitoyl-transferase and specific ceramide synthase isoforms are shown to play roles in mediating neuronal responses to metabolic stress. The findings also emphasize that hypothalamic ceramide metabolism is modulated by both nutritional and hormonal cues and suggest that targeting this pathway may offer new strategies for treating metabolic disorders.

Preterm birth and its related complications have become more and more common as neonatal medicine advances. The concept of “developmental origins of health and disease” has raised awareness of adverse perinatal events in the development of diseases later in life. To explore this concept, we propose that encephalopathy of prematurity (EoP) as a potential pro-inflammatory early life event becomes a novel risk factor for metabolic diseases in children/adolescents and adulthood. Here, we review epidemiological evidence that links preterm birth to metabolic diseases and discuss possible synergic roles of preterm birth and neuroinflammation from EoP in the development of metabolic diseases. In addition, we explore theoretical underlying mechanisms regarding developmental programming of the energy control system and HPA axis.

Sphingolipid-mediated signaling pathways are described as important players in the normal functioning of neurons and non-neuronal cells of the central nervous system (CNS). Recent evidence suggests that de novo ceramide synthesis in the CNS is involved in the regulation of key physiological processes, including food intake and thermogenesis. The corollary is that conditions leading to dysfunction of ceramide metabolism in these central regions can have major consequences on the physiological regulation of energy balance. Indeed, excessive hypothalamic ceramide synthesis has been shown to lead to central insulin resistance, dysregulation of glucose homeostasis associated with changes in autonomic nervous system activity. As such, dysregulation of hypothalamic ceramide synthesis therefore constitutes a key starting point for the setting in of pathophysiological conditions such as obesity and type 2 diabetes.

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 ### Competing Interest Statement The authors have declared no competing interest.

DHA is abundant in brain where it regulates cell survival, neurogenesis and neuroinflammation. DHA can be obtained from the diet or synthesized from alpha-linolenic acid (ALA; 18:3n-3) via a series of desaturation and elongation reactions occurring in the liver. Tracer studies suggest that dietary DHA can downregulate its own synthesis, but the mechanism remains undetermined and is the primary objective of this paper. First, we show by tracing 13C content (δ13C) of DHA via compound-specific isotope analysis (CSIA), that following low dietary DHA, the brain receives DHA synthesized from ALA. We then show that dietary DHA increases mouse liver and serum EPA, which is dependant on ALA. Furthermore, by CSIA we demonstrate that the source of increased EPA is slowed EPA metabolism, not increased DHA retroconversion as previously assumed. DHA feeding alone or with ALA lowered liver elongation of very long-chain (ELOVL2, EPA elongation) enzyme activity despite no change in protein content. To further evaluate the role of ELOVL2, a liver-specific Elovl2 knockout was generated showing that DHA feeding in the presence or absence of a functional liver ELOVL2 yields similar results. An enzyme competition assay for EPA elongation suggests both uncompetitive and non-competitive inhibition by DHA depending on DHA levels. To translate our findings, we show that DHA supplementation in men and women increases EPA levels in a manner dependent on a SNP (rs953413) in the ELOVL2 gene. In conclusion, we identify a novel feedback inhibition pathway where dietary DHA downregulates its liver synthesis by inhibiting EPA elongation.

Long-chain n-3 PUFA (LC n-3 PUFA) prevent, in rodents, insulin resistance (IR) induced by a high-fat and/or fructose diet but not IR induced by glucocorticoids. In humans, contrasting effects have also been reported. We investigated their effects on insulin sensitivity, feed intake (FI) and body weight gain in genetically insulin resistant male obese (fa/fa) Zucker (ZO) rats during the development of obesity. ZO rats were fed a diet supplemented with 7 % fish oil (FO) + 1 % corn oil (CO) (wt/wt) (ZOFO), while the control group was fed a diet containing 8 % fat from CO (wt/wt) (ZOCO). Male lean Zucker (ZL) rats fed either FO (ZLFO) or CO (ZLCO) diet were used as controls. FO was a marine-derived TAG oil containing EPA 90 mg/g + DHA 430 mg/g. During an oral glucose tolerance test, glucose tolerance remained unaltered by FO while insulin response was reduced in ZOFO only. Liver insulin sensitivity (euglycaemic-hyperinsulinaemic clamp + 2 deoxyglucose) was improved in ZOFO rats, linked to changes in phosphoenolpyruvate carboxykinase expression, activity and glucose-6-phosphatase activity. FI in response to intra-carotid insulin/glucose infusion was decreased similarly in ZOFO and ZOCO. Hypothalamic ceramides levels were lower in ZOFO than in ZOCO. Our study demonstrates that LC n-3 PUFA can minimise weight gain, possibly by alleviating hypothalamic lipotoxicity, and liver IR in genetically obese Zucker rats.

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. In this Review, the authors examine current guidelines for metabolic tolerance tests in mice and provide a set of revisited recommendations to improve the reproducibility and clinical translation of the findings.

The central nervous system continuously detects circulating concentrations of lipids such as fatty acids and troglycerides. Once information has been detected, the central nervous system can in turn participate in the control of energy balance and blood sugar levels and in particular regulate the secretion and action of insulin. Neurons capable of detecting circulating lipid variations are located in the hypothalamus and in other regions such as the nucleus accumbens, the striatum or the hippocampus. An excess of lipids will have deleterious effects and may induce central lipotoxicity, in particular following local production of ceramides and the appearance of neuroinflammation which may lead to metabolic diseases such as obesity and type 2 diabetes

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.