Hepatic noradrenergic innervation acts via CREB/CRTC2 to activate gluconeogenesis during cold.

BACKGROUND AND AIM: Although it is well established that hormones like glucagon stimulates gluconeogenesis via the PKA-mediated phosphorylation of CREB and dephosphorylation of the cAMP-regulated CREB coactivators CRTC2, the role of neural signals in the regulation of gluconeogenesis remains uncertain. METHODS AND RESULTS: Here, we characterize the noradrenergic bundle architecture in mouse liver; we show that the sympathoexcitation induced by acute cold exposure promotes hyperglycemia and upregulation of gluconeogenesis via triggering of the CREB/CRTC2 pathway. Following its induction by dephosphorylation, CRTC2 translocates to the nucleus and drives the transcription of key gluconeogenic genes. Rodents submitted to different models of sympathectomy or knockout of CRTC2 do not activate gluconeogenesis in response to cold. Norepinephrine directly acts in hepatocytes mainly through a Ca2+-dependent pathway that stimulates CREB/CRTC2, leading to activation of the gluconeogenic program. CONCLUSION: Our data demonstrate the importance of the CREB/CRTC2 pathway in mediating effects of hepatic sympathetic inputs on glucose homeostasis, providing new insights into the role of norepinephrine in health and disease.

PANX1-mediated ATP release confers FAM3A's suppression effects on hepatic gluconeogenesis and lipogenesis.

BACKGROUND: Extracellular adenosine triphosphate (ATP) is an important signal molecule. In previous studies, intensive research had revealed the crucial roles of family with sequence similarity 3 member A (FAM3A) in controlling hepatic glucolipid metabolism, islet ß cell function, adipocyte differentiation, blood pressure, and other biological and pathophysiological processes. Although mitochondrial protein FAM3A plays crucial roles in the regulation of glucolipid metabolism via stimulating ATP release to activate P2 receptor pathways, its mechanism in promoting ATP release in hepatocytes remains unrevealed. METHODS: db/db, high-fat diet (HFD)-fed, and global pannexin 1 (PANX1) knockout mice, as well as liver sections of individuals, were used in this study. Adenoviruses and adeno-associated viruses were utilized for in vivo gene overexpression or inhibition. To evaluate the metabolic status in mice, oral glucose tolerance test (OGTT), pyruvate tolerance test (PTT), insulin tolerance test (ITT), and magnetic resonance imaging (MRI) were conducted. Protein-protein interactions were determined by coimmunoprecipitation with mass spectrometry (MS) assays. RESULTS: In livers of individuals and mice with steatosis, the expression of ATP-permeable channel PANX1 was increased (P < 0.01). Hepatic PANX1 overexpression ameliorated the dysregulated glucolipid metabolism in obese mice. Mice with hepatic PANX1 knockdown or global PANX1 knockout exhibited disturbed glucolipid metabolism. Restoration of hepatic PANX1 rescued the metabolic disorders of PANX1-deficient mice (P < 0.05). Mechanistically, ATP release is mediated by the PANX1-activated protein kinase B-forkhead box protein O1 (Akt-FOXO1) pathway to inhibit gluconeogenesis via P2Y receptors in hepatocytes. PANX1-mediated ATP release also activated calmodulin (CaM) (P < 0.01), which interacted with c-Jun N-terminal kinase (JNK) to inhibit its activity, thereby deactivating the transcription factor activator protein-1 (AP1) and repressing fatty acid synthase (FAS) expression and lipid synthesis (P < 0.05). FAM3A stimulated the expression of PANX1 via heat shock factor 1 (HSF1) in hepatocytes (P < 0.05). Notably, FAM3A overexpression failed to promote ATP release, inhibit the expression of gluconeogenic and lipogenic genes, and suppress gluconeogenesis and lipid deposition in PANX1-deficient hepatocytes and livers. CONCLUSIONS: PANX1-mediated release of ATP plays a crucial role in maintaining hepatic glucolipid homeostasis, and it confers FAM3A's suppressive effects on hepatic gluconeogenesis and lipogenesis.

Exploring mechanisms of insulin action and strategies to treat diabetes.

Insulin is a hormone that positively regulates anabolism and cell growth, whereas diabetes mellitus is a disease characterized by hyperglycemia associated with impaired insulin action. My colleagues and I have elucidated multifaceted insulin action in various tissues mainly by means of model mice. In the liver, insulin regulates endoplasmic reticulum (ER) stress response during feeding, whereas ER stress 'response failure' contributes to the development of steatohepatitis comorbid with diabetes. Not only the liver but also the proximal tubules of the kidney are important in the regulation of gluconeogenesis, and we revealed that insulin suppresses gluconeogenesis in accordance with absorbed glucose in the latter tissue. In skeletal muscle, another important insulin-targeted tissue, impaired insulin/IGF-1 signaling leads not only to sarcopenia, an aging-related disease of skeletal muscle, but also to osteopenia and shorter longevity. Aging is regulated by adipokines as well, and it should be considered that aging could be accelerated by 'imbalanced adipokines' in patients with a genetic background of progeria. Moreover, we reported the effects of intensive multifactorial intervention on diabetic vascular complications and mortality in patients with type 2 diabetes in a large-scale clinical trial, the J-DOIT3, and the results of subsequent sub-analyses of renal events and fracture events. Various approaches of research enable us of endocrinologists to elucidate the physiology of hormone signaling, the mechanisms underlying the development of endocrine diseases, and the appropriate treatment measures. These approaches also raise fundamental questions, but addressing them in an appropriate manner will surely contribute to the further development of endocrinology.

Gluconeogenesis in frogs during cooling and dehydration exposure: new insights into tissue plasticity of the gluconeogenic pathway dependent on abiotic factors.

Anurans undergo significant physiological changes when exposed to environmental stressors such as low temperatures and humidity. Energy metabolism and substrate management play a crucial role in their survival success. Therefore, understanding the role of the gluconeogenic pathway and demonstrating its existence in amphibians is essential. In this study, we exposed the subtropical frog Boana pulchella to cooling (-2.5°C for 24 h) and dehydration conditions (40% of body water loss), followed by recovery (24 h), and assessed gluconeogenesis activity from alanine, lactate, glycerol and glutamine in the liver, muscle and kidney. We report for the first time that gluconeogenesis activity by 14C-alanine and 14C-lactate conversion to glucose occurs in the muscle tissue of frogs, and this tissue activity is influenced by environmental conditions. Against the control group, liver gluconeogenesis from 14C-lactate and 14C-glycerol was lower during cooling and recovery (P<0.01), and gluconeogenesis from 14C-glutamine in the kidneys was also lower during cooling (P<0.05). In dehydration exposure, gluconeogenesis from 14C-lactate in the liver was lower during recovery, and that from 14C-alanine in the muscle was lower during dehydration (P<0.05). Moreover, we observed that gluconeogenesis activity and substrate preference respond differently to cold and dehydration. These findings highlight tissue-specific plasticity dependent on the nature of the encountered stressor, offering valuable insights for future studies exploring this plasticity, elucidating the importance of the gluconeogenic pathway and characterizing it in anuran physiology.

MicroRNA-721 regulates gluconeogenesis via KDM2A-mediated epigenetic modulation in diet-induced insulin resistance in C57BL/6J mice.

BACKGROUND: Aberrant gluconeogenesis is considered among primary drivers of hyperglycemia under insulin resistant conditions, with multiple studies pointing towards epigenetic dysregulation. Here we examine the role of miR-721 and effect of epigenetic modulator laccaic acid on the regulation of gluconeogenesis under high fat diet induced insulin resistance. RESULTS: Reanalysis of miRNA profiling data of high-fat diet-induced insulin-resistant mice model, GEO dataset (GSE94799) revealed a significant upregulation of miR-721, which was further validated in invivo insulin resistance in mice and invitro insulin resistance in Hepa 1-6 cells. Interestingly, miR-721 mimic increased glucose production in Hepa 1-6 cells via activation of FOXO1 regulated gluconeogenic program. Concomitantly, inhibition of miR-721 reduced glucose production in palmitate induced insulin resistant Hepa 1-6 cells by blunting the FOXO1 induced gluconeogenesis. Intriguingly, at epigenetic level, enrichment of the transcriptional activation mark H3K36me2 got decreased around the FOXO1 promoter. Additionally, identifying targets of miR-721 using miRDB.org showed H3K36me2 demethylase KDM2A as a potential target. Notably, miR-721 inhibitor enhanced KDM2A expression which correlated with H3K36me2 enrichment around FOXO1 promoter and the downstream activation of the gluconeogenic pathway. Furthermore, inhibition of miR-721 in high-fat diet-induced insulin-resistant mice resulted in restoration of KDM2A levels, concomitantly reducing FOXO1, PCK1, and G6PC expression, attenuating gluconeogenesis, hyperglycemia, and improving glucose tolerance. Interestingly, the epigenetic modulator laccaic acid also reduced the hepatic miR-721 expression and improved KDM2A expression, supporting our earlier report that laccaic acid attenuates insulin resistance by reducing gluconeogenesis. CONCLUSION: Our study unveils the role of miR-721 in regulating gluconeogenesis through KDM2A and FOXO1 under insulin resistance, pointing towards significant clinical and therapeutic implications for metabolic disorders. Moreover, the promising impact of laccaic acid highlights its potential as a valuable intervention in managing insulin resistance-associated metabolic diseases.

Intermittent Fasting-Improved Glucose Homeostasis Is Not Entirely Dependent on Caloric Restriction in db/db Male Mice.

Intermittent fasting (IF), which involves prolonged fasting intervals accompanied by caloric restriction (CR), is an effective dietary treatment for obesity and diabetes. Although IF offers many benefits, it is difficult to determine whether these benefits are the consequences of CR. Every-other-day feeding (EODF) is a commonly used IF research model. This study was designed to identify factors, in addition to CR, responsible for the effects of EODF and the possible underlying mechanisms. Diabetic db/db mice were divided into three groups: ad libitum (AL), meal feeding (MF), and EODF. The MF model was used to attain a level of CR comparable to that of EODF, with food distribution evenly divided between 10:00 a.m. and 6:00 p.m., thereby minimizing the fasting interval. EODF yielded greater improvements in glucose homeostasis than MF in db/db mice by reducing fasting glucose levels and enhancing glucose tolerance. However, these effects on glucose metabolism were less pronounced in lean mice. Furthermore, ubiquitination of the liver-specific glucocorticoid (GC) receptor (GR) facilitated its degradation and downregulation of Kruppel-like factor 9 (KLF9), which ultimately suppressed liver gluconeogenesis in diabetic EODF mice. Although GR and KLF9 might mediate the metabolic benefits of EODF, the potential benefits of EODF might be limited by elevated serum GC levels in diabetic EODF mice. Overall, this study suggests that the metabolic benefits of EODF in improving glucose homeostasis are independent of CR, possibly because of the downstream effects of liver-specific GR degradation.

Metabolic Fluxes in the Renal Cortex Are Dysregulated In Vivo in Response to High-Fat Diet.

Diabetes and obesity are risk factors for kidney disease. Whereas renal glucose production increases in diabetes, recent data suggest that gluconeogenic and oxidative capacity decline in kidney disease. Thus, metabolic dysregulation caused by diet-induced insulin resistance may sensitize the kidney for a loss in function. Here, we examined how diet-induced insulin resistance disrupts mitochondrial metabolic fluxes in the renal cortex in vivo. C57BL/6J mice were rendered insulin resistant through high-fat (HF) feeding; anaplerotic, cataplerotic, and oxidative metabolic fluxes in the cortex were quantified through 13C-isotope tracing during a hyperinsulinemic-euglycemic clamp. As expected, HF-fed mice exhibited increased body weight, gluconeogenesis, and systemic insulin resistance compared with chow-fed mice. Relative to the citric acid cycle, HF feeding increased metabolic flux through pyruvate carboxylation (anaplerosis) and phosphoenolpyruvate carboxykinase (cataplerosis) and decreased flux through the pyruvate dehydrogenase complex in the cortex. Furthermore, the relative flux from nonpyruvate sources of acetyl-CoA profoundly increased in the cortex of HF-fed mice, correlating with a marker of oxidative stress. The data demonstrate that HF feeding spares pyruvate from dehydrogenation at the expense of increasing cataplerosis, which may underpin renal gluconeogenesis during insulin resistance; the results also support the hypothesis that dysregulated oxidative metabolism in the kidney contributes to metabolic disease.

Enhanced glucose homeostasis via Clostridium symbiosum-mediated glucagon-like peptide 1 inhibition of hepatic gluconeogenesis in mid-intestinal bypass surgery.

BACKGROUND: The small intestine is known to play a crucial role in the development and remission of diabetes mellitus (DM). However, the exact mechanism by which mid-small intestinal bypass improves glucose metabolism in diabetic rats is not fully understood. AIM: To elucidate the mechanisms by which mid-small intestinal bypass improves glucose metabolism. METHODS: Streptozotocin (STZ) was used to induce DM in Sprague-Dawley (SD) rats at a dose of 60 mg/kg. The rats were then randomly divided into two groups: The mid-small intestine bypass (MSIB) group and the sham group (underwent switch laparotomy). Following a 6-wk recovery period post-surgery, the rats underwent various assessments, including metabolic parameter testing, analysis of liver glycogen levels, measurement of key gluconeogenic enzyme activity, characterization of the gut microbiota composition, evaluation of hormone levels, determination of bile acid concentrations, and assessment of the expression of the intestinal receptors Takeda G protein-coupled receptor 5 and farnesoid X receptor. RESULTS: The MSIB group of rats demonstrated improved glucose metabolism and lipid metabolism, along with increased hepatic glycogen content. Furthermore, there was a decrease in the expression of the key gluconeogenic enzymes phosphoenolpyruvate carboxykinase 1 and glucose-6-phosphatase. Importantly, the MSIB group exhibited a substantial increase in the abundances of intestinal Lactobacillus, Clostridium symbiosum, Ruminococcus gnavus, and Bilophila. Moreover, higher levels of secondary bile acids, such as intestinal lithocholic acid, were observed in this group. Remarkably, the changes in the gut microbiota showed a significant correlation with the expression of key gluconeogenic enzymes and glucagon-like peptide 1 (GLP-1) at 6 wk postoperatively, highlighting their potential role in glucose regulation. These findings highlight the beneficial effects of mid-small intestine bypass on glucose metabolism and the associated modulation of the gut microbiota. CONCLUSION: The findings of this study demonstrate that the introduction of postoperative intestinal Clostridium symbiosum in the mid-small intestine contributes to the enhancement of glucose metabolism in nonobese diabetic rats. This improvement is attributed to the increased inhibition of hepatic gluconeogenesis mediated by GLP-1, resulting in a favorable modulation of glucose homeostasis.

Endogenous renal adiponectin drives gluconeogenesis through enhancing pyruvate and fatty acid utilization.

Adiponectin is a secretory protein, primarily produced in adipocytes. However, low but detectable expression of adiponectin can be observed in cell types beyond adipocytes, particularly in kidney tubular cells, but its local renal role is unknown. We assessed the impact of renal adiponectin by utilizing male inducible kidney tubular cell-specific adiponectin overexpression or knockout mice. Kidney-specific adiponectin overexpression induces a doubling of phosphoenolpyruvate carboxylase expression and enhanced pyruvate-mediated glucose production, tricarboxylic acid cycle intermediates and an upregulation of fatty acid oxidation (FAO). Inhibition of FAO reduces the adiponectin-induced enhancement of glucose production, highlighting the role of FAO in the induction of renal gluconeogenesis. In contrast, mice lacking adiponectin in the kidney exhibit enhanced glucose tolerance, lower utilization and greater accumulation of lipid species. Hence, renal adiponectin is an inducer of gluconeogenesis by driving enhanced local FAO and further underlines the important systemic contribution of renal gluconeogenesis.

Enhancement of the SESN2-SHP cascade by melatonin ameliorates hepatic gluconeogenesis by inhibiting the CRBN-BTG2-CREBH signaling pathway.

Melatonin is involved in the regulation of various biological functions. Here, we explored a novel molecular mechanism by which the melatonin-induced sestrin2 (SESN2)-small heterodimer partner (SHP) signaling pathway protects against fasting- and diabetes-mediated hepatic glucose metabolism. Various key gene expression analyses were performed and multiple metabolic changes were assessed in liver specimens and primary hepatocytes of mice and human participants. The expression of the hepatic cereblon (CRBN) and b-cell translocation gene 2 (BTG2) genes was significantly increased in fasting mice, diabetic mice, and patients with diabetes. Overexpression of Crbn and Btg2 increased hepatic gluconeogenesis by enhancing cyclic adenosine monophosphate (cAMP)-responsive element-binding protein H (CREBH), whereas this phenomenon was prominently ablated in Crbn null mice and Btg2-silenced mice. Interestingly, melatonin-induced SESN2 and SHP markedly reduced hepatic glucose metabolism in diabetic mice and primary hepatocytes, and this protective effect of melatonin was strikingly reversed by silencing Sesn2 and Shp. Finally, the melatonin-induced SESN2-SHP signaling pathway inhibited CRBN- and BTG2-mediated hepatic gluconeogenic gene transcription via the competition of BTG2 and the interaction of CREBH. Mitigation of the CRBN-BTG2-CREBH axis by the melatonin-SESN2-SHP signaling network may provide a novel therapeutic strategy to treat metabolic dysfunction due to diabetes.

CD38/ADP-ribose/TRPM2-mediated nuclear Ca2+ signaling is essential for hepatic gluconeogenesis in fasting and diabetes.

Hepatic glucose production by glucagon is crucial for glucose homeostasis during fasting, yet the underlying mechanisms remain incompletely delineated. Although CD38 has been detected in the nucleus, its function in this compartment is unknown. Here, we demonstrate that nuclear CD38 (nCD38) controls glucagon-induced gluconeogenesis in primary hepatocytes and liver in a manner distinct from CD38 occurring in the cytoplasm and lysosomal compartments. We found that the localization of CD38 in the nucleus is required for glucose production by glucagon and that nCD38 activation requires NAD+ supplied by PKCδ-phosphorylated connexin 43. In fasting and diabetes, nCD38 promotes sustained Ca2+ signals via transient receptor potential melastatin 2 (TRPM2) activation by ADP-ribose, which enhances the transcription of glucose-6 phosphatase and phosphoenolpyruvate carboxykinase 1. These findings shed light on the role of nCD38 in glucagon-induced gluconeogenesis and provide insight into nuclear Ca2+ signals that mediate the transcription of key genes in gluconeogenesis under physiological conditions.

Proline hydroxylation of CREB-regulated transcriptional coactivator 2 controls hepatic glucose metabolism.

Prolyl hydroxylase domain (PHD) enzymes change HIF activity according to oxygen signal; whether it is regulated by other physiological conditions remains largely unknown. Here, we report that PHD3 is induced by fasting and regulates hepatic gluconeogenesis through interaction and hydroxylation of CRTC2. Pro129 and Pro615 hydroxylation of CRTC2 following PHD3 activation is necessary for its association with cAMP-response element binding protein (CREB) and nuclear translocation, and enhanced binding to promoters of gluconeogenic genes by fasting or forskolin. CRTC2 hydroxylation-stimulated gluconeogenic gene expression is independent of SIK-mediated phosphorylation of CRTC2. Liver-specific knockout of PHD3 (PHD3 LKO) or prolyl hydroxylase-deficient knockin mice (PHD3 KI) show attenuated fasting gluconeogenic genes, glycemia, and hepatic capacity to produce glucose during fasting or fed with high-fat, high-sucrose diet. Importantly, Pro615 hydroxylation of CRTC2 by PHD3 is increased in livers of fasted mice, diet-induced insulin resistance or genetically obese ob/ob mice, and humans with diabetes. These findings increase our understanding of molecular mechanisms linking protein hydroxylation to gluconeogenesis and may offer therapeutic potential for treating excessive gluconeogenesis, hyperglycemia, and type 2 diabetes.

The SLC25A47 locus controls gluconeogenesis and energy expenditure.

Mitochondria provide essential metabolites and adenosine triphosphate (ATP) for the regulation of energy homeostasis. For instance, liver mitochondria are a vital source of gluconeogenic precursors under a fasted state. However, the regulatory mechanisms at the level of mitochondrial membrane transport are not fully understood. Here, we report that a liver-specific mitochondrial inner-membrane carrier SLC25A47 is required for hepatic gluconeogenesis and energy homeostasis. Genome-wide association studies found significant associations between SLC25A47 and fasting glucose, HbA1c, and cholesterol levels in humans. In mice, we demonstrated that liver-specific depletion of SLC25A47 impaired hepatic gluconeogenesis selectively from lactate, while significantly enhancing whole-body energy expenditure and the hepatic expression of FGF21. These metabolic changes were not a consequence of general liver dysfunction because acute SLC25A47 depletion in adult mice was sufficient to enhance hepatic FGF21 production, pyruvate tolerance, and insulin tolerance independent of liver damage and mitochondrial dysfunction. Mechanistically, SLC25A47 depletion leads to impaired hepatic pyruvate flux and malate accumulation in the mitochondria, thereby restricting hepatic gluconeogenesis. Together, the present study identified a crucial node in the liver mitochondria that regulates fasting-induced gluconeogenesis and energy homeostasis.

Famsin, a novel gut-secreted hormone, contributes to metabolic adaptations to fasting via binding to its receptor OLFR796.

The intestine is responsible for nutrient absorption and orchestrates metabolism in different organs during feeding, a process which is partly controlled by intestine-derived hormones. However, it is unclear whether the intestine plays an important role in metabolism during fasting. Here we have identified a novel hormone, famsin, which is secreted from the intestine and promotes metabolic adaptations to fasting. Mechanistically, famsin is shed from a single-pass transmembrane protein, Gm11437, during fasting and then binds OLFR796, an olfactory receptor, to activate intracellular calcium mobilization. This famsin-OLFR796 signaling axis promotes gluconeogenesis and ketogenesis for energy mobilization, and torpor for energy conservation during fasting. In addition, neutralization of famsin by an antibody improves blood glucose profiles in diabetic models, which identifies famsin as a potential therapeutic target for treating diabetes. Therefore, our results demonstrate that communication between the intestine and other organs by a famsin-OLFR796 signaling axis is critical for metabolic adaptations to fasting.

Intestinal gluconeogenesis: metabolic benefits make sense in the light of evolution.

The intestine, like the liver and kidney, in various vertebrates and humans is able to carry out gluconeogenesis and release glucose into the blood. In the fed post-absorptive state, intestinal glucose is sensed by the gastrointestinal nervous system. The latter initiates a signal to the brain regions controlling energy homeostasis and stress-related behaviour. Intestinal gluconeogenesis (IGN) is activated by several complementary mechanisms, in particular nutritional situations (for example, when food is enriched in protein or fermentable fibre and after gastric bypass surgery in obesity). In these situations, IGN has several metabolic and behavioural benefits. As IGN is activated by nutrients capable of fuelling systemic gluconeogenesis, IGN could be a signal to the brain that food previously ingested is suitable for maintaining plasma glucose for a while. This process might account for the benefits observed. Finally, in this Perspective, we discuss how the benefits of IGN in fasting and fed states could explain why IGN emerged and was maintained in vertebrates by natural selection.

Hepatic Sam68 Regulates Systemic Glucose Homeostasis and Insulin Sensitivity.

Hepatic glucose production (HGP) is an important component of glucose homeostasis, and deregulated HGP, particularly through gluconeogenesis, contributes to hyperglycemia and pathology of type-2 diabetes (T2D). It has been shown that the gluconeogenic gene expression is governed primarily by the transcription factor cAMP-response element (CRE)-binding protein (CREB) and its coactivator, CREB-regulated transcriptional coactivator 2 (CRTC2). Recently, we have discovered that Sam68, an adaptor protein and Src kinase substrate, potently promotes hepatic gluconeogenesis by promoting CRTC2 stability; however, the detailed mechanisms remain unclear. Here we show that in response to glucagon, Sam68 increases CREB/CRTC2 transactivity by interacting with CRTC2 in the CREB/CRTC2 complex and occupying the CRE motif of promoters, leading to gluconeogenic gene expression and glucose production. In hepatocytes, glucagon promotes Sam68 nuclear import, whereas insulin elicits its nuclear export. Furthermore, ablation of Sam68 in hepatocytes protects mice from high-fat diet (HFD)-induced hyperglycemia and significantly increased hepatic and peripheral insulin sensitivities. Thus, hepatic Sam68 potentiates CREB/CRTC2-mediated glucose production, contributes to the pathogenesis of insulin resistance, and may serve as a therapeutic target for T2D.

Digital twin predicting diet response before and after long-term fasting.

Today, there is great interest in diets proposing new combinations of macronutrient compositions and fasting schedules. Unfortunately, there is little consensus regarding the impact of these different diets, since available studies measure different sets of variables in different populations, thus only providing partial, non-connected insights. We lack an approach for integrating all such partial insights into a useful and interconnected big picture. Herein, we present such an integrating tool. The tool uses a novel mathematical model that describes mechanisms regulating diet response and fasting metabolic fluxes, both for organ-organ crosstalk, and inside the liver. The tool can mechanistically explain and integrate data from several clinical studies, and correctly predict new independent data, including data from a new study. Using this model, we can predict non-measured variables, e.g. hepatic glycogen and gluconeogenesis, in response to fasting and different diets. Furthermore, we exemplify how such metabolic responses can be successfully adapted to a specific individual's sex, weight, height, as well as to the individual's historical data on metabolite dynamics. This tool enables an offline digital twin technology.

Gluconeogenesis Alteration and p53-SIRT6-Fox01 Signaling Adaptive Regulation in Sheep from Different Grazing Periods.

The decline in sheep health and meat quality caused by seasonal nutritional deficiencies has always been an important problem in the production of naturally grazing sheep. Glucose metabolism is crucial in ruminants for adequate cell function and maintenance of the body tissues and systems. However, whether glucose metabolism, especially gluconeogenesis, is affected by seasonal grazing conditions has not been fully uncovered. Thus, twelve sheep from two seasons (dry and green grass periods) in natural grazing areas of Inner Mongolia, China, were selected for this study. Their serum glucose, insulin, PC, and PEPCK levels and volatile fatty acid (gluconeogenesis material) concentrations in rumen fluid were analyzed. The expression of key enzymes including PC, PEPCK, GLUT2, and G6P of gluconeogenesis and their regulators INSR, PI3K/AKT and p53-SIRT6-Fox01 in the liver was detected by real-time PCR and western blotting. The results revealed significant variances in gluconeogenesis and its indicators and showed p53-SIRT6-Fox01 as having potential regulation in different grazing periods. This study offers new insights into the mechanism of gluconeogenesis and adaptive regulation between dry grass period and green grass period and also provides a reference for maintaining the health of sheep and meat quality despite seasonal nutritional deficiencies.

[Intestinal gluconeogenesis: an insulin-mimetic function]. / La néoglucogenèse intestinale : une fonction insulinomimétique.

Intestinal gluconeogenesis (IGN) is a regulatory function of energy homeostasis. IGN-produced glucose is sensed by the gastrointestinal nervous system and sends a signal to regions of the brain regulating food intake and glucose control. IGN is activated by dietary protein and dietary fibre, and by gastric bypass surgery of obesity. Glutamine, propionate and succinate are the main substrates used for glucose production by IGN. Activation of IGN accounts for the well-known satiety effect of protein-enriched diets and the anti-obesity and anti-diabetes effects associated with fibre feeding and gastric bypass surgery. Genetic activation of IGN in mice shows the same beneficial effects, independently of any nutritional manipulation, including a marked prevention of hepatic steatosis under hypercaloric feeding. The activation of IGN could thus be the basis for new approaches to prevent or correct metabolic diseases in humans.

Title: La néoglucogenèse intestinale : une fonction insulinomimétique. Abstract: La néoglucogenèse intestinale (NGI) est une fonction régulatrice de l'homéostasie énergétique. Le glucose qu'elle produit est détecté par le système nerveux gastrointestinal et envoie un signal aux régions du cerveau régulant la prise alimentaire et le contrôle glycémique. L'activation de la NGI par les protéines et les fibres alimentaires et par la chirurgie de type by-pass gastrique permet d'expliquer les effets anti-obésité et anti-diabète des régimes enrichis en protéines et/ou en fibres et de la chirurgie bariatrique. L'activation génétique de la NGI chez la souris présente les mêmes effets bénéfiques, indépendamment de toute manipulation nutritionnelle. L'activation de la NGI pourrait ainsi être la base de nouvelles approches préventives ou correctives des maladies métaboliques chez l'homme.

Dietary iron modulates hepatic glucose homeostasis via regulating gluconeogenesis.

Iron exerts significant influences on glucose metabolism. However, the regulatory mechanisms underlying disordered glucose response remains largely unclear. The aim of this study was to examine the impact of dietary iron on hepatic gluconeogenesis in mice and in rat liver-derived cells. High iron models of C57BL/6J mice were fed with 1.25 g Fe/kg diets for 9 weeks, and high-iron BRL-3A cell models were treated with 250 µmol/L FeSO4 for 12 h and 24 h. Our data showed that higher iron intake resulted in higher hepatic iron without iron toxicity, and reduced body weight gain with no difference of food intakes. High dietary iron significantly increased 61% of hepatic glycogen deposition, but exhibited impairment in glucose responses in mice. Moreover, high dietary iron suppressed hepatic gluconeogenesis by repressing the expression of key gluconeogenic enzymes, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. Meanwhile, mice fed with higher iron diets exhibited both decreased AMP-activated protein kinase (AMPK) activity and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) protein levels. Furthermore, in BRL-3A cells, iron treatment increased cellular glucose uptake, and altered gluconeogenesis rhythmically by regulating the activation of AMPK and expression of PGC-1α successively. This study demonstrated that dietary high iron was able to increase hepatic glycogen deposition by enhancement of glucose uptake, and suppress hepatic gluconeogenesis by regulation of AMPK and PGC-1α.