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Objective: Intestinal gluconeogenesis (IGN) regulates adult energy homeostasis in part by controlling the same hypothalamic targets as leptin. In neonates, leptin exhibits a neonatal surge controlling axonal outgrowth between the different hypothalamic nuclei involved in feeding circuits and autonomic innervation of peripheral tissues involved in energy and glucose homeostasis. Interestingly, IGN is induced during this specific time-window. We hypothesized that the neonatal pic of IGN also regulates the development of hypothalamic feeding circuits and sympathetic innervation of adipose tissues. Methods: We genetically induced neonatal IGN by overexpressing G6pc1 the catalytic subunit of glucose-6-phosphatase (the mandatory enzyme of IGN) at birth or at twelve days after birth. The neonatal development of hypothalamic feeding circuits was studied by measuring Agouti-related protein (AgRP) and Pro-opiomelanocortin (POMC) fiber density in hypothalamic nuclei of 20-day-old pups. The effect of the neonatal induction of intestinal G6pc1 on sympathetic innervation of the adipose tissues was studied via tyrosine hydroxylase (TH) quantification. The metabolic consequences of the neonatal induction of intestinal G6pc1 were studied in adult mice challenged with a high-fat/high-sucrose (HFHS) diet for 2 months. Results: Induction of intestinal G6pc1 at birth caused a neonatal reorganization of AgRP and POMC fiber density in the paraventricular nucleus of the hypothalamus, increased brown adipose tissue tyrosine hydroxylase levels, and protected against high-fat feeding-induced metabolic disorders. In contrast, inducing intestinal G6pc1 12 days after birth did not impact AgRP/POMC fiber densities, adipose tissue innervation or adult metabolism. Conclusion: These findings reveal that IGN at birth but not later during postnatal life controls the development of hypothalamic feeding circuits and sympathetic innervation of adipose tissues, promoting a better management of metabolism in adulthood.

Abstract Tissue repair after injury in adult mammals, usually results in scarring and loss of function in contrast to lower vertebrates such as the newt and zebrafish that regenerate. Understanding the regulatory processes that guide the outcome of tissue repair is therefore a concerning challenge for regenerative medicine. In multiple regenerative animal species, the nerve dependence of regeneration is well established, but the nature of the innervation required for tissue regeneration remains largely undefined. Using our model of induced adipose tissue regeneration in adult mice, we demonstrate here that nociceptive nerves promote regeneration and their removal impairs tissue regeneration. We also show that blocking the receptor for the nociceptive neuropeptide calcitonin gene-related peptide (CGRP) inhibits regeneration, whereas CGRP administration induces regeneration. These findings reveal that peptidergic nociceptive neurons are required for adult mice tissue regeneration.

Abstract Tissue repair after lesion usually leads to scar healing and thus loss of function in adult mammals. In contrast, other adult vertebrates such as amphibians have the ability to regenerate and restore tissue homeostasis after lesion. Understanding the control of the repair outcome is thus a concerning challenge for regenerative medicine. We recently developed a model of induced tissue regeneration in adult mice allowing the comparison of the early steps of regenerative and scar healing processes. By using studies of gain and loss of function, specific cell depletion approaches, and hematopoietic chimeras we demonstrate here that tissue regeneration in adult mammals depends on an early and transient peak of granulocyte producing reactive oxygen species and an efficient efferocytosis specifically by tissue-resident macrophages. These findings highlight key and early cellular pathways able to drive tissue repair towards regeneration in adult mammals.

Glycogen Storage Disease 1a (Gsd1a) is an inherited disorder caused by glucose 6-phosphatase (G6Pase-α) deficiency and characterized by hypoglycaemia and high risk of liver cancer. Here the authors develop a mRNA-based G6Pase-α delivery therapy that is efficacious and safe in a mouse model of GSD1a.

Objective: The respective contributions to endogenous glucose production (EGP) of the liver, kidney and intestine vary during fasting. We previously reported that the deficiency in either hepatic or intestinal gluconeogenesis modulates the repartition of EGP via glucagon secretion (humoral factor) and gut–brain–liver axis (neural factor), respectively. Considering renal gluconeogenesis reportedly accounted for approximately 50% of EGP during fasting, we examined whether a reduction in renal gluconeogenesis could promote alterations in the repartition of EGP in this situation. Methods: We studied mice whose glucose-6-phosphatase (G6Pase) catalytic subunit (G6PC) is specifically knocked down in the kidneys (K-G6pc-/- mice) during fasting. We also examined the additional effects of intestinal G6pc deletion, renal denervation and vitamin D administration on the altered glucose metabolism in K-G6pc-/- mice. Results: Compared with WT mice, K-G6pc-/- mice exhibited (1) lower glycemia, (2) enhanced intestinal but not hepatic G6Pase activity, (3) enhanced hepatic glucokinase (GK encoded by Gck) activity, (4) increased hepatic glucose-6-phosphate and (5) hepatic glycogen spared from exhaustion during fasting. Increased hepatic Gck expression in the post-absorptive state could be dependent on the enhancement of insulin signal (AKT phosphorylation) in K-G6pc-/- mice. In contrast, the increase in hepatic GK activity was not observed in mice with both kidney- and intestine-knockout (KI-G6pc-/- mice). Hepatic Gck gene expression and hepatic AKT phosphorylation were reduced in KI-G6pc-/- mice. Renal denervation by capsaicin did not induce any effect on glucose metabolism in K-G6pc-/- mice. Plasma level of 1,25 (OH)2 D3, an active form of vitamin D, was decreased in K-G6pc-/- mice. Interestingly, the administration of 1,25 (OH)2 D3 prevented the enhancement of intestinal gluconeogenesis and hepatic GK activity and blocked the accumulation of hepatic glycogen otherwise observed in K-G6pc-/- mice during fasting. Conclusions: A diminution in renal gluconeogenesis that is accompanied by a decrease in blood vitamin D promotes a novel repartition of EGP among glucose producing organs during fasting, featured by increased intestinal gluconeogenesis that leads to sparing glycogen stores in the liver. Our data suggest a possible involvement of a crosstalk between the kidneys and intestine (via the vitamin D system) and the intestine and liver (via a neural gut-brain axis), which might take place in the situations of deficient renal glucose production, such as chronic kidney disease. Keywords: Endogenous glucose production, Gluconeogenesis, Hypoglycemia, Glycogen, Chronic kidney disease, Vitamin D

Objective: Ectopic lipid accumulation in the liver and kidneys is a hallmark of metabolic diseases leading to non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD). Moreover, recent data have highlighted a strong correlation between NAFLD and CKD incidences. In this study, we use two mouse models of hepatic steatosis or CKD, each initiated independently of the other upon the suppression of glucose production specifically in the liver or kidneys, to elucidate the mechanisms underlying the development of CKD in the context of NAFLD-like pathology. Methods: Mice with a deletion of G6pc, encoding glucose-6 phosphatase catalytic subunit, specifically in the liver (L.G6pc−/− mice) or the kidneys (K.G6pc−/− mice), were fed with either a standard diet or a high fat/high sucrose (HF/HS) diet during 9 months. These mice represent two original models of a rare metabolic disease named Glycogen Storage Disease Type Ia (GSDIa) that is characterized by both NAFLD-like pathology and CKD. Two other groups of L.G6pc−/− and K.G6pc−/− mice were fed a standard diet for 6 months and then treated with fenofibrate for 3 months. Lipid and glucose metabolisms were characterized, and NAFLD-like and CKD damages were evaluated. Results: Lipid depot exacerbation upon high-calorie diet strongly accelerated hepatic and renal pathologies induced by the G6pc-deficiency. In L.G6pc−/− mice, HF/HS diet increased liver injuries, characterized by higher levels of plasmatic transaminases and increased hepatic tumor incidence. In K.G6pc−/− mice, HF/HS diet increased urinary albumin and lipocalin 2 excretion and aggravated renal fibrosis. In both cases, the worsening of NAFLD-like injuries and CKD was independent of glycogen content. Furthermore, fenofibrate, via the activation of lipid oxidation significantly decreased the hepatic or renal lipid accumulations and prevented liver or kidney damages in L.G6pc−/− and K.G6pc−/− mice, respectively. Finally, we show that L.G6pc−/− mice and K.G6pc−/− mice developed NAFLD-like pathology and CKD independently. Conclusions: This study highlights the crucial role that lipids play in the independent development of both NAFLD and CKD and demonstrates the importance of lipid-lowering treatments in various metabolic diseases featured by lipid load, from the “rare” GSDIa to the “epidemic” morbid obesity or type 2 diabetes. Keywords: Metabolic diseases, Lipids, Glycogen, Fenofibrate