Loss of atrial natriuretic peptide signaling causes insulin resistance, mitochondrial dysfunction, and low endurance capacity.

Type 2 diabetes (T2D) and obesity are strongly associated with low natriuretic peptide (NP) plasma levels and a down-regulation of NP guanylyl cyclase receptor-A (GCA) in skeletal muscle and adipose tissue. However, no study has so far provided evidence for a causal link between atrial NP (ANP)/GCA deficiency and T2D pathogenesis. Here, we show that both systemic and skeletal muscle ANP/GCA deficiencies in mice promote metabolic disturbances and prediabetes. Skeletal muscle insulin resistance is further associated with altered mitochondrial function and impaired endurance running capacity. ANP/GCA-deficient mice exhibit increased proton leak and reduced content of mitochondrial oxidative phosphorylation proteins. We further show that GCA is related to several metabolic traits in T2D and positively correlates with markers of oxidative capacity in human skeletal muscle. Together, these results indicate that ANP/GCA signaling controls muscle mitochondrial integrity and oxidative capacity in vivo and plays a causal role in the development of prediabetes.

Intestinal gluconeogenesis controls the neonatal development of hypothalamic feeding circuits.

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.

Long-term trajectories of weight loss and health outcomes: protocol of the SCOOP-RNPC nationwide observational study.

INTRODUCTION: Behavioural weight loss programmes are generally accepted as being beneficial in reducing cardiometabolic risk and improving patient-reported outcomes. However, prospective data from large real-world cohorts are scarce concerning the mid-term and long-term impact of such interventions. The objective of this large prospective cohort study (n>10 000 participants) is to demonstrate the effectiveness of the standardised Nutritional and Psycho-Behavioural Rehabilitation programme (RNPC Programme) in reducing the percentage of subjects requiring insulin and/or other diabetes drug therapy, antihypertensive drugs, lipid-lowering therapies and continuous positive airway pressure therapy for obstructive sleep apnoea after the end of the intervention. The rate of remission of hypertension, type 2 diabetes and sleep apnoea will also be prospectively assessed. METHODS: This is a prospective multicentre observational study carried out in 92 RNPC centres in France. Participants will follow the standardised RNPC Programme. The prospective dataset will include clinical, anthropometric and biochemical data, comorbidities, medications, body composition, patient-reported outcome questionnaire responses, sleep study data with objective measurements of sleep apnoea severity and surrogate markers of cardiovascular risk (ie, blood pressure and arterial stiffness). About 10 000 overweight or obese participants will be included over 2 years with a follow-up duration of up to 5 years. ETHICS AND DISSEMINATION: Ethical approval for this study has been granted by the Ethics Committee (Comité de protection des personnes Sud-Est I) of Saint-Etienne University Hospital, France (SI number: 23.00174.000237). Results will be submitted for publication in peer-review journals, presented at conferences and inform the design of a future randomised controlled trial in the specific population identified as good responders to the RNPC Programme. TRIAL REGISTRATION NUMBER: NCT05857319.

Absence of the Peptide Transporter 1 Induces a Prediabetic and Depressive-Like Phenotype in Mice.

INTRODUCTION: Protein-enriched diets improve glycemic control in diabetes or emotional behavior in depressive patients. In mice, these benefits depend on intestinal gluconeogenesis activation by di-/tripeptides. Intestinal di-/tripeptides absorption is carried out by the peptide transporter 1, PEPT1. The lack of PEPT1 might thus alter glucose and emotional balance. METHODS: To determine the effects of PEPT1 deficiency under standard dietary conditions or during a dietary challenge known to promote both metabolic and cognitive dysfunction, insulin sensitivity, anxiety, and depressive-like traits, hippocampal serotonin (5-HT) and insulin signaling pathway were measured in wild-type (WT) and Pept1-/- mice fed either a chow or a high-fat high-sucrose (HF-HS) diet. RESULTS: Pept1-/- mice exhibited slight defects in insulin sensitivity and emotional behavior, which were aggravated by an HF-HS diet. Pept1-/- mice fed a chow diet had lower hippocampal 5-HT levels and exhibited cerebral insulin resistance under HF-HS diet. These defects were independent of intestinal gluconeogenesis but might be linked to increased plasma amino acids levels. CONCLUSION: Pept1-/- mice develop prediabetic and depressive-like traits and could thus be used to develop strategies to prevent or cure both diseases.

Antiobesity effects of intestinal gluconeogenesis are mediated by the brown adipose tissue sympathetic nervous system.

OBJECTIVE: Intestinal gluconeogenesis (IGN), via the initiation of a gut-brain nervous circuit, accounts for the metabolic benefits linked to dietary proteins or fermentable fiber in rodents and has been positively correlated with the rapid amelioration of body weight after gastric bypass surgery in humans with obesity. In particular, the activation of IGN moderates the development of hepatic steatosis accompanying obesity. In this study, we investigated the specific effects of IGN on adipose tissue metabolism, independent of its induction by nutritional manipulation. METHODS: We used two transgenic mouse models of suppression or overexpression of G6pc1, the catalytic subunit of glucose-6 phosphatase, which is the key enzyme of endogenous glucose production specifically in the intestine. RESULTS: Under a hypercaloric diet, mice overexpressing IGN showed lower adiposity and higher thermogenic capacities than wild-type mice, featuring marked browning of white adipose tissue (WAT) and prevention of the whitening of brown adipose tissue (BAT). Sympathetic denervation restricted to BAT caused the loss of the antiobesity effects associated with IGN. Conversely, IGN-deficient mice exhibited an increase in adiposity under a standard diet, which was associated with decreased expression of markers of thermogenesis in both BAT and WAT. CONCLUSIONS: IGN is sufficient to activate the sympathetic nervous system and prevent the expansion and the metabolic alterations of BAT and WAT metabolism under a high-calorie diet, thereby preventing the development of obesity. These data increase knowledge of the mechanisms of weight reduction in gastric bypass surgery and pave the way for new approaches to prevent or cure obesity.

Fish oil minimises feed intake and improves insulin sensitivity in Zucker fa/fa rats.

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.

Intestinal gluconeogenesis: A translator of nutritional information needed for glycemic and emotional balance.

At the interface between the outside world and the self, the intestine is the first organ receiving nutritional information. One intestinal function, gluconeogenesis, is activated by various nutrients, particularly diets enriched in fiber or protein, and thus results in glucose production in the portal vein in the post-absorptive period. The detection of portal glucose induces a nervous signal controlling the activity of the central nuclei involved in the regulation of metabolism and emotional behavior. Induction of intestinal gluconeogenesis is necessary for the beneficial effects of fiber or protein-enriched diets on metabolism and emotional behavior. Through its ability to translate nutritional information from the diet to the brain's regulatory centers, intestinal gluconeogenesis plays an essential role in maintaining physiological balance.

Improvement of energy metabolism associated with NUTRIOSE® soluble fiber, a dietary ingredient exhibiting prebiotic properties, requires intestinal gluconeogenesis.

While the prevalence of obesity progresses worldwide, the consumption of sugars and dietary fiber increases and decreases, respectively. In this context, NUTRIOSE® soluble fiber is a plant-based food ingredient with beneficial effects in Humans. Here, we studied in mice the mechanisms involved, particularly the involvement of intestinal gluconeogenesis (IGN), the essential function in the beneficial effects of dietary fibers. To determine whether NUTRIOSE® exerts its beneficial effects via the activation of IGN, we studied the effects of dietary NUTRIOSE® on the development of obesity, diabetes and non-alcoholic fatty liver disease (NAFLD), which IGN is able to prevent. To assert the role of IGN in the observed effects, we studied wild-type (WT) and IGN-deficient mice. In line with our hypothesis, NUTRIOSE® exerts metabolic benefits in WT mice, but not in IGN-deficient mice. Indeed, WT mice are protected from body weight gain and NAFLD induced by a high calorie diet. In addition, our data suggests that NUTRIOSE® may improve energy balance by activating a browning process in subcutaneous white adipose tissue. While the gut microbiota composition changes with NUTRIOSE®, this is not sufficient in itself to account for the benefits observed. On the contrary, IGN is obligatory in the NUTRIOSE® benefits, since no benefit take place in absence of IGN. In conclusion, IGN plays a crucial and essential role in the set-up of the beneficial effects of NUTRIOSE®, highlighting the interest of the supplementation of food with healthy ingredients in the context of the current obesity epidemic.

Normalization of hepatic ChREBP activity does not protect against liver disease progression in a mouse model for Glycogen Storage Disease type Ia.

BACKGROUND: Glycogen storage disease type 1a (GSD Ia) is an inborn error of metabolism caused by a defect in glucose-6-phosphatase (G6PC1) activity, which induces severe hepatomegaly and increases the risk for liver cancer. Hepatic GSD Ia is characterized by constitutive activation of Carbohydrate Response Element Binding Protein (ChREBP), a glucose-sensitive transcription factor. Previously, we showed that ChREBP activation limits non-alcoholic fatty liver disease (NAFLD) in hepatic GSD Ia. As ChREBP has been proposed as a pro-oncogenic molecular switch that supports tumour progression, we hypothesized that ChREBP normalization protects against liver disease progression in hepatic GSD Ia. METHODS: Hepatocyte-specific G6pc knockout (L-G6pc-/-) mice were treated with AAV-shChREBP to normalize hepatic ChREBP activity. RESULTS: Hepatic ChREBP normalization in GSD Ia mice induced dysplastic liver growth, massively increased hepatocyte size, and was associated with increased hepatic inflammation. Furthermore, nuclear levels of the oncoprotein Yes Associated Protein (YAP) were increased and its transcriptional targets were induced in ChREBP-normalized GSD Ia mice. Hepatic ChREBP normalization furthermore induced DNA damage and mitotic activity in GSD Ia mice, while gene signatures of chromosomal instability, the cytosolic DNA-sensing cGAS-STING pathway, senescence, and hepatocyte dedifferentiation emerged. CONCLUSIONS: In conclusion, our findings indicate that ChREBP activity limits hepatomegaly while decelerating liver disease progression and protecting against chromosomal instability in hepatic GSD Ia. These results disqualify ChREBP as a therapeutic target for treatment of liver disease in GSD Ia. In addition, they underline the importance of establishing the context-specific roles of hepatic ChREBP to define its therapeutic potential to prevent or treat advanced liver disease.

A caveolin-1 dependent glucose-6-phosphatase trafficking contributes to hepatic glucose production.

OBJECTIVE: Deregulation of hepatic glucose production is a key driver in the pathogenesis of diabetes, but its short-term regulation is incompletely deciphered. According to textbooks, glucose is produced in the endoplasmic reticulum by glucose-6-phosphatase (G6Pase) and then exported in the blood by the glucose transporter GLUT2. However, in the absence of GLUT2, glucose can be produced by a cholesterol-dependent vesicular pathway, which remains to be deciphered. Interestingly, a similar mechanism relying on vesicle trafficking controls short-term G6Pase activity. We thus investigated whether Caveolin-1 (Cav1), a master regulator of cholesterol trafficking, might be the mechanistic link between glucose production by G6Pase in the ER and glucose export through a vesicular pathway. METHODS: Glucose production from fasted mice lacking Cav1, GLUT2 or both proteins was measured in vitro in primary culture of hepatocytes and in vivo by pyruvate tolerance tests. The cellular localization of Cav1 and the catalytic unit of glucose-6-phosphatase (G6PC1) were studied by western blotting from purified membranes, immunofluorescence on primary hepatocytes and fixed liver sections and by in vivo imaging of chimeric constructs overexpressed in cell lines. G6PC1 trafficking to the plasma membrane was inhibited by a broad inhibitor of vesicular pathways or by an anchoring system retaining G6PC1 specifically to the ER membrane. RESULTS: Hepatocyte glucose production is reduced at the step catalyzed by G6Pase in the absence of Cav1. In the absence of both GLUT2 and Cav1, gluconeogenesis is nearly abolished, indicating that these pathways can be considered as the two major pathways of de novo glucose production. Mechanistically, Cav1 colocalizes but does not interact with G6PC1 and controls its localization in the Golgi complex and at the plasma membrane. The localization of G6PC1 at the plasma membrane is correlated to glucose production. Accordingly, retaining G6PC1 in the ER reduces glucose production by hepatic cells. CONCLUSIONS: Our data evidence a pathway of glucose production that relies on Cav1-dependent trafficking of G6PC1 to the plasma membrane. This reveals a new cellular regulation of G6Pase activity that contributes to hepatic glucose production and glucose homeostasis.

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.

Increased atherosclerosis in a mouse model of glycogen storage disease type 1a.

Glycogen storage disease type 1a (GSD Ia) is an inborn error of carbohydrate metabolism. Despite severe hyperlipidemia, GSD Ia patients show limited atherogenesis compared to age-and-gender matched controls. Employing a GSD Ia mouse model that resembles the severe hyperlipidemia in patients, we here found increased atherogenesis in GSD Ia. These data provide a rationale for investigating atherogenesis in GSD Ia in a larger patient cohort.

[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.

A hypometabolic defense strategy against malaria.

Hypoglycemia is a clinical hallmark of severe malaria, the often-lethal outcome of Plasmodium falciparum infection. Here, we report that malaria-associated hypoglycemia emerges from a non-canonical resistance mechanism, whereby the infected host reduces glycemia to starve Plasmodium. This hypometabolic response is elicited by labile heme, a byproduct of hemolysis that induces illness-induced anorexia and represses hepatic glucose production. While transient repression of hepatic glucose production prevents unfettered immune-mediated inflammation, organ damage, and anemia, when sustained over time it leads to hypoglycemia, compromising host energy expenditure and adaptive thermoregulation. The latter arrests the development of asexual stages of Plasmodium via a mechanism associated with parasite mitochondrial dysfunction. In response, Plasmodium activates a transcriptional program associated with the reduction of virulence and sexual differentiation toward the generation of transmissible gametocytes. In conclusion, malaria-associated hypoglycemia represents a trade-off of a hypometabolic-based defense strategy that balances parasite virulence versus transmission.

The gut microbiota: stable bioreactor of variable composition?

The gut microbiota plays a crucial role in host health, providing energy and vitamins from food undigested by the gut enzymes of the host. Bacterial metabolites, such as short-chain fatty acids (SCFAs), are essentially metabolized by the gut mucosa. The importance to metabolic health of gut microbiota composition versus function is discussed.

Portal Glucose Infusion, Afferent Nerve Fibers, and Glucose and Insulin Tolerance of Insulin-Resistant Rats.

BACKGROUND: The role of hepatoportal glucose sensors is poorly understood in the context of insulin resistance. OBJECTIVES: We assessed the effects of glucose infusion in the portal vein on insulin tolerance in 2 rat models of insulin resistance, and the role of capsaicin sensitive nerves in this signal. METHODS: Male Wistar rats, 8 weeks old, weighing 250-275 g, were used. Insulin and glucose tolerance were assessed following a 4-hour infusion of either glucose or saline through catheterization in the portal vein in 3 paradigms. In experiment 1, for diet-induced insulin resistance, rats were fed either a control diet (energy content: proteins = 22.5%, carbohydrates = 64.1%, and lipids = 13.4%) or a high-fat diet (energy content: proteins = 15.3%, carbohydrates = 40.3%, and lipids =44.4%) for 4 months. In experiment 2, for centrally induced peripheral insulin resistance, catheters were inserted in the carotid artery to deliver either an emulsion of triglycerides [intralipid (IL)] or saline towards the brain for 24 hours. In experiment 3, for testing the role of capsaicin-sensitive nerves, experiment 2 was repeated following a periportal treatment with capsaicin or vehicle. RESULTS: In experiment 1, when compared to rats fed the control diet, rats fed the high-fat diet exhibited decreased insulin and glucose tolerance (P ≤ 0.05) that was restored with a glucose infusion in the portal vein (P ≤ 0.05). In experiment 2, infusion of a triglyceride emulsion towards the brain (IL rats) decreased insulin and glucose tolerance and increased hepatic endogenous production when compared to saline-infused rats (P ≤ 0.05). Glucose infusion in the portal vein in IL rats restored insulin and glucose tolerance, as well as hepatic glucose production, to controls levels (P ≤ 0.05). In experiment 3, portal infusion of glucose did not increase insulin tolerance in IL rats that received a periportal pretreatment with capsaicin. CONCLUSIONS: Stimulation of hepatoportal glucose sensors increases insulin tolerance in rat models of insulin resistance and requires the presence of capsaicin-sensitive nerves.

Intestinal gluconeogenesis shapes gut microbiota, fecal and urine metabolome in mice with gastric bypass surgery.

Intestinal gluconeogenesis (IGN), gastric bypass (GBP) and gut microbiota positively regulate glucose homeostasis and diet-induced dysmetabolism. GBP modulates gut microbiota, whether IGN could shape it has not been investigated. We studied gut microbiota and microbiome in wild type and IGN-deficient mice, undergoing GBP or not, and fed on either a normal chow (NC) or a high-fat/high-sucrose (HFHS) diet. We also studied fecal and urine metabolome in NC-fed mice. IGN and GBP had a different effect on the gut microbiota of mice fed with NC and HFHS diet. IGN inactivation increased abundance of Deltaproteobacteria on NC and of Proteobacteria such as Helicobacter on HFHS diet. GBP increased abundance of Firmicutes and Proteobacteria on NC-fed WT mice and of Firmicutes, Bacteroidetes and Proteobacteria on HFHS-fed WT mice. The combined effect of IGN inactivation and GBP increased abundance of Actinobacteria on NC and the abundance of Enterococcaceae and Enterobacteriaceae on HFHS diet. A reduction was observed in the amounf of short-chain fatty acids in fecal (by GBP) and in both fecal and urine (by IGN inactivation) metabolome. IGN and GBP, separately or combined, shape gut microbiota and microbiome on NC- and HFHS-fed mice, and modify fecal and urine metabolome.