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.

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.

Association between caregiver and household alcohol use and child behavior problems in KwaZulu Natal, South Africa.

We explored the association between household alcohol use and behavior problems among South-African children, using data from the Asenze study, a population-based cohort of South African children and their caregivers. Household alcohol use and child behavior were assessed when children were 6-8 years old. To examine the association, we performed linear regressions. The sample included 1383 children with complete data under the care of 1251 adults. Children living in a household where self-reported caregiver alcohol use was scored as hazardous (4.6%) had higher levels of problem behavior (ß = 1.94, 95% CI 0.06-3.82). There were no statistically significant associations between reported hazardous alcohol use by another member of the household (14.5%) and child problem behavior. Hazardous household alcohol use was associated with child problem behavior and this effect appeared to be mainly driven by primary caregiver use.

Trends in gender and socioeconomic inequalities in adolescent health over 16 years (2002-2018): findings from the Canadian Health Behaviour in School-aged Children study. / Évolution des inégalités en santé chez les adolescents selon le genre et le statut socioéconomique sur 16 ans (2002 à 2018) : résultats de l'Enquête sur les comportements de santé des jeunes d'âge scolaire.

INTRODUCTION: Monitoring health inequalities in adolescents informs policy approaches to reducing these inequalities early in the life course. The purpose of this study was to investigate trends in gender and socioeconomic inequalities in six health domains. METHODS: Data were from five quadrennial survey cycles of the Health Behaviour in School-aged Children (HBSC) study in Canada (pooled n = 94 887 participants). Differences in health between socioeconomic groups (based on material deprivation) and between genders were assessed using slope and relative indices of inequality in six health domains: daily physical activity, excess body weight, frequent physical symptoms, frequent psychological symptoms, low life satisfaction, and fair or poor self-rated health. RESULTS: Over a 16-year period, adolescents in Canada reported progressively worse health in four health domains, with those at the lowest socioeconomic position showing the steepest declines. Socioeconomic differences increased in excess body weight, physical symptoms, low life satisfaction, and fair or poor health. Gender differences also increased. Females showed poorer health than males in all domains except excess body weight, and gender differences increased over time in physical symptoms, psychological symptoms and low life satisfaction. CONCLUSION: Socioeconomic and gender inequalities in health are persistent and widening among adolescents in Canada. Policies that address material and social factors that contribute to health disparities in adolescence are warranted.

Shielding children from food insecurity and its association with mental health and well-being in Canadian households.

OBJECTIVE: Adults in food-insecure households will often sacrifice their own nutritional needs so that children are fed first. This shielding may protect children from malnutrition, but its links to mental health and well-being have not been closely examined. The aim of this study is to explore these links. METHODS: We used data from three cycles of the Canadian Community Health Survey (n = 28,871 youth, 74,416 adults) to identify shielded children (those who reported not being food insecure but lived in food-insecure households). Using Poisson regression, we examined youth and adult mental health and well-being (mood disorder, anxiety disorder, fair/poor mental health, fair/poor health, and low life satisfaction) in shielding households compared to food-secure households and food-insecure households where children were not shielded. RESULTS: About one in six (15.3%) households with children was food insecure. One third of these (6.3%) included children who were shielded from experiencing food insecurity. Shielded youth did not differ significantly from food-secure youth in three of the five outcomes examined. However, unshielded youth, compared to food-secure youth, showed increased risks of every health outcome we investigated. Adults in food-insecure households also reported worse mental health than food-secure adults but better mental health if children were shielded. CONCLUSION: Shielding is associated with reduced risk of common psychiatric outcomes and poor mental health in youth and adults, possibly because it is associated with milder forms of food insecurity. The inability to protect children from having inadequate access to food may compound the psychological strain of food insecurity on mental health and well-being among adults.

RéSUMé: OBJECTIF: Les adultes d'un ménage en insécurité alimentaire sacrifient souvent leurs propres besoins nutritionnels afin que les enfants soient nourris en priorité. Cette protection peut préserver les enfants de la malnutrition, mais ses liens avec la santé mentale et le bien-être n'ont pas été spécifiquement examinés. L'objectif de cette étude est d'explorer ces liens. MéTHODE: Nous avons utilisé les données de trois cycles de l'Enquête sur la santé dans les collectivités canadiennes (n = 28 871 jeunes, 74 416 adultes) dans le but d'identifier les ménages en insécurité alimentaire dans lesquels les enfants ne se trouvaient pas en insécurité alimentaire ( « protégés ¼). Afin de comparer la santé mentale et le bien-être des jeunes et adultes vivant au sein d'un ménage en insécurité alimentaire « protégé ¼ par rapport aux individus vivant au sein d'un ménage en sécurité alimentaire et d'un ménage en insécurité alimentaire où les enfants n'étaient pas protégés de cette insécurité, nous avons utilisé la régression de Poisson. RéSULTATS: Environ un ménage avec des enfants sur six (15,3 %) était en insécurité alimentaire. Un tiers de ces enfants (6,3 %) étaient protégés de l'insécurité alimentaire. Les enfants « protégés ¼ ne différaient pas significativement des enfants vivant au sein d'un ménage en sécurité alimentaire pour la plupart des résultats concernant la santé mentale. Les enfants « non protégés ¼ ont montré des risques accrus pour chaque indicateur étudié (trouble de l'humeur, trouble de l'anxiété, santé mentale moyenne/ mauvaise, santé moyenne/ mauvaise, faible satisfaction de la vie). Les adultes vivant dans un ménage en insécurité alimentaire ont également déclaré une plus mauvaise santé mentale que les adultes vivant dans un ménage en sécurité alimentaire, mais une meilleure santé mentale lorsque les enfants du ménage étaient protégés de l'insécurité alimentaire. CONCLUSION: La protection des enfants au sein d'un ménage en insécurité alimentaire est associé à une réduction du risque de problèmes psychiatriques communs et de mauvaise santé mentale chez les jeunes et les adultes, possiblement parce que les ménages dans lesquels les enfants sont protégés font face à des formes plus légères d'insécurité alimentaire. L'incapacité de protéger les enfants et l'accès inadéquat à la nourriture peut aggraver la pression psychologique de l'insécurité alimentaire sur la santé mentale et le bien-être des adultes.

Cellular and metabolic effects of renin-angiotensin system blockade on glycogen storage disease type I nephropathy.

Glycogen Storage Disease Type I (GSDI) is an inherited disease caused by glucose-6 phosphatase (G6Pase) deficiency, leading to a loss of endogenous glucose production and severe hypoglycemia. Moreover, most GSDI patients develop a chronic kidney disease (CKD) due to lipid accumulation in the kidney. Similar to diabetic CKD, activation of renin-angiotensin system (RAS) promotes renal fibrosis in GSDI. Here, we investigated the physiological and molecular effects of RAS blockers in GSDI patients and mice. A retrospective analysis of renal function was performed in 21 GSDI patients treated with RAS blockers. Cellular and metabolic impacts of RAS blockade were analyzed in K.G6pc-/- mice characterized by G6pc1 deletion in kidneys. GSDI patients started RAS blocker treatment at a median age of 21 years and long-term treatment reduced the progression of CKD in about 50% of patients. However, CKD progressed to kidney failure in 20% of treated patients, requiring renal transplantation. In K.G6pc-/- mice, CKD was associated with an impairment of autophagy and ER stress. RAS blockade resulted in a rescue of autophagy and decreased ER stress, concomitantly with decreased fibrosis and improved renal function, but without impact on glycogen and lipid contents. In conclusion, these data confirm the partial beneficial effect of RAS blockers in the prevention of CKD in GSDI. Mechanistically, we show that these effects are linked to a reduction of cell stress, without affecting metabolism.

Pain sensing neurons promote tissue regeneration in adult mice.

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.

Driving regeneration, instead of healing, in adult mammals: the decisive role of resident macrophages through efferocytosis.

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.

mRNA therapy restores euglycemia and prevents liver tumors in murine model of glycogen storage disease.

Glycogen Storage Disease 1a (GSD1a) is a rare, inherited metabolic disorder caused by deficiency of glucose 6-phosphatase (G6Pase-α). G6Pase-α is critical for maintaining interprandial euglycemia. GSD1a patients exhibit life-threatening hypoglycemia and long-term liver complications including hepatocellular adenomas (HCAs) and carcinomas (HCCs). There is no treatment for GSD1a and the current standard-of-care for managing hypoglycemia (Glycosade®/modified cornstarch) fails to prevent HCA/HCC risk. Therapeutic modalities such as enzyme replacement therapy and gene therapy are not ideal options for patients due to challenges in drug-delivery, efficacy, and safety. To develop a new treatment for GSD1a capable of addressing both the life-threatening hypoglycemia and HCA/HCC risk, we encapsulated engineered mRNAs encoding human G6Pase-α in lipid nanoparticles. We demonstrate the efficacy and safety of our approach in a preclinical murine model that phenotypically resembles the human condition, thus presenting a potential therapy that could have a significant therapeutic impact on the treatment of GSD1a.

Tamoxifen Treatment in the Neonatal Period Affects Glucose Homeostasis in Adult Mice in a Sex-Dependent Manner.

Tamoxifen is a selective estrogen receptor modulator used to activate the CREERT2 recombinase, allowing tissue-specific and temporal control of the somatic mutagenesis to generate transgenic mice. Studies integrating development and metabolism require a genetic modification induced by a neonatal tamoxifen administration. Here, we investigate the effects of a neonatal tamoxifen administration on energy homeostasis in adult male and female C57BL/6J mice. C57BL/6J male and female mouse pups received a single injection of tamoxifen 1 day after birth (NTT) and were fed a high-fat/high-sucrose diet at 6 weeks of age. We measured weight, body composition, glucose and insulin tolerance, basal metabolism, and tibia length and weight in adult mice. The neonatal tamoxifen administration exerted long-term, sex-dependent effects on energy homeostasis. NTT female mice became overweight and developed impaired glucose control in comparison to vehicle-treated littermates. NTT females exhibited 60% increased fat mass, increased food intake, decreased physical activity and energy expenditure, impaired glucose and insulin tolerance, and fasting hyperglycemia and hyperinsulinemia. In contrast, NTT male mice exhibited a modest amelioration of glucose and insulin tolerance and long-term decreased lean mass linked to decreased bone weight. These results suggest that the neonatal tamoxifen administration exerted a marked and sex-dependent influence on adult energy homeostasis and bone weight and must therefore be used with caution for the development of transgenic mouse models regarding studies on energy homeostasis and bone biology.

Food insecurity, state fragility and youth mental health: A global perspective.

Youth in fragile settings face disproportionate risks of experiencing food insecurity and poor mental health. Cross-national evidence is lacking on the association between food insecurity and mental health in youth populations, and on state fragility as a social determinant of these experiences. We analysed data from six cycles of the Gallup World Poll (2014-2019), an annual survey that contains multi-item scales of food insecurity, mental health problems and positive wellbeing. The analytic sample included 164,118 youth aged 15-24 years in 160 states. We linked individual responses to state-level data from the Fragile States Index-an aggregate measure of state vulnerability to collapse or conflict (coded: sustainable, stable, warning, or alert) and estimated adjusted relative risk (RR) of food insecurity as a function of state fragility. We then used linear regression to examine associations of state fragility and food insecurity with mental health and wellbeing. The prevalence of moderate or severe food insecurity rose from 22.93% in 2014 to 37.34% in 2019. State fragility (alert vs. sustainable) was related to an increased risk of food insecurity (RR = 2.28 [95% CI 1.30 to 4.01]), more mental health symptoms (b = 6.36 [95% CI 1.79 to 10.93]), and lower wellbeing (b = -4.49 [95% CI -8.28 to -0.70]) after controlling for state wealth and household income. Increased food insecurity (severe vs. none or mild) was uniquely related to more mental health symptoms (b = 18.44 [95% CI 17.24 to 19.64]) and reduced wellbeing (b = -9.85 [95% CI -10.88 to -8.83]) after state fragility was also controlled. Globally, youth experience better mental health where states are more robust and food access is more secure. The findings underscore the importance of strong governance and coordinated policy actions that may improve youth mental health.

Dietary Fibers and Proteins Modulate Behavior via the Activation of Intestinal Gluconeogenesis.

INTRODUCTION: Several studies have suggested that diet, especially the one enriched in microbiota-fermented fibers or fat, regulates behavior. The underlying mechanisms are currently unknown. We previously reported that certain macronutrients (fermentable fiber and protein) regulate energy homeostasis via the activation of intestinal gluconeogenesis (IGN), which generates a neural signal to the brain. We hypothesized that these nutriments might control behavior using the same gut-brain circuit. METHODS: Wild-type and IGN-deficient mice were fed chow or diets enriched in protein or fiber. Changes in their behavior were assessed using suited tests. Hippocampal neurogenesis, extracellular levels of serotonin, and protein expression levels were assessed by immunofluorescence, in vivo dialysis, and Western blotting, respectively. IGN was rescued by infusing glucose into the portal vein of IGN-deficient mice. RESULTS: We show here that both fiber- and protein-enriched diets exert beneficial actions on anxiety-like and depressive-like behaviors. These benefits do not occur in mice lacking IGN. Consistently, IGN-deficient mice display hallmarks of depressive-like disorders, including decreased hippocampal neurogenesis, basal hyperactivity, and deregulation of the hypothalamic-pituitary-adrenal axis, which are associated with increased expression of the precursor of corticotropin-releasing hormone in the hypothalamus and decreased expression of the glucocorticoid receptor in the hippocampus. These neurobiological alterations are corrected by portal glucose infusion mimicking IGN. CONCLUSION: IGN translates nutritional information, allowing the brain to finely coordinate energy metabolism and behavior.

Calcitonin Gene-Related Peptide-Induced Phosphorylation of STAT3 in Arcuate Neurons Is a Link in the Metabolic Benefits of Portal Glucose.

INTRODUCTION: Intestinal gluconeogenesis (IGN) exerts metabolic benefits in energy homeostasis via the neural sensing of portal glucose. OBJECTIVE: The aim of this work was to determine central mechanisms involved in the effects of IGN on the control of energy homeostasis. METHODS: We investigated the effects of glucose infusion into the portal vein, at a rate that mimics IGN, in conscious wild-type, leptin-deficient Ob/Ob and calcitonin gene-related peptide (CGRP)-deficient mice. RESULTS: We report that portal glucose infusion decreases food intake and plasma glucose and induces in the hypothalamic arcuate nucleus (ARC) the phosphorylation of STAT3, the classic intracellular messenger of leptin signaling. This notably takes place in POMC-expressing neurons. STAT3 phosphorylation does not require leptin, since portal glucose effects are observed in leptin-deficient Ob/Ob mice. We hypothesized that the portal glucose effects could require CGRP, a neuromediator previously suggested to suppress hunger. In line with this hypothesis, neither the metabolic benefits nor the phosphorylation of STAT3 in the ARC take place upon portal glucose infusion in CGRP-deficient mice. Moreover, intracerebroventricular injection of CGRP activates hypothalamic phosphorylation of STAT3 in mice, and CGRP does the same in hypothalamic cells. Finally, no metabolic benefit of dietary fibers (known to depend on the induction of IGN), takes place in CGRP-deficient mice. CONCLUSIONS: CGRP-induced phosphorylation of STAT3 in the ARC is part of the neural chain determining the hunger-modulating and glucose-lowering effects of IGN/portal glucose.

Relative food insecurity, mental health and wellbeing in 160 countries.

Food insecurity contributes to various stress-related health problems and previous research found that its association with mental illness is stronger in more affluent countries. We hypothesised that this pattern is a function of relative deprivation whereby the severity of individual food insecurity relative to others in a reference group determines its associations with mental health and wellbeing after differences in absolute food insecurity are controlled for. Using survey data from the Gallup World Poll collected in 160 countries and a measure of relative deprivation (Yitzhaki index), we found that relative food insecurity-based on national or regional reference groups-related to more mental health symptoms, lower positive wellbeing and lower life satisfaction after controlling for absolute food insecurity, household income, and country differences. Our analysis also found that relative food insecurity was more strongly related to mental health and wellbeing where the prevalence of food insecurity was lower. The findings underscore the negative health consequences of material deprivation and unfavourable social comparisons. Consistent with relative deprivation theory, individuals who live with constant worries about not getting enough food, have to skip meals, or face chronic hunger are deprived of material and social resources that support mental health and wellbeing, especially in settings where food insecurity is less common and potentially more stigmatised. The implications of these findings for global food policy and surveillance efforts are discussed.

The absence of hepatic glucose-6 phosphatase/ChREBP couple is incompatible with survival in mice.

OBJECTIVE: Glucose production in the blood requires the expression of glucose-6 phosphatase (G6Pase), a key enzyme that allows glucose-6 phosphate (G6P) hydrolysis into free glucose and inorganic phosphate. We previously reported that the hepatic suppression of G6Pase leads to G6P accumulation and to metabolic reprogramming in hepatocytes from liver G6Pase-deficient mice (L.G6pc-/-). Interestingly, the activity of the transcription factor carbohydrate response element-binding protein (ChREBP), central for de novo lipid synthesis, is markedly activated in L.G6pc-/- mice, which consequently rapidly develop NAFLD-like pathology. In the current work, we assessed whether a selective deletion of ChREBP could prevent hepatic lipid accumulation and NAFLD initiation in L.G6pc-/- mice. METHODS: We generated liver-specific ChREBP (L.Chrebp-/-)- and/or G6Pase (L.G6pc-/-)-deficient mice using a Cre-lox strategy in B6.SACreERT2 mice. Mice were fed a standard chow diet or a high-fat diet for 10 days. Markers of hepatic metabolism and cellular stress were analysed in the liver of control, L. G6pc-/-, L. Chrebp-/- and double knockout (i.e., L.G6pc-/-.Chrebp-/-) mice. RESULTS: We observed that there was a dramatic decrease in lipid accumulation in the liver of L.G6pc-/-.Chrebp-/- mice. At the mechanistic level, elevated G6P concentrations caused by lack of G6Pase are rerouted towards glycogen synthesis. Importantly, this exacerbated glycogen accumulation, leading to hepatic water retention and aggravated hepatomegaly. This caused animal distress and hepatocyte damage, characterised by ballooning and moderate fibrosis, paralleled with acute endoplasmic reticulum stress. CONCLUSIONS: Our study reveals the crucial role of the ChREBP-G6Pase duo in the regulation of G6P-regulated pathways in the liver.

Mutual Influences on Bullying Perpetration and Substance Use Among Adolescents in the United States.

PURPOSE: Identifying temporal pattern of associations between bullying perpetration and substance use among youth is useful for optimal targeting of intervention and prevention. We examined the mutual influences on bullying perpetration and substance use and test the cumulative effects of bullying perpetration and substance use over time. METHODS: We used data from the Population Assessment of Tobacco and Health cohort study, a nationally representative sample of youth, on bullying perpetration and substance use at three points in time over 3 years. We analyzed the associations of bullying perpetration with alcohol, cannabis and cigarette use using binary logistic regressions. The 13,068 youths aged 12-17 years at baseline (2013-2014) were included in the analytical sample. RESULTS: Cross-sectional associations between bullying perpetration and substance use were found at baseline (odds ratio [OR]alcohol = 1.62, 95% confidence interval [CI] 1.33-1.97; ORmarijuana = 1.28, 95% CI .99-1.66; ORcigarette = 1.86, 95% CI 1.44-2.39). Cumulative episodic and frequent bullying perpetration over three data waves predicted an increased likelihood of substance use at follow-up (ORs between 1.18, 95% CI 1.02-1.36 and 2.13, 95% CI 1.66-2.74). Conversely, both episodic and frequent substance use predicted an increased probability of bullying others at follow-up (ORs between 1.50, 95% CI 1.20-1.86, and 2.10, 95% CI 1.69-2.61). CONCLUSIONS: Associations between bullying perpetration and substance use appears to be bidirectional. In addition, episodic bullying perpetrators displayed intermediate levels of risk, suggesting a graded association between bullying perpetration pattern and substance use.

Intestinal gluconeogenesis prevents obesity-linked liver steatosis and non-alcoholic fatty liver disease.

OBJECTIVE: Hepatic steatosis accompanying obesity is a major health concern, since it may initiate non-alcoholic fatty liver disease (NAFLD) and associated complications like cirrhosis or cancer. Intestinal gluconeogenesis (IGN) is a recently described function that contributes to the metabolic benefits of specific macronutrients as protein or soluble fibre, via the initiation of a gut-brain nervous signal triggering brain-dependent regulations of peripheral metabolism. Here, we investigate the effects of IGN on liver metabolism, independently of its induction by the aforementioned macronutrients. DESIGN: To study the specific effects of IGN on hepatic metabolism, we used two transgenic mouse lines: one is knocked down for and the other overexpresses glucose-6-phosphatase, the key enzyme of endogenous glucose production, specifically in the intestine. RESULTS: We report that mice with a genetic overexpression of IGN are notably protected from the development of hepatic steatosis and the initiation of NAFLD on a hypercaloric diet. The protection relates to a diminution of de novo lipogenesis and lipid import, associated with benefits at the level of inflammation and fibrosis and linked to autonomous nervous system. Conversely, mice with genetic suppression of IGN spontaneously exhibit increased hepatic triglyceride storage associated with activated lipogenesis pathway, in the context of standard starch-enriched diet. The latter is corrected by portal glucose infusion mimicking IGN. CONCLUSION: We conclude that IGN per se has the capacity of preventing hepatic steatosis and its eventual evolution toward NAFLD.

Bidirectional Association Between Bullying Perpetration and Internalizing Problems Among Youth.

PURPOSE: Identification of the temporal pattern of associations between bullying perpetration and mental health problems among youth is needed for the optimal targeting of intervention and prevention. We examined the bidirectional association between bullying perpetration and internalizing problems among youth in the U.S. METHODS: We used data from the prospective cohort study of the Population Assessment of Tobacco and Health waves 1 (September 12, 2013, to December 14, 2014) and 2 (October 23, 2014, to October 30, 2015), a nationally representative sample of youth. We analyzed the associations of bullying perpetration with internalizing problems using binary and multinomial logistic regressions. The 13,200 youths aged 12-17 years were included in the analytic sample. RESULTS: There was a cross-sectional association between bullying perpetration and moderate/high lifetime internalizing problems (ORmoderate vs. no/low = 3.13, 95% CI 2.67-3.65; and ORhigh vs. no/low = 8.77, 95% CI 7.53-10.20). In the prospective analyses, bullying perpetration was associated with increased likelihood of moderate/high internalizing problems at follow-up (ORmoderate vs. no/low = 1.49, 95% CI 1.15-1.94; and ORhigh vs. no/low = 1.71, 95% CI 1.23-2.38), and youth with moderate/high internalizing problems had higher odds of bullying perpetration at follow-up (ORmoderate = 1.95, 95% CI 1.65-2.31; and ORhigh = 3.21, 95% CI 2.74-3.76). CONCLUSIONS: The association between bullying perpetration and internalizing problems appears to be bidirectional. Bullying behaviors prevention and intervention strategies among youth should consider how to take into account and handle negative feelings and mental health problems.

Does liberalisation of cannabis policy influence levels of use in adolescents and young adults? A systematic review and meta-analysis.

OBJECTIVES: To examine the effect of cannabis policy liberalisation (decriminalisation and legalisation) levels of use in adolescents and young adults. DESIGN: Systematic review and meta-analysis. INCLUSION CRITERIA: Included studies were conducted among individuals younger than 25 years and quantitatively assessing consequences of cannabis policy change. We excluded articles: (A) exclusively based on participants older than 25 years; (B) only reporting changes in perceptions of cannabis use; (C) not including at least two measures of cannabis use; (D) not including quantitative data; and (E) reviews, letters, opinions and policy papers. PubMed, PsycINFO, Embase and Web of Science were searched through 1 March 2018. DATA EXTRACTION AND SYNTHESIS: Two independent readers reviewed the eligibility of titles and abstracts and read eligible articles, and four authors assessed the risk of bias (Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies). Extracted data were meta-analysed. The protocol was registered with PROSPERO. RESULTS: 3438 records were identified via search terms and four via citation lists; 2312 were retained after removal of duplicates, 99 were assessed for eligibility and 41 were included in our systematic review. 13 articles examined cannabis decriminalisation, 20 examined legalisation for medical purposes and 8 examined legalisation for recreational purposes. Findings regarding the consequences of cannabis decriminalisation or legalisation for medical purposes were too heterogeneous to be meta-analysed. Our systematic review and meta-analysis suggest a small increase in cannabis use among adolescents and young adults following legalisation of cannabis for recreational purposes (standardised mean difference of 0.03, 95% CI -0.01 to -0.07). Nevertheless, studies characterised by a very low/low risk of bias showed no evidence of changes in cannabis use following policy modifications. CONCLUSIONS: Cannabis policy liberalisation does not appear to result in significant changes in youths' use, with the possible exception of legalisation for recreational purposes that requires monitoring. TRIAL REGISTRATION NUMBER: CRD42018083950.

Long-term occupational trajectories and suicide: a 22-year follow-up of the GAZEL cohort study.

Objective Most suicides occur among individuals of working age. Risk is elevated in some occupational groups, however relations between long-term occupational trajectories and suicide are not well known. We describe career-long occupational trajectories and examine their influence on suicide. Methods Data come from GAZEL, a French cohort study set among employees of a large national utilities company. Occupational grade was obtained from company records from the time of hiring (1953‒1988). Group-based trajectory models were used to define occupational trajectories over a mean time period of 25.0 (standard deviation 6.5) years. Causes of mortality, coded using the International Classification of Diseases, were recorded from 1993‒2014 and studied using Cox regression models. Results Of the 20 452 participants included in the study, 73 died by suicide between 1993‒2014. Results suggested an increased risk of suicide [hazard ratio (HR) 2.57, 95% confidence interval (CI) 1.08-6.15] among participants with persistently low occupational grade compared to those with higher occupational grade and career development. After adjustment for all covariates, especially psychological factors, this association was reduced and no longer statistically significant (HR 2.02, 95% CI 0.82-4.95). Conclusions Persistently low occupational grade could be related to an elevated risk of suicide. This association partly reflects psychological and health characteristics, which can influence occupational trajectories and be reinforced by unfavorable work conditions.