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Non-alcoholic fatty liver disease (NAFLD) is a heterogeneous disorder, but the factors that determine this heterogeneity remain poorly understood. Adipose tissue dysfunction is causally linked to NAFLD since it causes intrahepatic triglyceride (IHTG) accumulation through increased hepatic lipid flow, due to insulin resistance and pro-inflammatory adipokines release. While many studies in NAFLD have looked at total adiposity (i.e. mainly subcutaneous fat, SC-AT), it is still unclear the possible impact of visceral fat (VF). Thus, we investigated how VF versus SC-AT was related to NAFLD severity in lean, overweight and obese individuals versus lean controls.Thirty-two non-diabetic NAFLD with liver biopsy (BMI 21.4-34.7 kg/mIntrahepatic triglyceride was positively associated with lipolysis, adipose tissue insulin resistance (Adipo-IR), TAG concentrations, and increased saturated/unsaturated FFA ratio. Compared to controls VF was higher in NAFLD (including lean individuals), increased with fibrosis stage and associated with insulin resistance in liver, muscle and adipose tissue, increased lipolysis and decreased adiponectin levels. Collectively, our results suggest that VF accumulation, given its location close to the liver, is one of the major risk factors for NAFLD.These findings propose VF as an early indicator of NAFLD progression independently of BMI, which may allow for evidence-based prevention and intervention strategies.

Hepatocyte Nuclear Factor-1A (HNF1A) is a master regulator of key glucose-responsive genes in metabolic organs such as the intestine, liver, kidney, and pancreas. Heterozygous mutations in HNF1A cause Maturity-Onset-Diabetes-of-the-Young (HNF1A-MODY) . Mutant carriers are normoglycemic in childhood, but with age, they develop hyperglycemia. Although insulin secretory defects have been extensively studied, it is unclear whether HNF1A deficiency contributes to a progressive decline in alpha cell function. HNF1A-MODY patients display glycosuria and endogenous glucose production linked to reduced renal SGLT2 expression. Since SGLT2 is also expressed in alpha cells and is required for glucagon regulation, we hypothesized that HNF1A coordinates renal and alpha cell SGLT2 activity to maintain glucose homeostasis. Here, we studied Hnf1a regulation of renal Sglt2, Sglt1, and Glut2 in Hnf1a-/- mutant mice, glucagon expression and secretion in siHNF1A transfected human islets and we developed a novel Hnf1a mutant mouse model (Hnf1a+/Δe4-10) . Sglt2 protein was significantly reduced in the kidney of Hnf1a-/- mice, with no changes in Sglt1 or Glut2 protein expression. We observed that HNF1A is heterogeneously expressed in alpha, beta, and delta cells. siHNF1A islets displayed reduced insulin secretion and content, which was rescued by GLP1 treatment. HNF1A deficiency reduced SGLT2 levels, correlating with increased glucagon content and secretion. The Hnf1a+/Δe4-mice were born normoglycemic but became glucose intolerant at 12 weeks of age, mimicking the clinical characteristics of HNF1A-MODY patients. Collectively, these findings indicate that HNF1A deficiency downregulates renal and alpha cell SGLT2 expression, which is associated with an alteration in glucagon secretion in response to glucose stimulation. The new Hnf1a+/Δe4-mouse model may be a useful tool to study the progression of MODY with and without chronic drug treatment. Disclosure A.Acosta-montalvo: None. V.Gmyr: None. M.Cnop: None. J.A.Kerr-conte: None. F.Pattou: None. M.Pontoglio: None. A.Liston: None. C.Bonner: None. C.Saponaro: None. J.Thevenet: None. M.Chiral: None. A.Piron: None. N.Delalleau: None. G.Pasquetti: None. A.Coddeville: None. M.Moreno: None. Funding EFSD/Lilly (2017) awarded to Caroline Bonner, I-SITE ULNE awarded to Caroline Bonner, the European Genomic Institute for Diabetes (ANR-10-LABX-46) , the European Consortium for Islet Transplantation funded by the Juvenile Diabetes Research Foundation. TIGER was developed within the European Union’s Horizon 2020 research and innovation program project T2DSystems, under grant agreement 667191 (to Miriam Cnop) .

Background & AimsNonalcoholic fatty liver disease (NAFLD) is a heterogeneous disorder, but the factors that determine this heterogeneity remain poorly understood. Adipose tissue (AT) dysfunction is causally linked to NAFLD since it causes intrahepatic triglyceride (IHTG) accumulation through increased hepatic lipid flow, due to insulin resistance (IR) and pro-inflammatory adipokines release. While many studies in NAFLD have looked at total adiposity (that is mainly subcutaneous fat, SC-AT), it is still unclear the impact of visceral fat (VF). Thus, we investigated how VF vs. SC-AT were related to NAFLD in lean, overweight, and obese individuals compared to lean controls.MethodsThirty-four non-diabetic NAFLD with liver biopsy and eight lean control individuals (CT) were enrolled in this study. We measured fat distribution (VF, SC-AT and IHTG) by magnetic resonance imaging (MRI), adiponectin concentration, free fatty acids (FFAs) and triglyceride (TAG) concentration and composition by mass spectrometry (MS), lipolysis and IR by tracer infusion.ResultsIHTG was positively associated with lipolysis, adipose tissue IR, TG concentrations, and increased ratio of saturated/unsaturated fatty acids. VF was higher in NAFLD (including lean individuals) compared to controls, was increased with fibrosis stage and was associated with IR in liver, muscle and adipose tissue, increased lipolysis, and decreased adiponectin levels. Collectively, our results suggest that VF accumulation, given its location close to the liver, is one of the major risk factors for NAFLD.ConclusionsThese findings propose VF as an early indicator of NAFLD independently of BMI, which may allow for evidence-based prevention and intervention strategies.

International audience; Liraglutide, an anti-diabetic drug and agonist of the glucagon-like peptide one receptor (GLP1R), has recentlybeen approved to treat obesity in individuals with or without type 2 diabetes. Despite its extensive metabolicbenefits, the mechanism and site of action of liraglutide remain unclear. Here, we demonstrate that liraglutideis shuttled to target cells in the mouse hypothalamus by specialized ependymoglial cells called tanycytes,bypassing the blood-brain barrier. Selectively silencing GLP1R in tanycytes or inhibiting tanycytic transcytosisby botulinum neurotoxin expression not only hampers liraglutide transport into the brain and its activationof target hypothalamic neurons, but also blocks its anti-obesity effects on food intake, body weight and fatmass, and fatty acid oxidation. Collectively, these striking data indicate that the liraglutide-induced activationof hypothalamic neurons and its downstream metabolic effects are mediated by its tanycytic transport intothe mediobasal hypothalamus, strengthening the notion of tanycytes as key regulators of metabolic homeostasis.

A high prevalence of cardiovascular disease (CVD), not fully explained by the prevalence of traditional risk factors only, is reported in patients with idiopathic inflammatory myopathies (IIMs). Thus, we investigated if novel markers of CVD risk, like carotid diameter and advanced glycated end products, can better predict increased CVD risk in IIM patients.We studied 43 consecutive patients diagnosed with IIM. All the patients underwent a clinical and laboratory evaluation of cardiovascular risk factors and characterisation of myositis disease activity. Non-invasive instrumental examinations performed included the measurement of carotid parameters (intima-media thickness, IMT and mean arterial diameter, mAD) by ultrasonic techniques, advanced glycation end-product accumulation in the skin by autofluorescence (AF) and body composition by bioelectrical impedance analysis. The parameters were compared to those measured in 29 controls, with similar mean age, BMI, blood pressure and smoking habits.IIM patients showed normal carotid IMT and distensibility, but higher carotid mAD (p=0.012), higher skin AF (p0.001), lower fat free mass (p=0.036) and increased waist circumference compared to controls. A significant correlation was observed among AF and mAD (rho=0.317 p0.05), carotid distension (rho=0.391 p=0.036) and IMT (rho=0.627 p0.001).Abnormalities of the studied parameters suggest a higher risk of CV disease in IIM patients independent of disease activity. In this population, a thorough assessment of CV risk is recommended also in absence of overt CV disease during the clinical evaluation.