Both sleep-wake behavior and circadian rhythms are tightly coupled to energy metabolism and food intake. Altered feeding times in mice are known to entrain clock gene rhythms in the brain and liver, and sleep-deprived humans tend to eat more and gain weight. Previous observations in mice showing that sleep deprivation (SD) changes clock gene expression might thus relate to altered food intake, and not to the loss of sleep per se. Whether SD affects food intake in the mouse and how this might affect clock gene expression is, however, unknown. We therefore quantified (i) the cortical expression of the clock genes Per1, Per2, Dbp, and Cry1 in mice that had access to food or not during a 6 h SD, and (ii) food intake during baseline, SD, and recovery sleep. We found that food deprivation did not modify the SD-incurred clock gene changes in the cortex. Moreover, we discovered that although food intake during SD did not differ from the baseline, mice lost weight and increased food intake during subsequent recovery. We conclude that SD is associated with food deprivation and that the resulting energy deficit might contribute to the effects of SD that are commonly interpreted as a response to sleep loss.

Cyclin-dependent kinase 4 (CDK4) canonical role is to control cell cycle progression from G1 to S phases. However, recent studies reported that CDK4 regulates energy metabolism in non-proliferating cells such as hepatocytes or adipocytes. The objective of our work is to study CDK4 function in skeletal muscle using a model of mice lacking CDK4 ( cdk4 -/- ). By coupling treadmill running to indirect calorimetry, we show that cdk4 -/- mice display improved endurance and higher capacity to use fat as fuel during exercise. Isolated muscles lacking CDK4 are more resistant to fatigue in response to repeated contractions and have increased oxidative capacity and mitochondrial content compared to cdk4 +/+ muscles. Transcriptomic analysis reveals upregulation of genes controlled by the nuclear receptors estrogen-related receptors (ERRs) in cdk4 -/- skeletal muscle, associated with elevated levels of the ERR co-activator PGC1a. Supporting in vivo results, C2C12 myotubes treated with a CDK4 inhibitor have increased mitochondrial oxygen consumption, PGC1α expression and ERR transcriptional activity measured by a luciferase reporter. In normal housing conditions, cdk4 -/- mice show an increased basal metabolic rate and are resistant to weight gain and fat accumulation. In conclusion, our study uncovers a role for CDK4 in the control of skeletal muscle metabolism. Moreover, CDK4 inhibition may be an alternative strategy against obesity-associated metabolic disorders. ### Competing Interest Statement The authors have declared no competing interest.

SCOPE:Intake of fructose-sweetened beverages and chronic stress (CS) both increase risk of cardiometabolic diseases. The aim is to investigate whether these factors synergistically perturb lipid metabolism in rat liver and kidney.METHODS AND RESULTS:Fractional de novo lipogenesis (fDNL), intrahepatic- and intrarenal-triglycerides (IHTG and IRTG), de novo palmitate (DNPalm) content, FA composition, VLDL-TGs kinetics, and key metabolic gene expression at the end of the feeding and non-feeding phases in rats exposed to standard chow diet, chow diet + CS, 20% liquid high-fructose supplementation (HFr), or HFr+CS are measured. HFr induces hypertriglyceridemia, up-regulates fructose-metabolism and gluconeogenic enzymes, increases IHTG and DNPalm content in IHTG and IRTG, and augments fDNL at the end of the feeding phase. These changes are diminished after the non-feeding phase. CS does not exert such effects, but when combined with HFr, it reduces IHTG and visceral adiposity, enhances lipogenic gene expression and fDNL, and increases VLDL-DNPalm secretion.CONCLUSION:Liquid high-fructose supplementation increases IHTG and VLDL-TG secretion after the feeding phase, the latter being the result of stimulated hepatic and renal DNL. Chronic stress potentiates the effects of high fructose on fDNL and export of newly synthesized VLDL-TGs, and decreases fructose-induced intrahepatic TG accumulation after the feeding phase.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

PURPOSE:High-fructose consumption and chronic stress are both associated with metabolic inflammation and insulin resistance. Recently, disturbed activity of energy sensor AMP-activated protein kinase (AMPK) was recognized as mediator between nutrient-induced stress and inflammation. Thus, we analyzed the effects of high-fructose diet, alone or in combination with chronic stress, on glucose homeostasis, inflammation and expression of energy sensing proteins in the rat liver.METHODS:In male Wistar rats exposed to 9-week 20% fructose diet and/or 4-week chronic unpredictable stress we measured plasma and hepatic corticosterone level, indicators of glucose homeostasis and lipid metabolism, hepatic inflammation (pro- and anti-inflammatory cytokine levels, Toll-like receptor 4, NLRP3, activation of NFκB, JNK and ERK pathways) and levels of energy-sensing proteins AMPK, SIRT1 and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α).RESULTS:High-fructose diet led to glucose intolerance, activation of NFκB and JNK pathways and increased intrahepatic IL-1β, TNFα and inhibitory phosphorylation of insulin receptor substrate 1 on Ser307. It also decreased phospho-AMPK/AMPK ratio and increased SIRT1 expression. Stress alone increased plasma and hepatic corticosterone but did not influence glucose tolerance, nor hepatic inflammatory or energy-sensing proteins. After the combined treatment, hepatic corticosterone was increased, glucose tolerance remained preserved, while hepatic inflammation was partially prevented despite decreased AMPK activity.CONCLUSION:High-fructose diet resulted in glucose intolerance, hepatic inflammation, decreased AMPK activity and reduced insulin sensitivity. Chronic stress alone did not exert such effects, but when applied together with high-fructose diet it could partially prevent fructose-induced inflammation, presumably due to increased hepatic glucocorticoids.

BACKGROUND:The peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-dependent transcription factor involved in many aspects of metabolism, immune response and development. Numerous studies relying on tissue-specific invalidation of the Pparg gene have shown distinct facets of its activity, whereas the effects of its systemic inactivation remain unexplored due to embryonic lethality. By maintaining PPARγ expression in the placenta, we recently generated a mouse model carrying Pparg full body deletion (PpargΔ/Δ), which in contrast to a previously published model is totally deprived of any form of adipose tissue. Herein, we propose an in-depth study of the metabolic alterations observed in this new model.METHODS:Young adult mice, both males and females analyzed separately, were first phenotyped for their gross anatomical alterations. Systemic metabolic parameters were analyzed in the blood, in static and in dynamic conditions. A full exploration of energy metabolism was performed in calorimetric cages as well as in metabolic cages. Our study was completed by expression analyses of a set of specific genes.MAIN FINDINGS:PpargΔ/Δ mice show a striking complete absence of any form of adipose tissue, which triggers a complex metabolic phenotype including increased lean mass with organomegaly, hypermetabolism, urinary energy loss, hyperphagia, and increased amino acid metabolism. PpargΔ/Δ mice develop severe type 2 diabetes, characterized by hyperglycemia, hyperinsulinemia, polyuria and polydispsia. They show a remarkable metabolic inflexibility, as indicated by the inability to shift substrate oxidation between glucose and lipids, in both ad libitum fed state and fed/fasted/refed transitions. Moreover, upon fasting PpargΔ/Δ mice enter a severe hypometabolic state.CONCLUSIONS:Our data comprehensively describe the impact of lipoatrophy on metabolic homeostasis. As such, the presented data on PpargΔ/Δ mice gives new clues on what and how to explore severe lipodystrophy and its subsequent metabolic complications in human.

Glucose transporter 2 (Glut2)-positive cells are sparsely distributed in brain and play an important role in the stimulation of glucagon secretion in response to hypoglycemia. We aimed to determine if Glut2-positive cells can influence another response to hypoglycemia, i.e. increased cerebral blood flow (CBF). CBF of adult male mice devoid of Glut2, either globally (ripglut1:glut2-/-) or in the nervous system only (NG2KO), and their respective controls were studied under basal glycemia and insulin-induced hypoglycemia using quantitative perfusion magnetic resonance imaging at 9.4 T. The effect on CBF of optogenetic activation of hypoglycemia responsive Glut2-positive neurons of the paraventricular thalamic area was measured in mice expressing channelrhodopsin2 under the control of the Glut2 promoter. We found that in both ripglut1:glut2-/- mice and NG2KO mice, CBF in basal conditions was higher than in their respective controls and not further activated by hypoglycemia, as measured in the hippocampus, hypothalamus and whole brain. Conversely, optogenetic activation of Glut2-positive cells in the paraventricular thalamic nucleus induced a local increase in CBF similar to that induced by hypoglycemia. Thus, Glut2 expression in the nervous system is required for the control of CBF in response to changes in blood glucose concentrations.

Both fructose overconsumption and increased glucocorticoids secondary to chronic stress may contribute to overall dyslipidemia. In this study we specifically assessed the effects and interactions of dietary fructose and chronic stress on lipid metabolism in the visceral adipose tissue (VAT) of male Wistar rats. We analyzed the effects of 9-week 20% high fructose diet and 4-week chronic unpredictable stress, separately and in combination, on VAT histology, glucocorticoid prereceptor metabolism, glucocorticoid receptor subcellular redistribution and expression of major metabolic genes. Blood triglycerides and fatty acid composition were also measured to assess hepatic Δ9 desaturase activity. The results showed that fructose diet increased blood triglycerides and Δ9 desaturase activity. On the other hand, stress led to corticosterone elevation, glucocorticoid receptor activation and decrease in adipocyte size, while phosphoenolpyruvate carboxykinase, adipose tissue triglyceride lipase, FAT/CD36 and sterol regulatory element binding protein-1c (SREBP-1c) were increased, pointing to VAT lipolysis and glyceroneogenesis. The combination of stress and fructose diet was associated with marked stimulation of fatty acid synthase and acetyl-CoA carboxylase mRNA level and with increased 11β-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase protein levels, suggesting a coordinated increase in hexose monophosphate shunt and de novo lipogenesis. It however did not influence the level of peroxisome proliferator-activated receptor-gamma, SREBP-1c and carbohydrate responsive element-binding protein. In conclusion, our results showed that only combination of dietary fructose and stress increase glucocorticoid prereceptor metabolism and stimulates lipogenic enzyme expression suggesting that interaction between stress and fructose may be instrumental in promoting VAT expansion and dysfunction.

Background One characteristic feature of acute gout is the infiltration of neutrophils into the inflamed joints, where they recognise monosodium urate (MSU) crystals leading to an acute inflammatory response. The development of chronic kidney disease (CKD) is associated with increased serum uric acid (UA) levels also known as hyperuricemia, a major risk factor for gout. Despite hyperuricemia, acute gout is less frequent in CKD patients. However, the effects of hyperuricemia on leukocyte chemotaxis in CKD are not fully understood. Objectives We hypothesised that hyperuricemia affects neutrophil chemotaxis in CKD patients. Furthermore, we made use of a novel mouse model of chronic uric acid nephropathy. Methods Human study: Serum was collected and neutrophils isolated from CKD patients or healthy subjects. Serum BUN (blood urea nitrogen), creatinine and uric acid levels were measured. Neutrophil transwell assays were carried out and the number of migrated neutrophils towards fMLP, human IL-8 determined by flow cytomentry. Animal study: Six week old Alb-creERT2;Glut9lox/lox mice (ki/ki) and mice without active Cre (+/+) were injected with tamoxifen. The ki/ki mice received either a high fat diet with Inosine (HFD+Ino) to induce hyperuricemia-associated CKD or a chow diet with Inosine (Chow+Ino) to induce only hyperuricemia without CKD. Control +/+mice either received HFD+Ino or Chow+Ino diet. After two weeks, all groups were injected either with MSU crystals or vehicle into a preexisting air pouch, a mouse model for acute gouty arthritis. After 12 hours, neutrophil infiltration and the extent of inflammation were assessed via flow cytometry, ELISA, and colorimetric assays. Results Human study: Compared to healthy subjects, CKD stage 5 patients presented with significant higher levels of serum BUN (14.1 vs 52.1 mg/dl, p=0.001), creatinine (1.5 vs 9.3 mg/dl, p=0.001) and UA (2.3 vs 10.3 mg/dl, p=0.001). Neutrophils from CKD patients showed an impaired migratory ability due to the down-regulation of the adhesion molecules P-Selectin and αβIntegrin. Animal study: Two weeks post-HFD +Ino, ki/ki mice developed hyperuricemia-associated CKD (serum UA: 10–14 mg/dl; BUN: 80 mg/dl), whereas the ki/ki mice on Chow+Ino diet became hyperuricemic without CKD. Control +/+mice on both diets did neither develop hyperuricemia nor CKD. Interestingly, the number of infiltrating neutrophils into the air pouch was reduced in hyperuricemic ki/ki mice with CKD as well as in hyperuricemic ki/ki mice without CKD compared to +/+control mice. We observed less inflammation indicated by decreased IL-1β, TNFα, CXCL1 and myeloperoxidase levels, and a down-regulation of adhesion molecules on infiltrated neutrophils in hyperuricemic ki/ki mice with CKD compared to +/+control mice. Conclusions Our data show that neutrophils from CKD patients are less able to migrate, which was consistent with data from our novel mouse model demonstrating that hyperuricemia impairs neutrophil chemotaxis in MSU crystal-induced inflammation. This indicated that the mechanism for defective neutrophil migration might be responsible for the lower incidence of acute gouty arthritis in hyperuricemic CKD patients. Acknowledgements This work was supported by grants from the Deutsche Forschungsgemeinschaft and the LMUexcellent junior researcher fund. Disclosure of Interest None declared

Glucose is the most important metabolic substrate of the retina and maintenance of normoglycemia is an essential challenge for diabetic patients. Chronic, exaggerated, glycemic excursions could lead to cardiovascular diseases, nephropathy, neuropathy and retinopathy. We recently showed that hypoglycemia induced retinal cell death in mouse via caspase 3 activation and glutathione (GSH) decrease. Ex vivo experiments in 661W photoreceptor cells confirmed the low-glucose induction of death via superoxide production and activation of caspase 3, which was concomitant with a decrease of GSH content. We evaluate herein retinal gene expression 4 h and 48 h after insulin-induced hypoglycemia. Microarray analysis demonstrated clusters of genes whose expression was modified by hypoglycemia and we discuss the potential implication of those genes in retinal cell death. In addition, we identify by gene set enrichment analysis, three important pathways, including lysosomal function, GSH metabolism and apoptotic pathways. Then we tested the effect of recurrent hypoglycemia (three successive 4h periods of hypoglycemia spaced by 48 h recovery) on retinal cell death. Interestingly, exposure to multiple hypoglycemic events prevented GSH decrease and retinal cell death, or adapted the retina to external stress by restoring GSH level comparable to control situation. We hypothesize that scavenger GSH is a key compound in this apoptotic process, and maintaining “normal” GSH level, as well as a strict glycemic control, represents a therapeutic challenge in order to avoid side effects of diabetes, especially diabetic retinopathy.

MAF1 functions to promote metabolic economy by repressing RNA polymerase (pol) III transcription of highly abundant cellular RNAs, most notably tRNAs, under conditions of nutrient limitation and cellular stress. This function of MAF1, along with its phosphoregulation in response to TOR kinase activity and its interactions with the RNA pol III transcription machinery, is conserved from yeast to humans. In addition to its effect on RNA pol III, the mammalian MAF1 protein has been shown to repress several genes transcribed by RNA pol II. However, the scope of MAF1 in repressing transcription at the genome level is not well defined in mammalian systems and studies on the impact of ablating MAF1 in metazoans have only just begun. To address these questions, we generated a whole body Maf1 knockout (KO) mouse. Maf1 KO mice are unconditionally viable and demonstrate a striking resistance to diet‐induced obesity and non‐alcoholic fatty liver disease. These phenotypes result from reduced food intake and increased metabolic inefficiency. Gene expression profiling of adipose tissue indicates that the pol II transcriptome is not significantly affected and together with other experiments, show that the increased energy expenditure of Maf1 KO mice does not result from induction of adaptive thermogenesis. Instead the data indicate that the obesity resistance of Maf1 KO mice is achieved by novel mechanisms of energy expenditure. These include the increased synthesis and turnover (futile cycling) of tRNAs in the whole animal and increased futile cycling of hepatic lipids. Metabolism in Maf1 KO mice is altered to meet the increased demand for metabolic energy: Lipolysis is increased in eWAT; polyamine synthesis is affected in liver and skeletal muscle via down‐regulation of nicotinamide N‐methyltransferase and autophagy is activated in the liver. These changes are supported by metabolite profiling which reveal elevated levels of many amino acids and spermidine in both liver and muscle and increased levels of NAD+ in muscle. The importance of MAF1 for metabolic economy reveals the potential for MAF1 modulators to protect against obesity and its harmful consequences. Support or Funding Information The work was supported by National Institutes of Health grants GM085177 (I.M.W.), AG043930 (J.A.), and T32 GM07491 (A.B.); the University of Lausanne, Swiss National Science Foundation grants 31003A_132958 (N.H.) and 31003A‐140780 (J.A.) and funds from the Albert Einstein College of Medicine.

Glutathione (GSH) deficits have been observed in several mental or degenerative illness, and so has the metabolic syndrome. The impact of a decreased glucose metabolism on the GSH system is well-known, but the effect of decreased GSH levels on the energy metabolism is unclear. The aim of the present study was to investigate the sensitivity to insulin in the mouse knockout (KO) for the modulatory subunit of the glutamate cysteine ligase (GCLM), the rate-limiting enzyme of GSH synthesis. Compared to wildtype (WT) mice, GCLM-KO mice presented with reduced basal plasma glucose and insulin levels. During an insulin tolerance test, GCLM-KO mice showed a normal fall in glycemia, indicating normal insulin secretion. However, during the recovery phase, plasma glucose levels remained lower for longer in KO mice despite normal plasma glucagon levels. This is consistent with a normal counterregulatory hormonal response but impaired mobilization of glucose from endogenous stores. Following a resident-intruder stress, during which stress hormones mobilize glucose from hepatic glycogen stores, KO mice showed a lower hyperglycemic level despite higher plasma cortisol levels when compared to WT mice. The lower hepatic glycogen levels observed in GCLM-KO mice could explain the impaired glycogen mobilization following induced hypoglycemia. Altogether, our results indicate that reduced liver glycogen availability, as observed in GCLM-KO mice, could be at the origin of their lower basal and challenged glycemia. Further studies will be necessary to understand how a GSH deficit, typically observed in GCLM-KO mice, leads to a deficit in liver glycogen storage.

Urate is the metabolic end point of purines in humans. Although supra-physiological plasma urate levels are associated with obesity, insulin resistance, dyslipidemia, and hypertension, a causative role is debated. We previously established a mouse model of hyperuricemia by liver-specific deletion of Glut9, a urate transporter that provides urate to the hepatocyte enzyme uricase. These LG9 knockout mice show mild hyperuricemia (120 mu mol/l), which can be further increased by the urate precursor inosine. Here, we explored the role of progressive hyperuricemia on the cardiovascular function. Arterial blood pressure and heart rate were periodically measured by telemetry over 6 months in LG9 knockout mice supplemented with incremental amounts of inosine in a normal chow diet. This long-term inosine treatment elicited a progressive increase in uricemia up to 300 mu mol/l; however, it did not modify heart rate or mean arterial blood pressure in LG9 knockout compared with control mice. Inosine treatment did not alter cardiac morphology or function measured by ultrasound echocardiography. However, it did induce mild renal dysfunction as revealed by higher plasma creatinine levels, lower glomerular filtration rate, and histological signs of chronic inflammation and fibrosis. Thus, in LG9 knockout mice, inosine-induced hyperuricemia was not associated with hypertension despite partial renal deficiency. This does not support a direct role of urate in the control of blood pressure.

MAF1 is a global repressor of RNA polymerase III transcription that regulates the expression of highly abundant noncoding RNAs in response to nutrient availability and cellular stress. Thus, MAF1 function is thought to be important for metabolic economy. Here we show that a whole-body knockout of Maf1 in mice confers resistance to diet-induced obesity and nonalcoholic fatty liver disease by reducing food intake and increasing metabolic inefficiency. Energy expenditure in Maf1(-/-) mice is increased by several mechanisms. Precursor tRNA synthesis was increased in multiple tissues without significant effects on mature tRNA levels, implying increased turnover in a futile tRNA cycle. Elevated futile cycling of hepatic lipids was also observed. Metabolite profiling of the liver and skeletal muscle revealed elevated levels of many amino acids and spermidine, which links the induction of autophagy in Maf1(-/-) mice with their extended life span. The increase in spermidine was accompanied by reduced levels of nicotinamide N-methyltransferase, which promotes polyamine synthesis, enables nicotinamide salvage to regenerate NAD(+), and is associated with obesity resistance. Consistent with this, NAD(+) levels were increased in muscle. The importance of MAF1 for metabolic economy reveals the potential for MAF1 modulators to protect against obesity and its harmful consequences.

Le transporteur aux monocarboxylates MCT1 permet le passage transmembranaire du lactate et des corps cétoniques dans un grand nombre de tissus. Son rôle dans l’homéostasie énergétique de l’organisme est inconnu. L’invalidation du gène codant pour MCT1 a été obtenue par recombinaison homologue permettant de générer une souris transgénique. Une série d’investigations biochimiques, histologiques, métaboliques, comportementales et moléculaires ont été effectuées pour caractériser son phénotype sous diète standard ou riche en graisses. Bien que l’homozygote soit létale à un stade embryonnaire, l’hétérozygote est viable et se développe normalement. Peu de différences sont visibles entre les souris sauvages et les souris MCT1 +/– nourries avec une diète standard. Après avoir soumis les animaux à une diète riche en graisses, les souris MCT1 +/– ont démontré une résistance au développement de l’obésité induite par la diète, moins de résistance à l’insuline et l’absence de stéatose hépatique comparativement aux souris sauvages. Une analyse de la composition corporelle montre que la réduction de prise de poids chez les souris MCT1 +/– est due à une diminution de la masse grasse au niveau du foie et du tissu adipeux. Ce phénotype est associé à une réduction de la prise alimentaire, à une diminution de l’absorption intestinale ainsi qu’à une augmentation du métabolisme basal sans modification du niveau d’activité physique. Une analyse sanguine a mon-tré que les niveaux d’insuline et de leptine qui sont élevés chez les souris sauvages obèses sont normaux chez les souris MCT1 +/– Au niveau du foie, l’expression des gènes impliqués dans le métabolisme des lipides qui est aug-mentée chez les souris sauvages sous diète riche en graisses ne l’est pas chez les souris MCT1 +/–. Ces résultats montrent le rôle clé joué par MCT1 dans la régulation de l’homéostasie énergétique lorsque les animaux sont exposés à une diète obé-sogène. Les auteurs déclarent ne pas avoir d’intérêt direct ou indirect (financier ou en nature) avec un organisme privé, industriel ou commercial en relation avec le sujet présenté.

MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression post-transcriptionally. MiRNAs are implicated in various biological processes associated with obesity, including adipocyte differentiation and lipid metabolism. We used a neuronal-specific inhibition of miRNA maturation in adult mice to study the consequences of miRNA loss on obesity development. Camk2a-CreERT2 (Cre+) and floxed Dicer (Dicerlox/lox) mice were crossed to generate tamoxifen-inducible conditional Dicer knockouts (cKO). Vehicle- and/or tamoxifen-injected Cre+;Dicerlox/lox and Cre+;Dicer+/+ served as controls. Four cohorts were used to a) measure body composition, b) follow food intake and body weight dynamics, c) evaluate basal metabolism and effects of food deprivation, and d) assess the brain transcriptome consequences of miRNA loss. cKO mice developed severe obesity and gained 18 g extra weight over the 5 weeks following tamoxifen injection, mainly due to increased fat mass. This phenotype was highly reproducible and observed in all 38 cKO mice recorded and in none of the controls, excluding possible effects of tamoxifen or the non-induced transgene. Development of obesity was concomitant with hyperphagia, increased food efficiency, and decreased activity. Surprisingly, after reaching maximum body weight, obese cKO mice spontaneously started losing weight as rapidly as it was gained. Weight loss was accompanied by lowered O2-consumption and respiratory-exchange ratio. Brain transcriptome analyses in obese mice identified several obesity-related pathways (e.g. leptin, somatostatin, and nemo-like kinase signaling), as well as genes involved in feeding and appetite (e.g. Pmch, Neurotensin) and in metabolism (e.g. Bmp4, Bmp7, Ptger1, Cox7a1). A gene cluster with anti-correlated expression in the cerebral cortex of post-obese compared to obese mice was enriched for synaptic plasticity pathways. While other studies have identified a role for miRNAs in obesity, we here present a unique model that allows for the study of processes involved in reversing obesity. Moreover, our study identified the cortex as a brain area important for body weight homeostasis.

INTRODUCTION: The liver plays an important role in storing energetic fuels from food intake in the form of glycogen or lipids. The liver is also able to produce and release glucose to the blood stream to be used for oxidation in other organs during fasting. The H MR spectrum of the mouse liver is dominated by resonances from intra-hepatic lipids. However, under certain conditions, the contribution from other metabolites may become significant. Glucose transport across the liver is facilitated by the glucose transporter 2 (GLUT2). Ablation of GLUT2 in mice results in the lack of net hepatic glycogen breakdown with fasting and is accompanied by persistent high levels of glycogen and glucose-6-phosphate that are nonetheless comparable to those observed in fed control mice [1]. We have performed H MRS measurements to assess the hepatic profile of GLUT2 mice and non-invasively investigate possible alterations in intra-hepatic metabolite levels in that model. By working at a high field strength (14.1T) we could compensate for the low sensitivity inherent to the small size of the subjects.

Liver glucose metabolism plays a central role in glucose homeostasis and may also regulate feeding and energy expenditure. Here we assessed the impact of glucose transporter 2 (Glut2) gene inactivation in adult mouse liver (LG2KO mice). Loss of Glut2 suppressed hepatic glucose uptake but not glucose output. In the fasted state, expression of carbohydrate-responsive element-binding protein (ChREBP) and its glycolytic and lipogenic target genes was abnormally elevated. Feeding, energy expenditure, and insulin sensitivity were identical in LG2KO and control mice. Glucose tolerance was initially normal after Glut2 inactivation, but LG2KO mice exhibited progressive impairment of glucose-stimulated insulin secretion even though β cell mass and insulin content remained normal. Liver transcript profiling revealed a coordinated downregulation of cholesterol biosynthesis genes in LG2KO mice that was associated with reduced hepatic cholesterol in fasted mice and reduced bile acids (BAs) in feces, with a similar trend in plasma. We showed that chronic BAs or farnesoid X receptor (FXR) agonist treatment of primary islets increases glucose-stimulated insulin secretion, an effect not seen in islets from Fxr(-/-) mice. Collectively, our data show that glucose sensing by the liver controls β cell glucose competence and suggest BAs as a potential mechanistic link.