An inverse agonist of estrogen-related receptor γ regulates 2-arachidonoylglycerol synthesis by modulating diacylglycerol lipase expression in alcohol-intoxicated mice.

Chronic alcohol feeding increases the levels of 2-arachidonoylglycerol (2-AG) in the liver, which activates hepatic cannabinoid receptor type 1 (CB1R), leading to oxidative liver injury. 2-AG biosynthesis is catalyzed by diacylglycerol lipase (DAGL). However, the mechanisms regulating hepatic DAGL gene expression and 2-AG production are largely unknown. In this study, we show that CB1R-induced estrogen-related receptor γ (ERRγ) controls hepatic DAGL gene expression and 2-AG levels. Arachidonyl-2'-chloroethylamide (ACEA), a synthetic CB1R agonist, significantly upregulated ERRγ, DAGLα, and DAGLß, and increased 2-AG levels in the liver (10 mg/kg) and hepatocytes (10 µM) of wild-type (WT) mice. ERRγ overexpression upregulated DAGLα and DAGLß expressions and increased 2-AG levels, whereas ERRγ knockdown abolished ACEA-induced DAGLα, DAGLß, and 2-AG in vitro and in vivo. Promoter assays showed that ERRγ positively regulated DAGLα and DAGLß transcription by binding to the ERR response element in the DAGLα and DAGLß promoters. Chronic alcohol feeding (27.5% of total calories) induced hepatic steatosis and upregulated ERRγ, leading to increased DAGLα, DAGLß, or 2-AG in WT mice, whereas these alcohol-induced effects did not occur in hepatocyte-specific CB1R knockout mice or in those treated with the ERRγ inverse agonist GSK5182 (40 mg/kg in mice and 10 µM in vitro). Taken together, these results indicate that suppression of alcohol-induced DAGLα and DAGLß gene expressions and 2-AG levels by an ERRγ-specific inverse agonist may be a novel and attractive therapeutic approach for the treatment of alcoholic liver disease.

Anti-inflammatory effects of Agar free-Gelidium amansii (GA) extracts in high-fat diet-induced obese mice.

BACKGROUND/OBJECTIVES: Gelidium amansii (GA) contains plenty of agars and various biological substances, which make them a popular functional food to control body weight in previous studies. Unlike previous studies focused on agar in GA, objectives of this study were to investigate the effects of agar-free GA extract (AfGAE) on preventive and treatment models by using diets-induced obese (DIO) C57BL/6J mice. MATERIALS/METHODS: AfGAE were used to test their effects on the prevention (Exp-1) and treatment (Exp-2) against obesity after pilot study in DIO mice. The weight changes of the body and fat tissues and protein expression related to lipid metabolism and inflammation as well as plasma lipid profile and insulin were detected. RESULTS: Although AfGAE did not prevent long-term DIO, it did increase the levels of anti-inflammatory cytokine production and lipolysis protein. We further evaluated various doses of AfGAE in preventive and treatment models. As a result, our findings suggested that an AfGAE administration as a preventive model might be a better approach to achieve its anti-inflammatory and lipolysis-promoting effects in DIO mice. CONCLUSION: Although future studies to investigate the target materials such as polyphenols in AfGAE are required, the result suggests that GA without agar might be a therapeutic tool to improve health conditions related to inflammation.

Gα12 ablation exacerbates liver steatosis and obesity by suppressing USP22/SIRT1-regulated mitochondrial respiration.

Nonalcoholic fatty liver disease (NAFLD) arises from mitochondrial dysfunction under sustained imbalance between energy intake and expenditure, but the underlying mechanisms controlling mitochondrial respiration have not been entirely understood. Heterotrimeric G proteins converge with activated GPCRs to modulate cell-signaling pathways to maintain metabolic homeostasis. Here, we investigated the regulatory role of G protein α12 (Gα12) on hepatic lipid metabolism and whole-body energy expenditure in mice. Fasting increased Gα12 levels in mouse liver. Gα12 ablation markedly augmented fasting-induced hepatic fat accumulation. cDNA microarray analysis from Gna12-KO liver revealed that the Gα12-signaling pathway regulated sirtuin 1 (SIRT1) and PPARα, which are responsible for mitochondrial respiration. Defective induction of SIRT1 upon fasting was observed in the liver of Gna12-KO mice, which was reversed by lentivirus-mediated Gα12 overexpression in hepatocytes. Mechanistically, Gα12 stabilized SIRT1 protein through transcriptional induction of ubiquitin-specific peptidase 22 (USP22) via HIF-1α increase. Gα12 levels were markedly diminished in liver biopsies from NAFLD patients. Consistently, Gna12-KO mice fed a high-fat diet displayed greater susceptibility to diet-induced liver steatosis and obesity due to decrease in energy expenditure. Our results demonstrate that Gα12 regulates SIRT1-dependent mitochondrial respiration through HIF-1α-dependent USP22 induction, identifying Gα12 as an upstream molecule that contributes to the regulation of mitochondrial energy expenditure.

First Case of Canine Infection with Hepatozoon canis (Apicomplexa: Haemogregarinidae) in the Republic of Korea.

This report describes a dog infected with Hepatozoon canis, the first canine infection in the Republic of Korea. A 2-year-old intact male Maltese dog presented with anorexia and depression. Physical examinations revealed mild dehydration and hyperthermia (39.8°C), and blood analysis showed pancytopenia. Diff-Quik staining of blood smear specimens showed the presence of ellipsoidal shaped structures (gamonts of H. canis) within a small number of neutrophils. Real-time PCR analysis using whole blood confirmed infection by H. canis. The clinical condition of the dog improved after symptomatic treatment and administration of doxycycline. Although a molecular epidemiologic survey in Korea showed H. canis infection of dogs, to our knowledge this is the first report of a dog infection in Korea molecularly shown to be H. canis.

Glutamate dehydrogenase activator BCH stimulating reductive amination prevents high fat/high fructose diet-induced steatohepatitis and hyperglycemia in C57BL/6J mice.

Individuals with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) induced by high calorie western diet are characterized by enhanced lipogenesis and gluconeogenesis in the liver. Stimulation of reductive amination may shift tricarboxylic acid cycle metabolism for lipogenesis and gluconeogenesis toward glutamate synthesis with increase of NAD+/NADH ratio and thus, ameliorate high calorie diet-induced fatty liver and hyperglycemia. Stimulation of reductive amination through glutamate dehydrogenase (GDH) activator 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) reduced both de novo lipogenesis and gluconeogenesis but increased the activities of sirtuins and AMP-activated kinase in primary hepatocytes. Long-term BCH treatment improved most metabolic alterations induced by high fat/high fructose (HF/HFr) diet in C57BL/6J mice. BCH prevented HF/HFr-induced fat accumulation and activation of stress/inflammation signals such as phospho-JNK, phospho-PERK, phospho-p38, and phospho-NFκB in liver tissues. Furthermore, BCH treatment reduced the expression levels of inflammatory cytokines such as TNF-α and IL-1ß in HF/HFr-fed mouse liver. BCH also reduced liver collagen and plasma levels of alanine transaminase and aspartate transaminase. On the other hand, BCH significantly improved fasting hyperglycemia and glucose tolerance in HF/HFr-fed mice. In conclusion, stimulation of reductive amination through GDH activation can be used as a strategy to prevent high calorie western diet-induced NAFLD and T2D.

The Gender Association of the SIRT1 rs7895833 Polymorphism with Pediatric Obesity: A 3-Year Panel Study.

OBJECTIVES: Sirtuin 1 (SIRT1), a longevity-associated gene, has pleiotropic functions. We investigated whether SIRT1 variation is associated with pediatric obesity. METHODS: During 3 years of follow-up of 219 children (101 boys, 118 girls) aged 8 or 9 years at baseline, obesity parameters such as anthropometrics, plasma lipid and insulin resistance profiles, and nutrient intakes were analyzed with regard to 3 genotypes of SIRT1 rs7895833 (GG, GA, and AA). RESULTS: The prevalence of obesity including overweight had increased from 18.3% (in 2007) to 25.1% (in 2010), and the incidence of obesity over 3 years from nonobesity at the baseline was 11.7%. In the obesity group (BMI >85th percentile) that had been nonobese 3 years before, the frequency of the GA+AA genotypes was higher than that of the GG genotype. Among the total number of subjects, the values for criteria for obesity such as BMI and waist circumference were higher in the GA+AA group than in the GG group. In boys, the reductions in total cholesterol and low-density lipoprotein cholesterol levels in the GG group were considerably greater than those in the GA+AA group, even though the changes in carbohydrate, fat, and protein intake in the GG group were higher than in the GA+AA group. In girls, the reductions in fasting blood sugar and homeostatic model assessment insulin resistance (HOMA-IR) levels were greater in the GA+AA group than in the GG group, despite unchanged energy intakes over 3 years. CONCLUSIONS: We identified an association between SIRT1 variation and pediatric obesity in Korean children with a gender difference.

A potent and selective 11ß-hydroxysteroid dehydrogenase type 1 inhibitor, SKI2852, ameliorates metabolic syndrome in diabetic mice models.

11ß-Hydroxysteroid dehydrogenase type 1 (11ßHSD1) has been targeted for new drugs to treat type 2 diabetes and metabolic syndrome. In this study, we determined whether the inhibition of 11ßHSD1 with a new selective inhibitor, SKI2852, could improve lipid profiles, glucose levels, and insulin sensitivity in type 2 diabetic and obese conditions. SKI2852 showed a potent inhibition of cortisone to cortisol conversion for over 80% in both liver and adipose tissue ex vivo from orally administered C57BL/6 mice, and in vivo analysis results were consistent with this. Repeated oral administrations of SKI2852 in diet-induced obesity (DIO) and ob/ob mice revealed a partially beneficial effect of SKI2852 in improving levels of cholesterols, triglycerides, free fatty acids, postprandial glucose, and/or blood hemoglobinA1c. SKI2852 significantly reduced body weight increase in ob/ob mice, and efficiently suppressed hepatic mRNA levels of gluconeogenic enzymes in DIO mice. Moreover, SKI2852 enhanced hepatic and whole body insulin sensitivities in hyperinsulinemic-euglycemic clamp experiment in DIO mice. In conclusion, these results indicate that selective and potent inhibition of 11ßHSD1 by SKI2852, thus blockade of active glucocorticoid conversion, may improve many aspects of metabolic parameters in type 2 diabetes and metabolic diseases, mainly by inhibitions of hepatic gluconeogenesis and partial improvements of lipid profiles. Our study strongly support that SKI2852 may have a great potential as a novel candidate drug for the treatment of diabetes and metabolic diseases.

Whole blood glucose analysis based on smartphone camera module.

Complementary metal oxide semiconductor (CMOS) image sensors have received great attention for their high efficiency in biological applications. The present work describes a CMOS image sensor-based whole blood glucose monitoring system through a point-of-care (POC) approach. A simple poly-ethylene terephthalate (PET) chip was developed to carry out the enzyme kinetic reaction at various concentrations (110­586 mg∕dL) of mouse blood glucose. In this technique, assay reagent is immobilized onto amine functionalized silica (AFSiO2) nanoparticles as an electrostatic attraction in order to achieve glucose oxidation on the chip. The assay reagent immobilized AFSiO2 nanoparticles develop a semi-transparent reaction platform, which is technically a suitable chip to analyze by a camera module. The oxidized glucose then produces a green color according to the glucose concentration and is analyzed by the camera module as a photon detection technique; the photon number decreases when the glucose concentration increases. The combination of these components, the CMOS image sensor and enzyme immobilized PET film chip, constitute a compact, accurate, inexpensive, precise, digital, highly sensitive, specific, and optical glucose-sensing approach for POC diagnosis.

Insulin resistance and white adipose tissue inflammation are uncoupled in energetically challenged Fsp27-deficient mice.

Fsp27 is a lipid droplet-associated protein almost exclusively expressed in adipocytes where it facilitates unilocular lipid droplet formation. In mice, Fsp27 deficiency is associated with increased basal lipolysis, 'browning' of white fat and a healthy metabolic profile, whereas a patient with congenital CIDEC deficiency manifested an adverse lipodystrophic phenotype. Here we reconcile these data by showing that exposing Fsp27-null mice to a substantial energetic stress by crossing them with ob/ob mice or BATless mice, or feeding them a high-fat diet, results in hepatic steatosis and insulin resistance. We also observe a striking reduction in adipose inflammation and increase in adiponectin levels in all three models. This appears to reflect reduced activation of the inflammasome and less adipocyte death. These findings highlight the importance of Fsp27 in facilitating optimal energy storage in adipocytes and represent a rare example where adipose inflammation and hepatic insulin resistance are disassociated.

Anti-obesity effects of KR-66195, a synthetic DPP-IV inhibitor, in diet-induced obese mice and obese-diabetic ob/ob mice.

OBJECTIVE: We investigated whether KR-66195, a new synthetic dipeptidyl dipeptidase IV inhibitor, could prevent weight gain, as well as improving glycemic control in diet-induced obese (DIO) and ob/ob mice. MATERIALS/METHODS: Male C57BL/6 mice were randomly assigned to the following groups: chow diet, high-fat diet, and high-fat diet with KR-66195. After KR-66195 treatment for eight weeks, intraperitoneal glucose tolerance tests were performed. A pair-feeding study was performed to investigate the mechanisms of the anti-obesity effects of KR-66195 in DIO mice. Female ob/ob mice were treated with KR-66195 for three weeks and compared to the vehicle-treated group. RESULTS: In DIO mice, KR-66195 treatment increased the plasma glucagon-like peptide (GLP)-1 levels and improved glucose tolerance. This treatment also reduced body weight gain (5.38±0.94 g vs. 12.08±0.55 g, P<0.01) and food intake (2.41±0.09 g vs. 2.79±0.11 g, P<0.05). In ob/ob mice, KR-66195 treatment for three weeks resulted in comparable effects in DIO mice. In the pair-feeding study, KR-66195-treated mice exhibited a 16% increase in energy expenditure (kcal/h/kg lean body mass) without significant differences in body weight or activities compared with pair-fed mice. These results suggest that KR-66195 prevented weight gain in DIO mice by decreasing food intake, as well as increasing energy expenditure. CONCLUSIONS: KR-66195 markedly increased plasma levels of GLP-1, resulting in the probable improvement in glucose tolerance and reduced body weight and food intake. Thus, KR-66195 might be further developed as a therapeutic drug to treat obesity, as well as diabetes.

Sodium meta-arsenite ameliorates hyperglycemia in obese diabetic db/db mice by inhibition of hepatic gluconeogenesis.

Sodium meta-arsenite (SA) is implicated in the regulation of hepatic gluconeogenesis-related genes in vitro; however, the effects in vivo have not been studied. We investigated whether SA has antidiabetic effects in a type 2 diabetic mouse model. Diabetic db/db mice were orally intubated with SA (10 mg kg(-1) body weight/day) for 8 weeks. We examined hemoglobin A1c (HbA1c), blood glucose levels, food intake, and body weight. We performed glucose, insulin, and pyruvate tolerance tests and analyzed glucose production and the expression of gluconeogenesis-related genes in hepatocytes. We analyzed energy metabolism using a comprehensive animal metabolic monitoring system. SA-treated diabetic db/db mice had reduced concentrations of HbA1c and blood glucose levels. Exogenous glucose was quickly cleared in glucose tolerance tests. The mRNA expressions of genes for gluconeogenesis-related enzymes, glucose 6-phosphatase (G6Pase), and phosphoenolpyruvate carboxykinase (PEPCK) were significantly reduced in the liver of SA-treated diabetic db/db mice. In primary hepatocytes, SA treatment decreased glucose production and the expression of G6Pase, PEPCK, and hepatocyte nuclear factor 4 alpha (HNF-4α) mRNA. Small heterodimer partner (SHP) mRNA expression was increased in hepatocytes dependent upon the SA concentration. The expression of Sirt1 mRNA and protein was reduced, and acetylated forkhead box protein O1 (FoxO1) was induced by SA treatment in hepatocytes. In addition, SA-treated diabetic db/db mice showed reduced energy expenditure. Oral intubation of SA ameliorates hyperglycemia in db/db mice by reducing hepatic gluconeogenesis through the decrease of Sirt1 expression and increase in acetylated FoxO1.

Resveratrol suppresses cancer cell glucose uptake by targeting reactive oxygen species-mediated hypoxia-inducible factor-1α activation.

UNLABELLED: Resveratrol is gaining attention for its anticancer effects and is also recognized for its antioxidant properties and influence on glucose metabolism. Augmented reactive oxygen species (ROS) and high glycolytic flux are common characteristics of malignant cells. We thus evaluated the effect of resveratrol on cancer cell glucose metabolism and investigated the role of ROS in the response. METHODS: Cancer cells were measured for cell content and (18)F-FDG uptake. Assays were performed for lactate production; hexokinase activity and intracellular ROS; and immunoblotting for hypoxia-inducible factor-1α (HIF-1α), Akt, mammalian target of rapamycin, and glucose transporter type 1 (Glut-1). Animal studies were performed with small-animal PET imaging of Lewis lung carcinoma tumor-bearing mice. RESULTS: Resveratrol mildly decreased cell content and more pronouncedly suppressed (18)F-FDG uptake in Lewis lung carcinoma, HT-29 colon, and T47D breast cancer cells. Hence, (18)F-FDG uptake normalized to cell content was reduced to less than half of controls by 24-h exposure to resveratrol. This reduction was attributed to reduced glycolytic flux and Glut-1 expression. Resveratrol also decreased intracellular ROS in patterns that closely paralleled (18)F-FDG uptake. Scavenging of ROS with N-acetyl cysteine, but not inhibition of nicotinamide adenine dinucleotide phosphate oxidase, was sufficient to suppress (18)F-FDG uptake. Conversely, ROS inducers effectively reversed the metabolic response of resveratrol. HIF-1α protein was markedly reduced by resveratrol, and inhibiting HIF-1α expression with cycloheximide or specific small interfering RNAs suppressed (18)F-FDG uptake. The proteosomal inhibitor MG132 partly restored HIF-1α level and (18)F-FDG uptake in resveratrol-treated cells. Resveratrol also inhibited Akt activation; in addition, inhibitors and small interfering RNAs against phosphoinositide 3-kinase decreased (18)F-FDG uptake. Finally, small-animal PET results showed resveratrol treatment to suppress tumor (18)F-FDG uptake in vivo. CONCLUSION: Resveratrol suppresses cancer cell (18)F-FDG uptake and glycolytic metabolism in a manner that depends on the capacity of resveratrol to inhibit intracellular ROS, which downregulates HIF-1α accumulation.

Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine.

Despite growing interest and a recent surge in papers, the role of autophagy in glucose and lipid metabolism is unclear. We produced mice with skeletal muscle-specific deletion of Atg7 (encoding autophagy-related 7). Unexpectedly, these mice showed decreased fat mass and were protected from diet-induced obesity and insulin resistance; this phenotype was accompanied by increased fatty acid oxidation and browning of white adipose tissue (WAT) owing to induction of fibroblast growth factor 21 (Fgf21). Mitochondrial dysfunction induced by autophagy deficiency increased Fgf21 expression through induction of Atf4, a master regulator of the integrated stress response. Mitochondrial respiratory chain inhibitors also induced Fgf21 in an Atf4-dependent manner. We also observed induction of Fgf21, resistance to diet-induced obesity and amelioration of insulin resistance in mice with autophagy deficiency in the liver, another insulin target tissue. These findings suggest that autophagy deficiency and subsequent mitochondrial dysfunction promote Fgf21 expression, a hormone we consequently term a 'mitokine', and together these processes promote protection from diet-induced obesity and insulin resistance.

TCF7L2 modulates glucose homeostasis by regulating CREB- and FoxO1-dependent transcriptional pathway in the liver.

Peripheral insulin resistance contributes to the development of type 2 diabetes. TCF7L2 has been tightly associated with this disease, although the exact mechanism was largely elusive. Here we propose a novel role of TCF7L2 in hepatic glucose metabolism in mammals. Expression of medium and short isoforms of TCF7L2 was greatly diminished in livers of diet-induced and genetic mouse models of insulin resistance, prompting us to delineate the functional role of these isoforms in hepatic glucose metabolism. Knockdown of hepatic TCF7L2 promoted increased blood glucose levels and glucose intolerance with increased gluconeogenic gene expression in wild-type mice, in accordance with the PCR array data showing that only the gluconeogenic pathway is specifically up-regulated upon depletion of hepatic TCF7L2. Conversely, overexpression of a nuclear isoform of TCF7L2 in high-fat diet-fed mice ameliorated hyperglycemia with improved glucose tolerance, suggesting a role of this factor in hepatic glucose metabolism. Indeed, we observed a binding of TCF7L2 to promoters of gluconeogenic genes; and expression of TCF7L2 inhibited adjacent promoter occupancies of CREB, CRTC2, and FoxO1, critical transcriptional modules in hepatic gluconeogenesis, to disrupt target gene transcription. Finally, haploinsufficiency of TCF7L2 in mice displayed higher glucose levels and impaired glucose tolerance, which were rescued by hepatic expression of a nuclear isoform of TCF7L2 at the physiological level. Collectively, these data suggest a crucial role of TCF7L2 in hepatic glucose metabolism; reduced hepatic expression of nuclear isoforms of this factor might be a critical instigator of hyperglycemia in type 2 diabetes.

The association of lipoprotein lipase PvuII polymorphism and niacin intake in the prevalence of metabolic syndrome: a KMSRI-Seoul study.

Lipoprotein lipase (LPL) polymorphism correlated with LPL activity is associated with plasma lipid and lipoprotein levels. We aimed to investigate the frequency of LPL PvuII polymorphism and effects of LPL PvuII polymorphism and niacin intake on the prevalence of metabolic syndrome (MetSyn) in Koreans. Lifestyle questionnaires, anthropometry, and dietary records were completed, and LPL PvuII polymorphism, LPL mass, and lipid profiles were determined in 548 Koreans (MetSyn: 278, Non-MetSyn: 270). The MetSyn group showed a significantly lower frequency of P1P1 (wild type) and a higher frequency of P1P2 (hetero type) than the non-MetSyn group. The P2P2 (mutant type) group significantly showed lower levels of HDLc and LPL mass and a higher level of TG than the P1P1 group. As niacin intake increased, LPL mass decreased in the P2P2 group (r (2) = 0.07). In particular, the lowest niacin intake group (≤14.82 mg/day) increased more than 3 times with regard to a higher risk of MetSyn than the others in the P2P2 mutant groups. However, the MetSyn risk declined 74% at the optimal levels of niacin intake (14.83-17.80 mg/day) in the P2P2 group compared to those of the P1 allele group. The findings indicate that optimal levels of niacin intake effectively decreased Korean MetSyn prevalence in the P2P2 mutant group.

Contribution of dietary intakes of antioxidants to homocysteine-induced low density lipoprotein (LDL) oxidation in atherosclerotic patients.

PURPOSE: Elevated circulating oxidized low density lipoprotein (Ox-LDL) levels are associated with increased risk of atherosclerosis, which may be due to high plasma homocysteine (Hcy) and low intakes of antioxidants. We investigated the contribution of dietary intakes of antioxidants to Hcy-induced LDL oxidation in atherosclerotic patients (AP) and controls. MATERIALS AND METHODS: Male AP (n = 101) who were confirmed by coronary angiography and 91 controls were evaluated by blood biochemistry and dietary intakes. To determine whether homocysteine is an independent risk factor for atherosclerosis, subjects were divided into three groups; low- (or= 12.1 uM/L) Hcy. RESULTS: Plasma levels of homocysteine and LDL were higher, but plasma apo A-I in HDL and folate were lower in the AP group. The odds ratio (OR) for the risk of atherosclerosis was 3.002 [95% confidence interval (CI), 1.27-7.09] for patients in the highest tertile with homocysteine >or= 12.1 uM/L. AP having high homocysteine levels had low intakes of vitamin A, beta-carotene and vitamin C. By logistic regression analysis, age, body mass index (BMI), plasma LDL, plasma folate, and low intakes of vitamin A and beta-carotene were found to be risk factors for atherosclerosis in patients with high-Hcy, but dietary B vitamins including folate were not. CONCLUSION: A high-Hcy level was a risk factor for atherosclerosis in patients with high Ox-LDL levels. High intakes of antioxidants appeared to be a protective factor for atherosclerosis, perhaps exerting a pro-oxidative effect on LDL when combined with high levels of Hcy and LDL. However, more evidence for the benefits of B vitamins as a homocysteine-lowering therapy is needed.

Regulation of hepatic gluconeogenesis by an ER-bound transcription factor, CREBH.

Endoplasmic reticulum (ER)-bound transcription factor families are shown to be involved in the control of various metabolic pathways. Here, we report a critical function of ER-bound transcription factor, CREBH, in the regulation of hepatic gluconeogenesis. Expression of CREBH is markedly induced by fasting or in the insulin-resistant state in rodents in a dexamethasone- and PGC-1alpha-dependent manner, which results in the accumulation of active nuclear form of CREBH (CREBH-N). Overexpression of constitutively active CREBH activates transcription of PEPCK-C or G6Pase by binding to its enhancer site that is distinct from the well-characterized CREB/CRTC2 regulatory sequences in vivo. Of interest, knockdown of CREBH in liver significantly reduces blood glucose levels without altering expression of genes involved in the ER stress signaling cascades in mice. These data suggest a crucial role for CREBH in the regulation of hepatic glucose metabolism in mammals.