Dysregulation Of Glucose Metabolism Research Articles

Albumin Deficiency Reduces Hepatic Steatosis and Improves Glucose Metabolism in a Mouse Model of Diet-Induced Obesity.

Serum albumin facilitates the transport of free fatty acids (FFAs) from adipose tissue to other organs. It was not known if impeding this process could protect from hepatic steatosis and metabolic dysfunction in obesity. We tested whether albumin knockout (Alb-/-) mice would exhibit a reduction in plasma FFA concentration, reduced hepatic lipid accumulation, and improved glucoregulation as compared to wild-type (WT) mice. Male homozygous albumin knockout mice (Alb-/-) and WT controls were fed a low-fat diet (LFD) or high-fat diet (HFD). Alb-/- mice exhibited a similar body weight gain and body composition as WT on both diets. Despite HFD-induced obesity, Alb-/- mice were protected from various comorbidities. Compared to WT mice on the HFD, Alb-/- exhibited lower plasma FFA levels, lower blood glucose levels during glucose tolerance and insulin tolerance tests, and lower hepatic steatosis and inflammation. Alb-/- mice on HFD also exhibited elevated expression of multiple genes in the liver and adipose tissues, such as peroxisome proliferator-activated receptor α in both tissues, as well as glucose transporter-4 and adiponectin in adipose tissues. The results indicate that albumin's FFA transport function may be involved in the development of hepatic lipid accumulation and dysregulated glucose metabolism in obesity.

Cholinergic drugs reduce metabolic inflammation and diabetic myocardial injury by regulating the gut bacterial component lipopolysaccharide-induced ERK/Egr-1 pathway.

Autonomic imbalance and metabolic inflammation are important pathological processes in diabetic cardiomyopathy. Gut microbiota dysbiosis and increased levels of bacterial component lipopolysaccharide (LPS) are associated with diabetic myocardial injury, but the mechanism by which gut microbes affect metabolic inflammation and cardiac injury remains unclear. We determined whether pyridostigmine (PYR), which inhibits cholinesterase to improve vagal activity, could regulate the disordered gut microbiota and attenuate gut barrier dysfunction, metabolic endotoxemia, and inflammation in diabetes. Db/db mice exhibited high blood glucose levels, insulin resistance, low vagal activity, and diabetic myocardial injury. Db/db mice also exhibited gut microbiota perturbations and subsequent disruption of gut barrier function, resulting in an influx of LPS, metabolic endotoxemia, and inflammation. PYR ameliorated the dysregulated glucose and lipid metabolism, modulated the overall structure of the gut microbiota, selectively enhanced the abundance of anti-inflammatory bacteria, and reduced the abundance of proinflammatory and potentially pathogenic bacteria in db/db mice. Importantly, PYR enhanced vagal activity, restored gut microbiota homeostasis, and alleviated gut barrier dysfunction. Therefore, the LPS-induced extracellular signal-regulated kinase (ERK)/early growth response-1 (Egr-1) pathway and consequent metabolic inflammation were inhibited, and eventually, cardiac hypertrophy, fibrosis, oxidative stress, and dysfunction were ameliorated in db/db mice. In vitro cardiomyocyte injury was induced by exposing primary neonatal rat ventricular cardiomyocytes to high glucose (HG) and LPS. In vitro analyses showed that HG + LPS induced ERK1/2 phosphorylation, Egr-1 expression, inflammation, and cell apoptosis, which were inhibited by acetylcholine (ACh). Alpha 7 nicotinic ACh receptor but not muscarinic 2 ACh receptor plays an important role in ACh-mediated anti-inflammatory effects and inhibiting the ERK/Egr-1 pathway in HG + LPS-administered neonatal rat ventricular cardiomyocytes. PYR and ACh ameliorated diabetic myocardial injury by inhibiting the LPS-induced ERK/Egr-1 pathway and metabolic inflammation. The vagus-gut-heart axis has provided new insights into the complex mechanisms of diabetes and offers novel therapeutic targets.

Modulation of Dietary Fatty Acids in an Open-Label Study Improves Psoriasis and Dampens the Inflammatory Activation Status

Obesity and high abdominal fat mass are risk factors for developing the chronic inflammatory skin disease psoriasis. They are associated with increased incidence, prevalence and severity of the disease. A positive effect of weight loss on psoriasis activity has been shown in several studies. Obesity-related factors such as the dysregulation of glucose and lipid metabolism, the activation of adipose tissue and resultant persistent low-grade inflammation have been discussed as links of obesity and inflammatory diseases. Recently, we demonstrated a critical role of free fatty acids (FFAs) in obesity-mediated exacerbation of psoriatic skin inflammation in both mice and humans. In the present study, we translated these findings into a therapeutic intervention. An open-label study focusing on the dietary reduction of FFAs was conducted in patients with mild-to-moderate plaque psoriasis, and disease severity and serum markers of inflammation were analyzed. Here, we show that such a dietary intervention improves psoriatic disease activity independently of weight loss. Diet-related metabolic changes, such as a reduction in saturated free fatty acids (SFAs), may thus be more important than weight loss itself. Moreover, dietary intervention inhibited the overall pro-inflammatory activation status in patients, as shown by analysis of serum inflammatory parameters using the Olink platform. From our pilot study, we conclude that dietary intervention focusing on SFA reduction has the capacity to reduce disease activity and general inflammatory status in psoriasis patients.

Can DPP-4 Enhibitors and SGLT-2 Inhibitors Pleotropic Effects be Extended to Treat Diabetic Nephropathy?

Impaired insulin secretion and resistance remain the core defects in T2DM, but at least six other pathophysiological abnormalities contribute to the dysregulation of glucose metabolism. Diabetic nephropathy is one of the most common microvascular complications and a major cause of end-stage renal disease. Despite many treatment options available, diabetic kidney disease continues to affect a large population with diabetes. The kidneys have the highest DPP-4 expression level in mammalians. DPP- 4 is expressed in several segments of the nephron and the tubule interstitium, placing it at the nexus of inflammation, immune system activation, glomerular and proximal tubular function, salt regulation, and kidney fibrosis. Moreover, DPP-4 expression and urinary activity are up-regulated in diabetic nephropathy, highlighting its role as a potential target to manage diabetic nephropathy. DPP-4 inhibition is associated with mitigation of diabetic and hypertensive renal injury and protection of renal function. Renal glucose reabsorption by SGLT proteins is a critical component of glycemic regulation. SGLT2 protein expression is increased in human diabetic nephropathy even with advanced kidney disease indicating that SGLT2 can be an effective target in treatment of diabetic nephropathy. This review article discusses roles played by DPP-4 inhibitors and SGLT-2 inhibitors alone and in combination in diabetic nephropathy supported by clinical evidences. MEDLINE and EMBASE were searched through September 2022. Randomized controlled trials published in English that evaluated SGLT2 inhibitors and/or DPP4 inhibitors in patients with T2DM were selected. J MEDICINE 2023; 24: 43-49

Differential disruption on glucose and insulin metabolism in two rat models of diet-induced obesity, based on carbohydrates or lipids.

Obesity is a relevant health public issue and is the main factor for glucose metabolism dysregulation and diabetes progression; however, the differential role of a high-fat diet or high sugar diet consumption on glucose metabolism and insulin processing is not well understood and has been scarcely described. Our research aimed to analyze the effects of chronic consumption of both high sucrose and high-fat diets on glucose and insulin metabolism regulation. Wistar rats were fed with high-sugar or high-fat diets for 12months; after that, fasting glucose and insulin levels were measured along with a glucose tolerance test (GTT). Proteins related to insulin synthesis and secretion were quantified in pancreas homogenates, whereas islets were isolated to analyze ROS generation and size measurement. Our results show that both diets induce metabolic syndrome, linked with central obesity, hyperglycemia, and insulin resistance. We observed alterations in the expression of proteins related with insulin synthesis and secretion, along with diminution of Langerhans islets size. Interestingly, the severity and number of alterations were more evident in the high-sugar diet than in the high-fat diet group. In conclusion, obesity and glucose metabolism dysregulation induced by carbohydrate consumption, led to worst outcomes than high-fat diet.

Sex-specific effects of high-fat diet on rat brain glucose metabolism and early-onset dementia symptoms

Peripheral metabolic disturbances are associated with a variety of clinical health consequences and may contribute to the development of neurocognitive disorders. This study investigates whether long-term high-fat diet (HFD) consumption changes the brain glucose metabolism and impairs memory performance in a sex-dependent manner. Male and female rats, after weaning, were fed HFD or normal chow diet (NCD) for 16 weeks. Behavioral tests for spatial memory and an 18 F-FDG-PET scan were performed. Also, the expression of brain insulin resistance markers and Alzheimer’s pathology-related genes was assessed by qPCR. The Morris water maze and Y-maze results showed, respectively, that memory retrieval and spatial working memory were impaired only in HFD male rats compared to NCD controls. In addition, measuring whole brain 18 F-FDG uptake indicated a significant reduction in glucose metabolism in male but not female HFD rats. Analysis of 15 genes related to glucose metabolism and Alzheimer's pathology, in the hippocampus, showed that expression of GLUT3, IRS2, and IDE is significantly reduced in HFD male rats. Our results suggest that sex affects the HFD-induced dysregulation of brain glucose metabolism and cognitive performance.

Multi-Omics Reveal Interplay between Circadian Dysfunction and Type2 Diabetes.

Type 2 diabetes is one of the leading threats to human health in the 21st century. It is a metabolic disorder characterized by a dysregulated glucose metabolism resulting from impaired insulin secretion or insulin resistance. More recently, accumulated epidemiological and animal model studies have confirmed that circadian dysfunction caused by shift work, late meal timing, and sleep loss leads to type 2 diabetes. Circadian rhythms, 24-h endogenous biological oscillations, are a fundamental feature of nearly all organisms and control many physiological and cellular functions. In mammals, light synchronizes brain clocks and feeding is a main stimulus that synchronizes the peripheral clocks in metabolic tissues, such as liver, pancreas, muscles, and adipose tissues. Circadian arrhythmia causes the loss of synchrony of the clocks of these metabolic tissues and leads to an impaired pancreas β-cell metabolism coupled with altered insulin secretion. In addition to these, gut microbes and circadian rhythms are intertwined via metabolic regulation. Omics approaches play a significant role in unraveling how a disrupted circadian metabolism causes type 2 diabetes. In the present review, we emphasize the discoveries of several genes, proteins, and metabolites that contribute to the emergence of type 2 diabetes mellitus (T2D). The implications of these discoveries for comprehending the circadian clock network in T2D may lead to new therapeutic solutions.

Glycolysis and de novo fatty acid synthesis cooperatively regulate pathological vascular smooth muscle cell phenotypic switching and neointimal hyperplasia.

Switching of vascular smooth muscle cells (VSMCs) from a contractile phenotype to a dedifferentiated (proliferative) phenotype contributes to neointima formation, which has been demonstrated to possess a tumor-like nature. Dysregulated glucose and lipid metabolism is recognized as a hallmark of tumors but has not thoroughly been elucidated in neointima formation. Here, we investigated the cooperative role of glycolysis and fatty acid synthesis in vascular injury-induced VSMC dedifferentiation and neointima formation. We found that the expression of hypoxia-inducible factor-1α (HIF-1α) and its target 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3), a critical glycolytic enzyme, were induced in the neointimal VSMCs of human stenotic carotid arteries and wire-injured mouse carotid arteries. HIF-1α overexpression led to elevated glycolysis and resulted in a decreased contractile phenotype while promoting VSMC proliferation and activation of the mechanistic target of rapamycin complex 1 (mTORC1). Conversely, silencing Pfkfb3 had the opposite effects. Mechanistic studies demonstrated that glycolysis generates acetyl coenzyme A to fuel de novo fatty acid synthesis and mTORC1 activation. Whole-transcriptome sequencing analysis confirmed the increased expression of PFKFB3 and fatty acid synthetase (FASN) in dedifferentiated VSMCs. More importantly, FASN upregulation was observed in neointimal VSMCs of human stenotic carotid arteries. Finally, interfering with PFKFB3 or FASN suppressed vascular injury-induced mTORC1 activation, VSMC dedifferentiation, and neointima formation. Together, this study demonstrated that PFKFB3-mediated glycolytic reprogramming and FASN-mediated lipid metabolic reprogramming are distinctive features of VSMC phenotypic switching and could be potential therapeutic targets for treating vascular diseases with neointima formation. © 2023 The Pathological Society of Great Britain and Ireland.

Combined Effect of Maternal Obesity and Diabetes on Excessive Fetal Growth: Pregnancy Risk Assessment Monitoring System (PRAMS), United States, 2012–2015

Obesity and dysregulation in glucose metabolism are risk factors for excessive fetal growth, but their combined effects are not often examined in a single study. Data from the Centers for Disease Control and Prevention's Pregnancy Risk Assessment Monitoring System Phase 7 (2012-2015) were used. Logistic regression was used to investigate the association between maternal prepregnancy BMI and pre-existing diabetes/gestational diabetes on the odds of delivering a large-for-gestational-age infant or an infant with macrosomia. Complete data for 128,199 singleton births were used. The proportions of large-for-gestational-age infants and infants with macrosomia increased with the degree of obesity (p<0.001) and were higher in women with diabetes than in those without (p<0.001). Compared with the AOR among normal-weight women, the AOR of delivering large-for-gestational-age infants and infants with macrosomia among women with morbid obesity (BMI≥40) were 2.82 (p<0.001) and 2.67 (p<0.001), respectively. Compared with the AOR among nondiabetic women, the AOR of delivering a large-for-gestational-age infant was 1.88 (p<0.001) among those with pre-existing diabetes and 1.49 (p<0.001) among those with gestational diabetes. Except for the underweight group, women with pre-existing diabetes were nearly twice as likely to deliver a large-for-gestational-age infant as those with similar BMI without diabetes. Women with morbid obesity and gestational diabetes were twice as likely to have a large-for-gestational-age infant and an infant with macrosomia as nondiabetic women with normal BMI. We have shown that when maternal obesity and diabetes, particularly pre-existing diabetes, occur together, the risk of delivering large-for-gestational-age and macrosomia increases significantly. Our findings call for public health attention to address maternal obesity and diabetes to minimize suboptimal fetal growth.

Intergenerational arsenic exposure on the mouse epigenome and metabolic physiology.

Inorganic arsenic (iAs) is one of the largest toxic exposures to impact humanity worldwide. Exposure to iAs during pregnancy may disrupt the proper remodeling of the epigenome of F1 developing offspring and potentially their F2 grand-offspring via disruption of fetal primordial germ cells (PGCs). There is a limited understanding between the correlation of disease phenotype and methylation profile within offspring of both generations and whether it persists to adulthood. Our study aims to understand the intergenerational effects of in utero iAs exposure on the epigenetic profile and onset of disease phenotypes within F1 and F2 adult offspring, despite the lifelong absence of direct arsenic exposure within these generations. We exposed F0 female mice (C57BL6/J) to the following doses of iAs in drinking water 2 weeks before pregnancy until the birth of the F1 offspring: 1, 10, 245, and 2300 ppb. We found sex- and dose-specific changes in weight and body composition that persist from early time to adulthood within both generations. Fasting blood glucose challenge suggests iAs exposure causes dysregulation of glucose metabolism, revealing generational, exposure, and sex-specific differences. Toward understanding the mechanism, genome-wide DNA methylation data highlights exposure-specific patterns in liver, finding dysregulation within genes associated with cancer, T2D, and obesity. We also identified regions containing persistently differentially methylated CpG sites between F1 and F2 generations. Our results indicate the F1 developing embryos and their PGCs, which will result in F2 progeny, retain epigenetic damage established during the prenatal period and are associated with adult metabolic dysfunction.

Psychosocial work conditions and prediabetes risks: a cross-sectional study in middle-aged men and women

Prediabetes is a condition between diabetes and normoglycemia, and is a state of major health concern, as a large proportion of people with prediabetes are likely to develop diabetes which is associated with high mortality and morbidity. The purpose of this study was to investigate whether adverse psychosocial work conditions, based on the Job Demand-Control-social support model, increases risk for early dysregulated glucose metabolism in 50–64-year-old men and women. Job conditions were measured with the Swedish Demand-Control-Support questionnaire. Impaired glucose metabolism was assessed by an oral glucose tolerance test. Differences between groups were analyzed with Chi-square test and one-way ANOVA with Bonferroni post-hoc test. Odds ratios (OR) and 95% confidence intervals (95% CI) between Job Demand-control-support and prediabetes outcome were calculated with multiple logistic regression. Results from an adjusted logistic regression model showed that in men and woman separately, an active work situation (high demands-high control) was associated with significantly lower prediabetes risk (OR 0.657, 95% CI 0.513–0.842). This finding is consistent through all logistic regression models with different levels of adjustments. Further, the current study does not lend support for the hypothesis that work conditions characterized by high demands-low control were associated with dysregulated glucose metabolism in men nor women despite accumulation of many life-style related risk factors in the high strain group. In conclusion, we could show that men and women assessing their work conditions as active, had lower risk for prediabetes.

α7 nicotinic acetylcholine receptor agonist improved brain injury and impaired glucose metabolism in a rat model of ischemic stroke.

Vagus nerve stimulation through the action of acetylcholine can modulate inflammatory responses and metabolism. α7 Nicotinic Acetylcholine Receptor (α7nAChR) is a key component in the biological functions of acetylcholine. To further explore the health benefits of vagus nerve stimulation, this study aimed to investigate whether α7nAChR agonists offer beneficial effects against poststroke inflammatory and metabolic changes and to identify the underlying mechanisms in a rat model of stroke established by permanent cerebral ischemia. We found evidence showing that pretreatment with α7nAChR agonist, GTS-21, improved poststroke brain infarction size, impaired motor coordination, brain apoptotic caspase 3 activation, dysregulated glucose metabolism, and glutathione reduction. In ischemic cortical tissues and gastrocnemius muscles with GTS-21 pretreatment, macrophages/microglia M1 polarization-associated Tumor Necrosis Factor-α (TNF-α) mRNA, Cluster of Differentiation 68 (CD68) protein, and Inducible Nitric Oxide Synthase (iNOS) protein expression were reduced, while expression of anti-inflammatory cytokine IL-4 mRNA, and levels of M2 polarization-associated CD163 mRNA and protein were increased. In the gastrocnemius muscles, stroke rats showed a reduction in both glutathione content and Akt Serine 473 phosphorylation, as well as an elevation in Insulin Receptor Substrate-1 Serine 307 phosphorylation and Dynamin-Related Protein 1 Serine 616 phosphorylation. GTS-21 reversed poststroke changes in the gastrocnemius muscles. Overall, our findings, provide further evidence supporting the neuroprotective benefits of α7nAChR agonists, and indicate that they may potentially exert anti-inflammatory and metabolic effects peripherally in the skeletal muscle in an acute ischemic stroke animal model.

Triterpenoid CDDO-EA inhibits lipopolysaccharide-induced inflammatory responses in skeletal muscle cells through suppression of NF-κB.

Chronic inflammation is a major contributor to the development of obesity-induced insulin resistance, which then can lead to the development of type 2 diabetes (T2D). Skeletal muscle plays a pivotal role in insulin-stimulated whole-body glucose disposal. Therefore, dysregulation of glucose metabolism by inflammation in skeletal muscle can adversely affect skeletal muscle insulin sensitivity and contribute to the pathogenesis of T2D. The mechanism underlying insulin resistance is not well known; however, macrophages are important initiators in the development of the chronic inflammatory state leading to insulin resistance. Skeletal muscle consists of resident macrophages which can be activated by lipopolysaccharide (LPS). These activated macrophages affect myocytes via a paracrine action of pro-inflammatory mediators resulting in secretion of myokines that contribute to inflammation and ultimately skeletal muscle insulin resistance. Therefore, knowing that synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acids (CDDOs) can attenuate macrophage pro-inflammatory responses in chronic disorders, such as cancer and obesity, and that macrophage pro-inflammatory responses can modulate skeletal muscle inflammation, we first examined whether CDDO-ethyl amide (CDDO-EA) inhibited chemokine and cytokine production in macrophages since this had not been reported for CDDO-EA. CDDO-EA blocked LPS-induced tumor necrosis factor-alpha (TNF-α), monocyte chemotactic protein-1 (MCP-1), interleukine-1beta (IL-1β), and interleukine-6 (IL-6) production in RAW 264.7 mouse and THP-1 human macrophages. Although many studies show that CDDOs have anti-inflammatory properties in several tissues and cells, little is known about the anti-inflammatory effects of CDDOs on skeletal muscle. We hypothesized that CDDO-EA protects skeletal muscle from LPS-induced inflammation by blocking nuclear factor kappa B (NF-κB) signaling. Our studies demonstrate that CDDO-EA prevented LPS-induced TNF-α and MCP-1 gene expression by inhibiting the NF-κB signaling pathway in L6-GLUT4myc rat myotubes. Our findings suggest that CDDO-EA suppresses LPS-induced inflammation in macrophages and myocytes and that CDDO-EA is a promising compound as a therapeutic agent for protecting skeletal muscle from inflammation.

Combination therapies in nonalcoholic fatty liver disease using antidiabetic and disease-specific drugs.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common diseases in the world, affecting approximately one fourth of the worldwide population. Glucose metabolism dysregulation and type 2 diabetes mellitus (T2DM), as part of the metabolic syndrome, are important factors implicated in the pathogenesis and progression of NAFLD to nonalcoholic steatohepatitis (NASH) and cirrhosis. Although a great deal of research has already been conducted regarding possible therapeutic medications for NAFLD/NASH, no drugs have been approved until now. Combination therapies in NAFLD seem to represent an attractive approach concerning treatment of the disease, as multiple pathophysiologic pathways contribute to the development and advance of NAFLD. In this review we discuss the impact of combining antidiabetic drugs, focusing on pioglitazone, sodium glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists. We also include data from the literature concerning combinations of newer "NAFLD-specific" drugs.

Is Helicobacter Pylori Infection Associated with Insulin Resistance? A Tertiary Care Centre Experience at Kattankulathur, Tamil Nadu, India

Introduction: H.pylori is the most common infection leading to gastrointestinal and extra-gastrointestinal lesions. Few studies had studied about H.pylori’s effect on glucose metabolism and insulin resistance and found that H.pylori is associated with increase in mean Glycated Haemoglobin (HbA1c) levels and insulin resistance. But few studies have found no association between H.pylori and glucose metabolism. Aim: To determine the relationship between H.pylori infection and glucose metabolism profiles in dyspeptic patients, based on the histopathological examination. Materials and Methods: This prospective case-control study was carried out in the Department of Pathology at SRM Medical College Hospital and Research Centre from April 2021 to September 2021 on 70 dyspeptic patients. They were split into two groups: H.pylori positive (Group-I, n=35) and H.pylori negative (Group-II, n=35) groups. The age and gender of Group-I were matched with Group-II. Endoscopic gastric biopsy was taken and tissue sections were stained with Haematoxylin and Eosin (H&amp;E), and Immunohistochemical (IHC) stain using H.pylori (Clone: EP279) rabbit monoclonal antibody. Blood samples were collected to test Fasting Blood Glucose (FBG) and insulin. Insulin resistance was calculated using Homeostatic Model Assessment of Insulin Resistance (HOMAIR). Histomorphological changes and H.pylori colonisation were graded according to Updated Sydney System and correlated with HOMA-IR levels. Statistical analysis was done using Statistical Package for the Social Sciences (SPSS) software version 22.0. Results: There was no significant variation between H.pylori positive and negative groups in demographic variables such as age (p-value=0.45) and gender (p-value=0.23). Body Mass Index (BMI) and H.pylori infection showed statistically significant association (p-value=0.04). Increase in mean values of FBG, insulin and HOMA-IR were statistically associated with H.pylori positive (p-value&lt;0.05). Degree of H.pylori bacterial density (rs =0.2992), chronic inflammation (rs =0.3193), activity (rs =0.4576) and atrophy (rs =0.2542) were positively correlated with HOMA-IR. Conclusion: This study showed that chronic active gastritis with atrophic related changes and H.pylori colonisation were significantly correlated with HOMA-IR. Patients with H.pylori induced gastritis should be followed with regular monitoring of HOMA-IR; as early diagnosis and eradication of H.pylori might reduce the risk of insulin resistance and glucose metabolism dysregulation.

PS-BPB01-2: VASCULAR ENDOTHELIAL NAMPT-MEDIATED NAD+ BIOSYNTHESIS REGULATES WHOLE-BODY BLOOD PRESSURE AND INSULIN RESISTANCE

Obesity is associated with dysregulation in blood pressure control and whole-body glucose metabolism, but the precise underlying mechanism(s) remain unclear. Here, we generated and characterized mice with vascular endothelial-cell specific deletion of nicotinamide phosphoribosyltransferase (NAMPT), which mediates the biosynthesis of nicotinamide adenine dinucleotide (NAD+), a key regulator of cellular energy metabolism. We found that vascular endothelial cell-specific Nampt knockout (VeNKO) mice exhibited 1) higher blood pressure (systolic blood pressure; flox/flox mice: 111 ± 2.6 mmHg, VeNKO mice: 134 ± 4.0 mmHg, p &lt; 0.05) with cardiac hypertrophy (flox/flox mice: 5.0 mg/g-body weight, VeNKO mice: 6.1 mg/g-body weight, p &lt; 0.05) and 2) insulin resistance with abnormal fat distribution, under high-fat diet feeding. These deleterious alterations were partially rescued by administering nicotinamide mononucleotide (NMN), a key NAD+ intermediate. Taken together, our findings demonstrate that vascular endothelial NAMPT-mediated NAD+ biosynthesis is involved in the regulation of blood pressure and whole-body glucose metabolism. Our study provides mechanistic and therapeutic insights into vascular endothelia NAD+ biology related to obesity-associated hypertension and insulin resistance.

Post Traumatic Epilepsy with Sequel of Frontal Contusion and Spontaneous Regression of Extradural Hematoma; Clinical Case and Review of the Literature

Post traumatic epilepsy are frequent complications of moderate and severe head injuries, they are found in hemorrhagic contusions and hematomas. Several isolated or associated mechanisms are involved in the occurrence of these convulsions (increased inflammatory markers, neuronal cell death, altered blood-brain barrier, changes in astrocytes, and glucose metabolism dysregulation changes in synaptic abundance and function).The first attacks can occur more than 2 years after the head trauma or after cranial surgery. Preventive treatment does not change the course of the disease. Treatment with Valproate and levetiracetam were also compared to phenytoin and no benefit was found in recovery.&#x0D; The particularity of our patient is the severe head trauma, with regressive frontal contusion with secular lesions, followed by the appearance at nearly three and a half months of the trauma of a fronto-parietal extradural hematoma with mass effect which resolved spontaneously. Two and three years after the trauma, he developed generalized epilepsy, suggesting post-traumatic epilepsy following the sequelae of the hemorrhagic contusion or the extradural hematoma, or the sequelae of these associated lesions. These seizures were treated with sodium valproate. This clinical case challenges clinicians to monitor in severe head injuries the occurrence of complications such as epilepsy that can occur beyond 2 years.

Activating transcription factor 3, glucolipid metabolism, and metabolic diseases.

Lipids and glucose exert many essential physiological functions, such as providing raw materials or energy for cellular biosynthesis, regulating cell signal transduction, and maintaining a constant body temperature. Dysregulation of lipid and glucose metabolism can lead to glucolipid metabolic disorders linked to various metabolic diseases, such as obesity, diabetes, and cardiovascular disease. Therefore, intervention in glucolipid metabolism is a key therapeutic strategy for the treatment of metabolic diseases. Activating transcription factor 3 (ATF3) is a transcription factor that acts as a hub of the cellular adaptive-response network and plays a pivotal role in the regulation of inflammation, apoptosis, DNA repair, and oncogenesis. Emerging evidence has illustrated the vital roles of ATF3 in glucolipid metabolism. ATF3 inhibits intestinal lipid absorption, enhances hepatic triglyceride hydrolysis and fatty acid oxidation, promotes macrophage reverse cholesterol transport, and attenuates the progression of western diet-induced nonalcoholic fatty liver disease and atherosclerosis. In addition to its role in lipid metabolism, ATF3 has also been identified as an important regulator of glucose metabolism. Here, we summarize the recent advances in the understanding of ATF3, mainly focusing on its role in glucose and lipid metabolism and potential therapeutic implications.

FAM3A maintains metabolic homeostasis by interacting with F1-ATP synthase to regulate the activity and assembly of ATP synthase

Reduced mitochondrial ATP synthase (ATPS) capacity plays crucial roles in the pathogenesis of metabolic disorders. However, there is currently no effective strategy for synchronously stimulating the expressions of ATPS key subunits to restore its assembly. This study determined the roles of mitochondrial protein FAM3A in regulating the activity and assembly of ATPS in hepatocytes. FAM3A is localized in mitochondrial matrix, where it interacts with F1-ATPS to initially activate ATP synthesis and release, and released ATP further activates P2 receptor-Akt-CREB pathway to induce FOXD3 expression. FOXD3 synchronously stimulates the transcriptions of ATPS key subunits and assembly genes to increase its assembly and capacity, augmenting ATP synthesis and inhibiting ROS production. FAM3A, FOXD3 and ATPS expressions were reduced in livers of diabetic mice and NAFLD patients. FOXD3 expression, ATPS capacity and ATP content were reduced in various tissues of FAM3A-deficient mice with dysregulated glucose and lipid metabolism. Hepatic FOXD3 activation increased ATPS assembly to ameliorate dysregulated glucose and lipid metabolism in obese mice. Hepatic FOXD3 inhibition or knockout reduced ATPS capacity to aggravate HFD-induced hyperglycemia and steatosis. In conclusion, FAM3A is an active ATPS component, and regulates its activity and assembly by activating FOXD3. Activating FAM3A-FOXD3 axis represents a viable strategy for restoring ATPS assembly to treat metabolic disorders.

The mitochondrial UPR regulator ATF5 promotes intestinal barrier function via control of the satiety response

Organisms use several strategies to mitigate mitochondrial stress, including the activation of the mitochondrial unfolded protein response (UPRmt). The UPRmt in Caenorhabditis elegans, regulated by the transcription factor ATFS-1, expands on this recovery program by inducing an antimicrobial response against pathogens that target mitochondrial function. Here, we show that the mammalian ortholog of ATFS-1, ATF5, protects the host during infection with enteric pathogens but, unexpectedly, by maintaining the integrity of the intestinal barrier. Intriguingly, ATF5 supports intestinal barrier function by promoting a satiety response that prevents obesity and associated hyperglycemia. This consequently averts dysregulated glucose metabolism that is detrimental to barrier function. Mechanistically, we show that intestinal ATF5 stimulates the satiety response by transcriptionally regulating the gastrointestinal peptide hormone cholecystokinin, which promotes the secretion of the hormone leptin. We propose that ATF5 protects the host from enteric pathogens by promoting intestinal barrier function through a satiety-response-mediated metabolic control mechanism.