scholarly journals ALOXE3 is a hepatic fasting-responsive lipoxygenase that enhances insulin sensitivity via hepatic PPARγ

2018 ◽  
Author(s):  
Cassandra B. Higgins ◽  
Yiming Zhang ◽  
Allyson L. Mayer ◽  
Hideji Fujiwara ◽  
Alicyn I. Stothard ◽  
...  
Keyword(s):  
Metabolic Disease ◽  
Fasting Glucose ◽  
Metabolic Effects ◽  
Diabetic Mice ◽  
Targeted Metabolomics ◽  
Atp Production ◽  
Promising Target ◽  
Hepatic Glucose ◽  
Host Metabolism ◽  
Fasting Response

ABSTARCTThe hepatic glucose fasting response is gaining traction as a therapeutic pathway to enhance hepatic and whole-host metabolism. However, the mechanisms underlying these metabolic effects remain unclear. Here, we demonstrate the lipoxygenase, ALOXE3, is a novel effector of the thepatic fasting response. We show that ALOXE3 is activated during fasting, glucose withdrawal, and trehalose/trehalose analogue treatment. Hepatocyte-specific ALOXE3 expression reduced weight gain and hepatic steatosis in dietaryand genetically obese (db/db) models. ALOXE3 expression moreover enhanced basal thermogenesis and abrogated insulin resistance in db/db diabetic mice. Targeted metabolomics demonstrated accumulation of the PPARγ ligand, 12-KETE in hepatocytes overexpressing ALOXE3. Strikingly, PPARγ inhibition reversed hepatic ALOXE3-mediated insulin sensitization, suppression of hepatocellular ATP production and oxygen consumption, and gene induction of PPARγ coactivator-1a (PGC1α) expression. Moreover, hepatocyte-specific PPARγ deletion reversed the therapeutic effect of hepatic ALOXE3 expression on diet-induced insulin intolerance. ALOXE3 is therefore a novel effector of the hepatocellular fasting response that leverages both PPARγ-mediated and pleiotropic effects to augment hepatic and whole-host metabolism, and is thus a promising target to ameliorate metabolic disease.

Effect of epinephrine on glucose metabolism in humans: contribution of the liver

1984 ◽  
Vol 247 (2) ◽  
pp. E157-E165 ◽  
Author(s):  
R. S. Sherwin ◽  
L. Sacca
Keyword(s):  
Fasting Glucose ◽  
Blood Glucose Concentration ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Metabolic Effects ◽  
Glucose Disposal ◽  
Glucose Levels ◽  
Hepatic Glucose ◽  
Patients With Diabetes ◽  
Insulin Dependent

Epinephrine causes a prompt increase in blood glucose concentration in the postabsorptive state. This effect is mediated by a transient increase in hepatic glucose production and an inhibition of glucose disposal by insulin-dependent tissues. Epinephrine augments hepatic glucose production by stimulating glycogenolysis and gluconeogenesis. Although its effect on glycogenolysis rapidly wanes, hyperglycemia continues because the effects of epinephrine on gluconeogenesis and glucose disposal persist. Epinephrine-induced hyperglycemia is markedly accentuated by concomitant elevations of glucagon and cortisol or in patients with diabetes. In both cases, the effect of epinephrine on hepatic glucose production is converted from a transient to a sustained response, thereby accounting for the exaggerated hyperglycemia. During glucose feeding, mild elevations of epinephrine that have little effect on fasting glucose levels cause marked glucose intolerance. This exquisite sensitivity to the diabetogenic effects of epinephrine is accounted for by its capacity to interfere with each of the components of the glucoregulatory response, i.e., stimulation of splanchnic and peripheral glucose uptake and suppression of hepatic glucose production. Our findings suggest that epinephrine is an important contributor to stress-induced hyperglycemia and the susceptibility of diabetics to the adverse metabolic effects of stress.

scholarly journals Clobetasol promotes neuromuscular plasticity in mice after motoneuronal loss via sonic hedgehog signaling, immunomodulation and metabolic rebalancing

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Nunzio Vicario ◽  
Federica M. Spitale ◽  
Daniele Tibullo ◽  
Cesarina Giallongo ◽  
Angela M. Amorini ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Neural Regeneration ◽  
Metabolic Effects ◽  
Motor Impairments ◽  
Sonic Hedgehog Signaling ◽  
Neuroprotective Effects ◽  
Promising Target ◽  
Translational Approach ◽  
Lateral Sclerosis

AbstractMotoneuronal loss is the main feature of amyotrophic lateral sclerosis, although pathogenesis is extremely complex involving both neural and muscle cells. In order to translationally engage the sonic hedgehog pathway, which is a promising target for neural regeneration, recent studies have reported on the neuroprotective effects of clobetasol, an FDA-approved glucocorticoid, able to activate this pathway via smoothened. Herein we sought to examine functional, cellular, and metabolic effects of clobetasol in a neurotoxic mouse model of spinal motoneuronal loss. We found that clobetasol reduces muscle denervation and motor impairments in part by restoring sonic hedgehog signaling and supporting spinal plasticity. These effects were coupled with reduced pro-inflammatory microglia and reactive astrogliosis, reduced muscle atrophy, and support of mitochondrial integrity and metabolism. Our results suggest that clobetasol stimulates a series of compensatory processes and therefore represents a translational approach for intractable denervating and neurodegenerative disorders.

scholarly journals Hepatic functions of GLP-1 and its based drugs: current disputes and perspectives

2016 ◽  
Vol 311 (3) ◽  
pp. E620-E627 ◽  
Author(s):  
Tianru Jin ◽  
Jianping Weng
Keyword(s):  
Insulin Resistance ◽  
Degradation Products ◽  
Hepatic Glucose Production ◽  
Wnt Signaling Pathway ◽  
Glucose Production ◽  
Metabolic Effects ◽  
Beneficial Effects ◽  
Metabolic Functions ◽  
Pathway Activation ◽  
Hepatic Glucose

GLP-1 and its based drugs possess extrapancreatic metabolic functions, including that in the liver. These direct hepatic metabolic functions explain their therapeutic efficiency for subjects with insulin resistance. The direct hepatic functions could be mediated by previously assumed “degradation” products of GLP-1 without involving canonic GLP-1R. Although GLP-1 analogs were created as therapeutic incretins, extrapancreatic functions of these drugs, as well as native GLP-1, have been broadly recognized. Among them, the hepatic functions are particularly important. Postprandial GLP-1 release contributes to insulin secretion, which represses hepatic glucose production. This indirect effect of GLP-1 is known as the gut-pancreas-liver axis. Great efforts have been made to determine whether GLP-1 and its analogs possess direct metabolic effects on the liver, as the determination of the existence of direct hepatic effects may advance the therapeutic theory and clinical practice on subjects with insulin resistance. Furthermore, recent investigations on the metabolic beneficial effects of previously assumed “degradation” products of GLP-1 in the liver and elsewhere, including GLP-128–36 and GLP-132–36, have drawn intensive attention. Such investigations may further improve the development and the usage of GLP-1-based drugs. Here, we have reviewed the current advancement and the existing controversies on the exploration of direct hepatic functions of GLP-1 and presented our perspectives that the direct hepatic metabolic effects of GLP-1 could be a GLP-1 receptor-independent event involving Wnt signaling pathway activation.

Metabolic Consequences of Solid Organ Transplantation

2020 ◽  
Author(s):  
Mamatha Bhat ◽  
Shirine E Usmani ◽  
Amirhossein Azhie ◽  
Minna Woo
Keyword(s):  
Metabolic Disease ◽  
Weight Gain ◽  
Dietary Habits ◽  
Solid Organ Transplantation ◽  
Calcineurin Inhibitors ◽  
Metabolic Effects ◽  
Current Evidence ◽  
Solid Organ ◽  
Metabolic Complications ◽  
Nonalcoholic Fatty Liver

Abstract Metabolic complications affect over 50% of solid organ transplant recipients. These include posttransplant diabetes, nonalcoholic fatty liver disease, dyslipidemia, and obesity. Preexisting metabolic disease is further exacerbated with immunosuppression and posttransplant weight gain. Patients transition from a state of cachexia induced by end-organ disease to a pro-anabolic state after transplant due to weight gain, sedentary lifestyle, and suboptimal dietary habits in the setting of immunosuppression. Specific immunosuppressants have different metabolic effects, although all the foundation/maintenance immunosuppressants (calcineurin inhibitors, mTOR inhibitors) increase the risk of metabolic disease. In this comprehensive review, we summarize the emerging knowledge of the molecular pathogenesis of these different metabolic complications, and the potential genetic contribution (recipient +/− donor) to these conditions. These metabolic complications impact both graft and patient survival, particularly increasing the risk of cardiovascular and cancer-associated mortality. The current evidence for prevention and therapeutic management of posttransplant metabolic conditions is provided while highlighting gaps for future avenues in translational research.

Histaminergic contribution to the metabolic effects of neuroglucopenia

1997 ◽  
Vol 272 (6) ◽  
pp. R1918-R1924
Author(s):  
P. E. Molina ◽  
P. Williams ◽  
N. N. Abumrad
Keyword(s):  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Histamine Receptor ◽  
Receptor Activation ◽  
Hepatic Uptake ◽  
Metabolic Effects ◽  
Cortisol Response ◽  
Hormonal Responses ◽  
Hepatic Glucose ◽  
Group 1

We examined the contribution of central histamine receptor (H1 and H2) blockade to the glucoregulatory responses to intracerebroventricular 2-deoxy-D-glucose (2-DG) in conscious dogs. Intracerebroventricular 2-DG (2.5 mg.kg-1.min-1 for 15 min) increased plasma glucose (2-fold), blood lactate (4-fold), and glycerol (2-fold) levels. The rate of hepatic glucose production (Ra), determined isotopically, was increased two-fold. Significant increases over basal were also noted in plasma epinephrine, norepinephrine, insulin, glucagon, and cortisol. Pretreatment with cyproheptadine and cimetidine (100 micrograms each icv 15 min before 2-DG) attenuated the 2-DG-induced hyperglycemia by approximately 50% and delayed and attenuated the increase in glucose Ra (approximately 85% vs. 2-fold in group 1). Pretreatment with H1 and H2 antagonists inhibited the increases in epinephrine, norepinephrine, and glucagon in response to neuroglucopenia but did not affect the cortisol response. These findings suggest that some of the metabolic effects of neuroglucopenia, particularly the hyperglycemic response, the increased hepatic uptake of gluconeogenic precursors, and the enhanced glucose Ra, are partly mediated through central histaminergic receptor activation. This appears to be through effects of histaminergic activation on the autonomic and hormonal responses to central neuroglucopenia.

Preventive Effect of Geniposide on Metabolic Disease Status in Spontaneously Obese Type 2 Diabetic Mice and Free Fatty Acid-Treated HepG2 Cells

2011 ◽  
Vol 34 (10) ◽  
pp. 1613-1618 ◽  
Author(s):  
Kazuko Kojima ◽  
Tsutomu Shimada ◽  
Yasuhiro Nagareda ◽  
Michiru Watanabe ◽  
Junko Ishizaki ◽  
...  
Keyword(s):  
Metabolic Disease ◽  
Fatty Acid ◽  
Free Fatty Acid ◽  
Hepg2 Cells ◽  
Disease Status ◽  
Diabetic Mice ◽  
Preventive Effect ◽  
Type 2 Diabetic

Disparate effects on renal and oxidative parameters following RAGE deletion, AGE accumulation inhibition, or dietary AGE control in experimental diabetic nephropathy

2010 ◽  
Vol 298 (3) ◽  
pp. F763-F770 ◽  
Author(s):  
Adeline L. Y. Tan ◽  
Karly C. Sourris ◽  
Brooke E. Harcourt ◽  
Vicki Thallas-Bonke ◽  
Sally Penfold ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Urinary Albumin Excretion ◽  
Uncoupling Protein ◽  
Therapeutic Interventions ◽  
Diabetic Mice ◽  
Wild Type ◽  
Atp Production ◽  
Mitochondrial Superoxide ◽  
Glycation End Products ◽  
Rage Expression

Advanced glycation end products (AGEs) and the receptor for AGEs (RAGE) generate ROS, and therefore this study evaluated the effects of RAGE deletion, decreasing AGE accumulation, or lowering dietary AGE content on oxidative parameters in diabetic nephropathy (DN). Control and diabetic male wild-type and RAGE-deficient (RAGE−/−) mice were fed high- or low-AGE diets, with two groups given the inhibitor of AGE accumulation, alagebrium chloride, and followed for 24 wk. Diabetic RAGE−/−mice were protected against albuminuria, hyperfiltration, glomerulosclerosis, decreased renal mitochondrial ATP production, and excess generation of both mitochondrial and cytosolic superoxide. Whereas glomerulosclerosis, tubulointerstitial expansion, and hyperfiltration were improved in diabetic mice treated with alagebrium, there was no effect on urinary albumin excretion. Both diabetic RAGE−/−and alagebrium-treated mice had an attenuation of renal RAGE expression and decreased renal and urinary AGE (carboxymethyllysine) levels. Low-AGE diets did not confer renoprotection, lower the AGE burden or renal RAGE expression, or improve cytosolic or mitochondrial superoxide generation. Renal uncoupling protein-2 gene expression and mitochondrial membrane potential were attenuated by all therapeutic interventions in diabetic mice. In the present study, diverse approaches to block the AGE-RAGE axis had disparate effects on DN, which has potential clinical implications for the way this axis should be targeted in humans.

scholarly journals The metabolic effects of sodium dichloroacetate in the starved rat

1974 ◽  
Vol 142 (2) ◽  
pp. 279-286 ◽  
Author(s):  
Perry J. Blackshear ◽  
Paul A. H. Holloway ◽  
K. George M. M. Albert
Keyword(s):  
Blood Glucose ◽  
Ketone Body ◽  
Metabolic Effects ◽  
Plasma Insulin Concentration ◽  
Hepatic Glucose ◽  
Extrahepatic Tissues ◽  
Lactate And Pyruvate ◽  
Gluconeogenic Substrates ◽  
Net Release ◽  
Pyruvate Ratio

1. Sodium dichloroacetate (300mg/kg body wt. per h) was infused in 24h-starved rats for 4h. 2. Blood glucose decreased significantly, an effect that had previously only been noted in diabetic animals 3. Plasma insulin concentration decreased by 63% blood lactate and pyruvate concentrations decreased by 50 and 33%, whereas concentrations of 3-hydroxybutyrate and acetoacetate increased by 81 and 73% respectively. 4. Livers were freeze-clamped at the end of the 4h infusion. There were significant decreases in hepatic [glucose], [glucose 6-phosphate], [2-phosphoglycerate], the [lactate]/[pyruvate] ratio, [citrate] and [malate], and also [alanine], [glutamate] and [glutamine], suggesting a diminished supply of gluconeogenic substrates. 5. Animals subjected to a functional hepatectomy at the end of 2h infusions showed no difference in blood-glucose disappearance but a highly significant decrease in the rate of accumulation of lactate, pyruvate, glycerol and alanine, compared with control animals. Dichloroacetate decreased ketone-body clearance. 6. After functional hepatectomy an increase in glutamine accumulation appeared to compensate for the decrease in alanine accumulation. 7. It is concluded that dichloroacetate causes hypoglycaemia by decreasing the net release of gluconeogenic precursors from extrahepatic tissues while inhibiting peripheral ketone-body uptake. 8. These findings are consistent with the activation of pyruvate dehydrogenase (EC 1.2.4.1) in rat muscle by dichloroacetate previously described by Whitehouse & Randle (1973).

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