Embryonic steroids control developmental programming of energy balance

Endocrinology ◽  
2021 ◽  
Author(s):  
Meng-Chun Monica Shih ◽  
Chen-Che Jeff Huang ◽  
Hsueh-Ping Chu ◽  
Nai-Chi Hsu ◽  
Bon-chu Chung
Keyword(s):  
Energy Source ◽  
Blood Glucose ◽  
Energy Homeostasis ◽  
De Novo ◽  
Glycogen Synthesis ◽  
Glucose Production ◽  
Liver Glycogen ◽  
Glycogen Storage ◽  
Expression Of Genes ◽  
Major Energy Source

Abstract Glucose is a major energy source for growth. At birth, neonates must change their energy source from maternal supply to its own glucose production. The mechanism of this transition has not been clearly elucidated. To evaluate the possible roles of steroids in this transition, here we examine the defects associated with energy production of a mouse line that cannot synthesize steroids de novo due to the disruption of its Cyp11a1 gene. The Cyp11a1 null embryos had insufficient blood insulin, and failed to store glycogen in the liver since embryonic day 16.5. Their blood glucose dropped soon after maternal deprivation, and the expression of hepatic gluconeogenic and glycogenic genes were reduced. Insulin was synthesized in the mutant fetal pancreas, but failed to be secreted. Maternal glucocorticoid supply rescued the amounts of blood glucose, insulin, and liver glycogen in the fetus, but did not restore expression of genes for glycogen synthesis, indicating the requirement of de novo glucocorticoid synthesis for glycogen storage. Thus, our investigation of Cyp11a1 null embryos reveals that the energy homeostasis is established before birth, and fetal steroids are required for the regulation of glycogen synthesis, hepatic gluconeogenesis and insulin secretion at the fetal stage.

Accelerated glycogenolysis in uremia and under sucrose feeding: role of phosphorylase alpha regulators

1997 ◽  
Vol 273 (1) ◽  
pp. E17-E27
Author(s):  
Z. Bakkour ◽  
D. Laouari ◽  
S. Dautrey ◽  
J. P. Yvert ◽  
C. Kleinknecht
Keyword(s):  
Hepatic Glucose Production ◽  
Glycogen Synthesis ◽  
Glucose Production ◽  
Glycogen Storage ◽  
Hepatic Insulin Resistance ◽  
Hepatic Glycogen ◽  
Glycogen Depletion ◽  
Sucrose Feeding

To understand the mechanism of hepatic glycogen depletion found in uremia and under sucrose feeding, we examined net hepatic glycogenolysis-associated active enzymes and metabolites during fasting. Liver was taken 2, 7, and 18 h after food removal in uremic and pair-fed control rats fed either a sucrose or cornstarch diet for 21 days. Other uremic and control rats fasted for 18 h were refed a sucrose meal to measure glycogen increment. Glycogen storage in uremia was normal, suggesting effective glycogen synthesis. During a short fast, sucrose feeding and uremia enhanced net glycogenolysis through different but additive mechanisms. Under sucrose feeding, there were high phosphorylase alpha levels associated with hepatic insulin resistance. In uremia, phosphorylase alpha levels were low, but the enzyme was probably activated in vivo by a fall of inhibitors (ATP, alpha-glycerophosphate, fructose-1,6-diphosphate, and glucose) and a rise of Pi, as verified in vitro. Enhanced gluconeogenesis was also suggested, but excessive hepatic glucose production was unlikely in uremia. During fasting, hypoglycemia occurred in uremia due to reduced glycogenolysis, inefficient hepatic gluconeogenesis, and impaired renal gluconeogenesis. This may be relevant to poor fasting tolerance in uremia, which could be aggravated under excessive sucrose intake.

scholarly journals CREBH Maintains Circadian Glucose Homeostasis by Regulating Hepatic Glycogenolysis and Gluconeogenesis

2017 ◽  
Vol 37 (14) ◽  
Author(s):  
Hyunbae Kim ◽  
Ze Zheng ◽  
Paul D. Walker ◽  
Gregory Kapatos ◽  
Kezhong Zhang
Keyword(s):  
Blood Glucose ◽  
Glucose Homeostasis ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Liver Glycogen ◽  
Glycogen Storage ◽  
Hepatic Glycogen ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose Levels ◽  
Blood Glucose Levels

ABSTRACT Cyclic AMP-responsive element binding protein, hepatocyte specific (CREBH), is a liver-enriched, endoplasmic reticulum-tethered transcription factor known to regulate the hepatic acute-phase response and lipid homeostasis. In this study, we demonstrate that CREBH functions as a circadian transcriptional regulator that plays major roles in maintaining glucose homeostasis. The proteolytic cleavage and posttranslational acetylation modification of CREBH are regulated by the circadian clock. Functionally, CREBH is required in order to maintain circadian homeostasis of hepatic glycogen storage and blood glucose levels. CREBH regulates the rhythmic expression of the genes encoding the rate-limiting enzymes for glycogenolysis and gluconeogenesis, including liver glycogen phosphorylase (PYGL), phosphoenolpyruvate carboxykinase 1 (PCK1), and the glucose-6-phosphatase catalytic subunit (G6PC). CREBH interacts with peroxisome proliferator-activated receptor α (PPARα) to synergize its transcriptional activities in hepatic gluconeogenesis. The acetylation of CREBH at lysine residue 294 controls CREBH-PPARα interaction and synergy in regulating hepatic glucose metabolism in mice. CREBH deficiency leads to reduced blood glucose levels but increases hepatic glycogen levels during the daytime or upon fasting. In summary, our studies revealed that CREBH functions as a key metabolic regulator that controls glucose homeostasis across the circadian cycle or under metabolic stress.

Sterol-regulatory-element-binding protein I c mediates insulin action on hepatic gene expression

2001 ◽  
Vol 29 (4) ◽  
pp. 547-552 ◽  
Author(s):  
P. Ferré ◽  
M. Foretz ◽  
D. Azzout-Marniche ◽  
D. Bécard ◽  
F. Foufelle
Keyword(s):  
Energy Homeostasis ◽  
Glucose Utilization ◽  
Binding Protein ◽  
Regulatory Element ◽  
Glucose Production ◽  
Pathological Conditions ◽  
Expression Of Genes ◽  
Adaptive Mechanisms ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

Effects of insulin on the expression of liver-specific genes are part of the adaptive mechanisms aimed at maintaining energy homeostasis in mammals. When the diet is rich in carbohydrates, secreted insulin stimulates the expression of genes for enzymes involved in glucose utilization (glucokinase, L-type pyruvate kinase and lipogenic enzymes) and inhibits genes for enzymes involved in glucose production (phosphenolpyruvate carboxykinase). The mechanisms by which insulin controls the expression of these genes have been poorly understood. Recently, the transcription factor sterol-regulatory-element-binding protein 1c has been proposed as a key mediator of insulin transcriptional effects. Here we review the evidence that has led to this proposal and the consequences for our understanding of insulin effects in physiological or pathological conditions.

scholarly journals N6-methyladenosine modification governs liver glycogenesis by stabilizing the glycogen synthase 2 mRNA

2021 ◽  
Author(s):  
Xiang Zhang ◽  
Huilong Yin ◽  
Xiaofang Zhang ◽  
Xunliang Jiang ◽  
Yongkang Liu ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Molecular Mechanism ◽  
Knockout Mice ◽  
Glycogen Synthase ◽  
Critical Role ◽  
Liver Glycogen ◽  
Glycogen Storage ◽  
Hepatic Glycogen

Abstract Hepatic glycogen is the main source of blood glucose and controls the intervals between meals in mammals. Hepatic glycogen storage in mammalian pups is insufficient compared to their adult counterparts; however, the detailed molecular mechanism is poorly understood. Here, we showed that, similar to glycogen storage pattern, N6-methyladenosine (m6A) modification in mRNAs gradually increases during the growth of mice in liver. Strikingly, in the liver-specific Mettl3 knockout mice, loss of m6A modification disrupts liver glycogen storage. On the mechanism, we screened and identified that glycogen synthase 2 (Gys2) plays a critical role in m6A-mediated regulation of liver glycogen storage. Furthermore, IGF2BP2, as a “reader” of m6A, stabilizes the mRNA of Gys2. More importantly, reconstitution of GYS2 rescues liver glycogenesis in Mettl3-cKO mice. Collectively, a METTL3-IGF2BP2-GYS2 axis, in which METTL3 and IGF2BP2 regulate glycogenesis as “writer” and “reader” respectively, plays a critical role on maintenance of liver glycogenesis in mammals.

scholarly journals Sex Hormones and Their Receptors Regulate Liver Energy Homeostasis

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Minqian Shen ◽  
Haifei Shi
Keyword(s):  
Estrogen Receptors ◽  
Hepatic Steatosis ◽  
Sex Hormones ◽  
Energy Homeostasis ◽  
Hormone Receptors ◽  
Androgen Receptors ◽  
Glycogen Synthesis ◽  
Glucose Production ◽  
Receptor Expression ◽  
Acid Uptake

The liver is one of the most essential organs involved in the regulation of energy homeostasis. Hepatic steatosis, a major manifestation of metabolic syndrome, is associated with imbalance between lipid formation and breakdown, glucose production and catabolism, and cholesterol synthesis and secretion. Epidemiological studies show sex difference in the prevalence in fatty liver disease and suggest that sex hormones may play vital roles in regulating hepatic steatosis. In this review, we summarize current literature and discuss the role of estrogens and androgens and the mechanisms through which estrogen receptors and androgen receptors regulate lipid and glucose metabolism in the liver. In females, estradiol regulates liver metabolism via estrogen receptors by decreasing lipogenesis, gluconeogenesis, and fatty acid uptake, while enhancing lipolysis, cholesterol secretion, and glucose catabolism. In males, testosterone works via androgen receptors to increase insulin receptor expression and glycogen synthesis, decrease glucose uptake and lipogenesis, and promote cholesterol storage in the liver. These recent integrated concepts suggest that sex hormone receptors could be potential promising targets for the prevention of hepatic steatosis.

Glucose production in glycogen storage disease I is not associated with increased cycling through hepatic glycogen

1995 ◽  
Vol 269 (4) ◽  
pp. E774-E778 ◽  
Author(s):  
K. I. Rother ◽  
W. F. Schwenk
Keyword(s):  
Glycogen Storage Disease ◽  
Plasma Glucose ◽  
Storage Disease ◽  
Glycogen Synthesis ◽  
Glucose Production ◽  
Glycogen Storage ◽  
Endogenous Glucose Production ◽  
Hepatic Glycogen ◽  
Type I ◽  
Glucose Flux

Children with glycogen storage disease type I (GSD I) lack the ability to convert glucose 6-phosphate to glucose and yet are able to produce glucose endogenously. To test the hypothesis that the source of this glucose is increased cycling of glucose moieties through hepatic glycogen, six children with GSD I were studied on two occasions during which they received enteral glucose for 6 h at 35 or 50 mumol.kg-1.min-1 along with [6,6-2H2]glucose to measure plasma glucose flux and [1-13C]galactose to label intrahepatic uridyl diphosphate (UDP)-glucose. After 3 h, acetaminophen was given to estimate UDP-glucose flux (reflecting the rate of glycogen synthesis). Mean steady-state plasma glucose concentrations (4.8 +/- 0.2 vs. 5.8 +/- 0.1 mM) and total flux (34.8 +/- 1.7 vs. 47.5 +/- 2.0 mumol.kg-1.min-1) were increased (P < 0.05 or better) on the high-infusion day. Endogenous glucose production was detectable only on the low-infusion day (2.0 +/- 0.5 mumol.kg-1.min-1). UDP-glucose flux was increased (P < 0.05) on the high-infusion day (25.8 +/- 1.6 vs. 34.7 +/- 4.1), ruling out cycling of glucose moieties through glycogen with release of glucose by debrancher enzyme as the source of glucose production.

Time course of insulin action on tissue-specific intracellular glucose metabolism in normal rats

1998 ◽  
Vol 274 (4) ◽  
pp. E642-E650 ◽  
Author(s):  
Sietse J. Koopmans ◽  
Lawrence Mandarino ◽  
Ralph A. Defronzo
Keyword(s):  
Insulin Action ◽  
Time Course ◽  
Hepatic Glucose Production ◽  
Glycogen Synthesis ◽  
Glucose Production ◽  
Liver Glycogen ◽  
Whole Body ◽  
Glucose Disposal ◽  
Muscle Glycogen Synthesis ◽  
The Face

We investigated the time course of insulin action in conscious rats exposed to constant physiological hyperinsulinemia (∼100 mU/l) while maintaining euglycemia (∼100 mg/dl) for 0, 0.5, 2, 4, 8, or 12 h. [3-3H]glucose was infused to quantitate whole body glucose disposal (rate of disappearance, Rd), glycolysis (generation of3H2O in plasma), hepatic glucose production (HGP), and skeletal muscle and liver glycogen synthesis ([3-3H]glucose incorporation into glycogen and time-dependent change in tissue glycogen concentration). The basal Rd, which equals HGP, was 6.0 ± 0.3 mg ⋅ kg−1 ⋅ min−1. With increased duration of hyperinsulinemia from 0 to 0.5 to 2 to 4 h, Rd increased from 6.0 ± 0.3 to 21.0 ± 1.1 to 24.1 ± 1.5 to 26.6 ± 0.6 mg ⋅ kg−1 ⋅ min−1( P < 0.05 for 2 and 4 h vs. 0.5 h). During the first 2 h the increase in Rd was explained by parallel increases in glycolysis and glycogen synthesis. From 2 to 4 h the further increase in Rd was entirely due to an increase in glycolysis without change in glycogen synthesis. From 4 to 8 to 12 h of hyperinsulinemia, Rd decreased by 19% from 26.6 ± 0.6 to 24.1 ± 1.1 to 21.6 ± 1.8 mg ⋅ kg−1 ⋅ min−1( P < 0.05 for 8 h vs. 4 h and 12 h vs. 8 h). The progressive decline in Rd, in the face of constant hyperinsulinemia, occurred despite a slight increase (8–14%) in glycolysis and was completely explained by a marked decrease (64%) in muscle glycogen synthesis. In contrast, liver glycogen synthesis increased fourfold, indicating an independent regulation of muscle and liver glycogen synthesis by long-term hyperinsulinemia. In the liver, during the entire 12-h period of insulin stimulation, the contribution of the direct (from glucose) and the indirect (from C-3 fragments) pathways to net glycogen formation remained constant at 77 ± 5 and 23 ± 5%, respectively. HGP remained suppressed throughout the 12-h period of hyperinsulinemia.

scholarly journals Effects in vivo of food deprivation and 3-mercaptopicolinate in the glycogen-storage-disease (gsd/gsd) rat

1985 ◽  
Vol 231 (3) ◽  
pp. 755-759 ◽  
Author(s):  
D G Clark ◽  
M Brinkman ◽  
S D Neville ◽  
W D Haynes
Keyword(s):  
Blood Glucose ◽  
Food Deprivation ◽  
Intraperitoneal Injection ◽  
Storage Disease ◽  
Liver Glycogen ◽  
Glycogen Storage ◽  
Hepatic Glycogen ◽  
Glycogen Stores ◽  
Female Control

Intraperitoneal injection of 3-mercaptopicolinate into 24 h-food-deprived 27-week-old female control (GSD/GSD) rats lowered the concentration of circulating glucose by 66%, but glycerol and lactate concentrations were increased up to 3- and 4-fold respectively. In phosphorylase b kinase-deficient (gsd/gsd) rats the corresponding changes for blood glucose, lactate and glycerol were half those observed in the controls. Although the concentration of liver glycogen (approx. 12%, w/w) in the gsd/gsd rats was not altered during food deprivation, total hepatic glycogen was decreased by 17%. It is suggested that the gradual breakdown of the extensive hepatic glycogen stores during starvation assists in the maintenance of normoglycaemia in the gsd/gsd rat.

scholarly journals Metabolism of glucose in hyper- and hypo-thyroid rats in vivo. Glucose-turnover values and futile-cycle activities obtained with 14C- and 3H-labelled glucose

1979 ◽  
Vol 182 (2) ◽  
pp. 565-575 ◽  
Author(s):  
F Okajima ◽  
M Ui
Keyword(s):  
Blood Glucose ◽  
Specific Radioactivity ◽  
Glucose Production ◽  
Liver Glycogen ◽  
Glucose Turnover ◽  
Futile Cycle ◽  
Futile Cycles ◽  
The Difference ◽  
Glucose Recycling

1. A trace amount of glucose labelled with 14C uniformly and with 3H at position 2, 3 or 6 was injected intravenously into starved rats to measure the turnover rate of blood glucose. 2. Reliable estimates were made based on the semilogarithmic plot of specific radioactivity of the glucose contained in whole blood samples taken from the tail vein. 3. Glucose turned over more rapidly in hyperthyroid and more slowly in hypothyroid than in euthyroid rats. The percentage contribution of glucose recycling (determined from the difference in replacement rates between [U-14C]glucose and [6-3H]glucose) to the glucose utilization increased on induction of hyperthyroidism. 4. Futile cycles between glucose and glucose 6-phosphate (determined from the difference between replacement rates of [2-3H]glucose and [6-3H]glucose) were activated and inactivated by induction of hyperthyroid and hypothyroid states respectively. 5. The hepatic content of glycogen was much lower in hyper- and hypo-thyroid than in euthyroid rats. The enhanced glucose production in hyperthyroid rats resulted from not only activationof hepatic gluconeogenesis but also diversion of the final product of gluconeogenesis from liver glycogen to blood glucose. In hypothyroidism, the inhibition of gluconeogensis led to suppression of both glucose production and glycogenesis in the liver.

Supplementation of a propionate-producing consortium improves markers of insulin resistance in an in vitro model of gut-liver axis

2020 ◽  
Vol 318 (5) ◽  
pp. E742-E749 ◽  
Author(s):  
Racha El Hage ◽  
Emma Hernandez-Sanabria ◽  
Marta Calatayud Arroyo ◽  
Tom Van de Wiele
Keyword(s):  
Insulin Resistance ◽  
Cross Talk ◽  
Energy Homeostasis ◽  
Metabolic Diseases ◽  
Glycogen Synthesis ◽  
Short Chain Fatty Acids ◽  
Glycogen Storage ◽  
Cellular Level ◽  
Low Grade

Gut-liver cross talk is an important determinant of human health with profound effects on energy homeostasis. While gut microbes produce a huge range of metabolites, specific compounds such as short-chain fatty acids (SCFAs) can enter the portal circulation and reach the liver (Brandl K, Schnabl B. Curr Opin Gastroenterol 33: 128–133, 2017), a central organ involved in glucose homeostasis and diabetes control. Propionate is a major SCFA involved in activation of intestinal gluconeogenesis (IGN), thereby regulating food intake, enhancing insulin sensitivity, and leading to metabolic homeostasis. Although microbiome-modulating strategies may target the increased microbial production of propionate, it is not clear whether such an effect spreads through to the hepatic cellular level. Here, we designed a propionate-producing consortium using a selection of commensal gut bacteria, and we investigated how their delivered metabolites impact an in vitro enterohepatic model of insulin resistance. Glycogen storage on hepatocyte-like cells and inflammatory markers associated with insulin resistance were evaluated to understand the role of gut metabolites on gut-liver cross talk in a simulated scenario of insulin resistance. The metabolites produced by our consortium increased glycogen synthesis by ~57% and decreased proinflammatory markers such as IL-8 by 12%, thus elucidating the positive effect of our consortium on metabolic function and low-grade inflammation. Our results suggest that microbiota-derived products can be a promising multipurpose strategy to modulate energy homeostasis, with the potential ability to assist in managing metabolic diseases due to their adaptability.

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