scholarly journals Differentiating external zeitgeber impact on peripheral circadian clock resetting

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Isabel Heyde ◽  
Henrik Oster
Keyword(s):  
Energy Metabolism ◽  
Metabolic Disorders ◽  
Circadian Clocks ◽  
Metabolic Homeostasis ◽  
Experimental Paradigm ◽  
Dark Cycle ◽  
Clock System ◽  
Specific Tissue ◽  
Hierarchical Manner

AbstractCircadian clocks regulate physiological functions, including energy metabolism, along the 24-hour day cycle. The mammalian clock system is organized in a hierarchical manner with a coordinating pacemaker residing in the hypothalamic suprachiasmatic nucleus (SCN). The SCN clock is reset primarily by the external light-dark cycle while other zeitgebers such as the timing of food intake are potent synchronizers of many peripheral tissue clocks. Under conflicting zeitgeber conditions, e.g. during shift work, phase synchrony across the clock network is disrupted promoting the development of metabolic disorders. We established a zeitgeber desynchrony (ZD) paradigm to quantify the differential contributions of the two main zeitgebers, light and food, to the resetting of specific tissue clocks and the effect on metabolic homeostasis in mice. Under 28-hour light-dark and 24-hour feeding-fasting conditions SCN and peripheral clock, as well as activity and hormonal rhythms showed specific periodicities aligning in-between those of the two zeitgebers. During ZD, metabolic homeostasis was cyclic with mice gaining weight under synchronous and losing weight under conflicting zeitgeber conditions. In summary, our study establishes an experimental paradigm to compare zeitgeber input in vivo and study the physiological consequences of chronodisruption.

scholarly journals Melatonin Adjusts the Phase of Mouse Circadian Clocks in the Cornea Both Ex Vivo and In Vivo

2021 ◽  
pp. 074873042110323
Author(s):  
Alex V. Huynh ◽  
Ethan D. Buhr
Keyword(s):  
Mammalian Cells ◽  
Ex Vivo ◽  
Circadian Clocks ◽  
Constant Darkness ◽  
Environmental Cues ◽  
Dark Cycle ◽  
Environmental Light ◽  
Advanced Phase ◽  
Different Tissues

The presence of an endogenous circadian clock within most mammalian cells is associated with the amazing observation that within a given tissue, these clocks are largely in synchrony with each other. Different tissues use a variety of systemic or environmental cues to precisely coordinate the phase of these clocks. The cornea is a unique tissue in that it is largely isolated from the direct blood supply that most tissues experience, it is transparent to visible light, and it is exposed directly to environmental light and temperature. Melatonin is a hormone that has been implicated in regulation of the cornea’s circadian clocks. Here, we analyze the ability of rhythmic melatonin to entrain corneas ex vivo, and analyze the phase of corneal circadian clocks in vivo both in light: dark cycles and in constant darkness. We find that the presence of a retina from a melatonin-proficient mouse strain, C3Sn, can photoentrain the circadian clocks of a co-cultured mouse cornea, but a retina from a melatonin-deficient strain, C57Bl/6, cannot. Furthermore, pharmacologic blockade of melatonin or use of a retina with advanced retinal degeneration, Pde6brd1, blocks the photoentraining effect. Corneal circadian clocks in vivo adopt an advanced phase in C3Sn mice compared with C57Bl/6, but the circadian clocks in the liver are unaffected. This observation is not attributable to a shorter endogenous period of the cornea or behavior between the strains. Some transcripts of circadian genes in the corneas of C3Sn mice also show an advanced phase of expression in a light: dark cycle, while the transcript of Per2 exhibits a light-dependent transient induction at the onset of darkness. We conclude that melatonin acts as a phase modifying factor in a rhythmic manner for the circadian clocks of the cornea.

scholarly journals PPAR-gamma Signaling in Metabolic Homeostasis

2016 ◽  
Vol 8 (3) ◽  
pp. 147
Author(s):  
Rina Triana ◽  
Nurrani Mustika Dewi ◽  
Siska Darmayanti ◽  
Eka Herawati ◽  
Maria Novalentina ◽  
...  
Keyword(s):  
Metabolic Disorders ◽  
Gastrointestinal Disease ◽  
Expression Profiles ◽  
Ppar Gamma ◽  
Peroxisome Proliferator ◽  
Metabolic Homeostasis ◽  
Ppar Γ ◽  
Natural And Synthetic

BACKGROUND: Peroxisome proliferator-activated receptor (PPAR)-γ, or also known as nuclear receptor subfamily 1 group C member 3 (NR1C3), is a PPAR which serves as master regulator of adipocytes differentiation, and plays an important role in lipid metabolism or adipogenesis. Recent study showed that PPAR-γ is expressed in most tissue and also has critical impact in many metabolic homeostasis disorders.CONTENT: Dysregulation of PPAR-γ is correlated to the development of obesity, type 2 diabetes, atherosclerosis, cardiovascular disease, acute kidney injury, autoimmune disease, gastrointestinal disease and Alzheimer’s disease. Abundant number of new emerging compounds, with in vitro and in vivo effectiveness as natural and synthetic agonists of PPARs, are investigated, developed and used as the treatment of metabolic disorders of glucose and/or lipid and other diseases.SUMMARY: Based on all studies explanation, targeting PPAR-γ is proven to be a good therapeutic method for reducing negative effect of several metabolic homeostasis disorder. Now, many natural and synthetic agonists of PPARs are used as the treatment of metabolic disorders of glucose and/or lipid or another metabolic homeostasis disorder. Such agonists have different properties and specificities for individual PPARs receptors, different absorption and distribution, and distinctive gene expression profiles, which ultimately lead to different clinical outcomes.KEYWORDS: PPAR-γ, dysregulation, agonist, adipogenesis, metabolic disorder, homeostasis

Different in vivo metabolic activities of suprachiasmatic nuclei of Turkish and golden hamsters

1990 ◽  
Vol 259 (5) ◽  
pp. R1083-R1085 ◽  
Author(s):  
W. J. Schwartz
Keyword(s):  
Energy Metabolism ◽  
Glucose Utilization ◽  
High Energy ◽  
Circadian Pacemaker ◽  
Suprachiasmatic Nuclei ◽  
Light Phase ◽  
Dark Cycle ◽  
Golden Hamsters ◽  
Metabolic Activities

The 14C-labeled 2-deoxy-D-glucose technique was used to measure in vivo glucose utilization of the suprachiasmatic nuclei (SCN) of Turkish and golden hamsters during the middle hours of the light phase of the 12:12 h light-dark cycle. The nuclei were clearly visible on autoradiographs made from the brains of Turkish hamsters, and their rate of glucose utilization (69 +/- 6 mumol.100 g-1.min-1) was similar to that previously measured in other rodents, whereas the nuclei were hardly visible on autoradiographs from golden hamsters, and their rate (33 +/- 2 mumol.100 g-1.min-1) was less than half this value. Thus the high energy metabolism characteristic of the SCN of most species is not required for the circadian pacemaker in the nuclei to generate its oscillation.

scholarly journals Oxyntomodulin regulates resetting of the liver circadian clock by food

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Dominic Landgraf ◽  
Anthony H Tsang ◽  
Alexei Leliavski ◽  
Christiane E Koch ◽  
Johanna L Barclay ◽  
...  
Keyword(s):  
Circadian Rhythm ◽  
Food Intake ◽  
Metabolic Disorders ◽  
Clock Genes ◽  
Circadian Clocks ◽  
Direct Link ◽  
Dark Cycle ◽  
The Core ◽  
Peripheral Clocks ◽  
Master Clock

Circadian clocks coordinate 24-hr rhythms of behavior and physiology. In mammals, a master clock residing in the suprachiasmatic nucleus (SCN) is reset by the light–dark cycle, while timed food intake is a potent synchronizer of peripheral clocks such as the liver. Alterations in food intake rhythms can uncouple peripheral clocks from the SCN, resulting in internal desynchrony, which promotes obesity and metabolic disorders. Pancreas-derived hormones such as insulin and glucagon have been implicated in signaling mealtime to peripheral clocks. In this study, we identify a novel, more direct pathway of food-driven liver clock resetting involving oxyntomodulin (OXM). In mice, food intake stimulates OXM secretion from the gut, which resets liver transcription rhythms via induction of the core clock genes Per1 and 2. Inhibition of OXM signaling blocks food-mediated resetting of hepatocyte clocks. These data reveal a direct link between gastric filling with food and circadian rhythm phasing in metabolic tissues.

scholarly journals Contributions of white and brown adipose tissues to the circadian regulation of energy metabolism

Endocrinology ◽  
2021 ◽  
Vol 162 (3) ◽  
Author(s):  
Isabel Heyde ◽  
Kimberly Begemann ◽  
Henrik Oster
Keyword(s):  
Adipose Tissue ◽  
Energy Metabolism ◽  
Energy Homeostasis ◽  
Energy Levels ◽  
High Energy ◽  
Circadian Clocks ◽  
Circadian Regulation ◽  
Metabolic Homeostasis ◽  
Brown Adipose ◽  
Releasing Factors

Abstract The term energy metabolism comprises the entirety of chemical processes associated with uptake, conversion, storage, and breakdown of nutrients. All these must be tightly regulated in time and space to ensure metabolic homeostasis in an environment characterized by cycles such as the succession of day and night. Most organisms evolved endogenous circadian clocks to achieve this goal. In mammals, a ubiquitous network of cellular clocks is coordinated by a pacemaker residing in the hypothalamic suprachiasmatic nucleus. Adipocytes harbor their own circadian clocks, and large aspects of adipose physiology are regulated in a circadian manner through transcriptional regulation of clock-controlled genes. White adipose tissue (WAT) stores energy in the form of triglycerides at times of high energy levels that then serve as fuel in times of need. It also functions as an endocrine organ, releasing factors in a circadian manner to regulate food intake and energy turnover in other tissues. Brown adipose tissue (BAT) produces heat through nonshivering thermogenesis, a process also controlled by the circadian clock. We here review how WAT and BAT contribute to the circadian regulation of energy metabolism. We describe how adipose rhythms are regulated by the interplay of systemic signals and local clocks and summarize how adipose-originating circadian factors feed-back on metabolic homeostasis. The role of adipose tissue in the circadian control of metabolism becomes increasingly clear as circadian disruption leads to alterations in adipose tissue regulation, promoting obesity and its sequelae. Stabilizing adipose tissue rhythms, in turn, may help to combat disrupted energy homeostasis and obesity.

Mitochondrial matrix calcium ions regulate energy production in myocardium: A cytochemical study

1990 ◽  
Vol 48 (2) ◽  
pp. 166-167
Author(s):  
W.A. Jacob ◽  
R. Hertsens ◽  
A. Van Bogaert ◽  
M. De Smet
Keyword(s):  
Energy Metabolism ◽  
Calcium Ions ◽  
Energy Production ◽  
Regulation Of Respiration ◽  
Free Calcium ◽  
Mitochondrial Matrix ◽  
Cytochemical Study ◽  
Nmr Techniques

In the past most studies of the control of energy metabolism focus on the role of the phosphorylation potential ATP/ADP.Pi on the regulation of respiration. Studies using NMR techniques have demonstrated that the concentrations of these compounds for oxidation phosphorylation do not change appreciably throughout the cardiac cycle and during increases in cardiac work. Hence regulation of energy production by calcium ions, present in the mitochondrial matrix, has been the object of a number of recent studies.Three exclusively intramitochondnal dehydrogenases are key enzymes for the regulation of oxidative metabolism. They are activated by calcium ions in the low micromolar range. Since, however, earlier estimates of the intramitochondnal calcium, based on equilibrium thermodynamic considerations, were in the millimolar range, a physiological correlation was not evident. The introduction of calcium-sensitive probes fura-2 and indo-1 made monitoring of free calcium during changing energy metabolism possible. These studies were performed on isolated mitochondria and extrapolation to the in vivo situation is more or less speculative.

734 A novel NQO1 specific anti-tumor agent, SBSC-S3001, selectively regresses the growth of tumors with high NQO1 expression

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A778-A778
Author(s):  
Minhyuk Yun ◽  
Goo-Young Kim ◽  
Sang Woo Jo ◽  
Changhoon In ◽  
Gyu-Young Moon ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Cancer Cells ◽  
Poor Prognosis ◽  
High Expression ◽  
List Type ◽  
Dependent Manner ◽  
Breast Cancers ◽  
Quinone Oxidoreductase ◽  
Key Enzymes

BackgroundNAD(P)H-quinone oxidoreductase 1 (NQO1) is a cytosolic two-electron oxidoreductase overexpressed in many types of cancers, including breast cancer, pancreatic cancer, colorectal cancer, cholangiocarcinoma, uterine cervical cancer, melanoma, and lung cancer.1Up-regulation of NQO1 protects cells from oxidative stress and various cytotoxic quinones and is associated with late clinical stage, poor prognosis and lymph node metastasis.2 3 NQO1 increases stability of HIF-1α protein, which has been implicated in survival, proliferation, and malignance of cancer.1 Therefore, accumulating evidences suggest NQO1 as a promising therapeutic target for cancer. Accordingly, we have characterized the effect of a novel synthetic NQO1 substrate SBSC-S3001, and demonstrated its selective cytotoxic effects in cancer cells with high expression of NQO1.MethodsIn vitro cytotoxicity was determined by sulforhodamine B (SRB) assay in cancer cells with high NQO1 expression and CRISPR-mediated NQO1 knockout cells. The effect of SBSC-S3001 on the energy metabolism pathway was evaluated by western blot analysis of metabolism associated proteins from NQO1-overexpressed cancer cells treated with the compound for 24 hours. In vivo anti-tumor activity was evaluated in MC38 syngeneic and DLD-1 orthotopic mice models.ResultsSBSC-S3001 exhibited selective cytotoxicity in cancer cells with high expression of NQO1 in a dose-dependent manner. The cytotoxicity was observed in both normoxia and hypoxia conditions, correlating with the energy metabolism, mitochondrial biogenesis, and cancer proliferative pathways. Also, stronger cytotoxicity was observed in NQO1-overexpressed cancer cells treated with SBSC-S3001 compared to beta-lapachone and analogue treatment.4 When evaluated in vivo, SBSC-S3001 effectively inhibited the growth of syngeneic and orthotopic tumors when administered as a monotherapy. SBSC-S3001 treatment associated with reduction in key enzymes of the glycolytic pathway (LDHa and GAPDH) and HIF-1α and increase in levels of mitochondrial oxidative phosphorylation (OXPHOS) complex.ConclusionsTreatment of SBSC-S3001, a novel, NQO1-specific substrate reduces HIF-1α and key enzymes associated with glycolysis and suppresses the growth of tumors overexpressing NQO1. Further characterization of SBSC-S3001 as a novel metabolic anti-cancer agent for cancers with NQO1 overexpression is warranted.Ethics ApprovalThe study was approved by Samyang Biopharmaceuticals Institution’s Ethics Board, approval number SYAU2031.ReferencesOh ET, Kim JW, Kim JMet. al., NQO1 inhibits proteasome-mediated degradation of HIF-1α. Nat Commun 2016; 14:13593.Ma, Y. et al. NQO1 overexpression is associated with poor prognosis in squamous cell carcinoma of the uterine cervix. BMC Cancer 2014;14: 414Yang, Y. et al. Clinical implications of high NQO1 expression in breast cancers. J. Exp. Clin. Cancer Res 2014;33:144.Yang Y, Zhou X, Xu M, et al., β-lapachone suppresses tumour progression by inhibiting epithelial-to-mesenchymal transition in NQO1-positive breast cancers. Sci Rep 2017;7:2681.

scholarly journals The Dual Role of Oat Bran Water Extract in Bone Homeostasis Through the Regulation of Osteoclastogenesis and Osteoblast Differentiation

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3119 ◽  
Author(s):  
Shin-Hye Kim ◽  
Kwang-Jin Kim ◽  
Hyeon Kang ◽  
Young-Jin Son ◽  
Sik-Won Choi ◽  
...  
Keyword(s):  
Osteoblast Differentiation ◽  
Metabolic Disorders ◽  
Bone Fractures ◽  
Osteoclast Differentiation ◽  
Water Extract ◽  
In Vivo Model ◽  
Bone Homeostasis ◽  
Number Of Patients ◽  
Oat Bran

The number of patients with bone metabolic disorders including osteoporosis is increasing worldwide. These disorders often facilitate bone fractures, which seriously impact the patient’s quality of life and could lead to further health complications. Bone homeostasis is tightly regulated to balance bone resorption and formation. However, many anti-osteoporotic agents are broadly categorized as either bone forming or anti-resorptive, and their therapeutic use is often limited due to unwanted side effects. Therefore, safe and effective therapeutic agents are needed for osteoporosis. This study aims to clarify the bone protecting effects of oat bran water extract (OBWE) and its mode of action. OBWE inhibited RANKL (receptor activator of nuclear factor-κB ligand)-induced osteoclast differentiation by blocking c-Fos/NFATc1 through the alteration of I-κB. Furthermore, we found that OBWE enhanced BMP-2-stimulated osteoblast differentiation by the induction of Runx2 via Smad signaling molecules. In addition, the anti-osteoporotic activity of OBWE was also evaluated using an in vivo model. OBWE significantly restored ovariectomy-induced bone loss. These in vitro and in vivo results showed that OBWE has the potential to prevent and treat bone metabolic disorders including osteoporosis.

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