Light regulation of glucose metabolism.

Central nervous system (CNS) insulin signaling is involved in a broad array of cardiometabolic physiology, including glucose and lipid metabolism, feeding, energy expenditure, and blood pressure regulation. A key role for hypothalamic neuroendocrine and autonomic centers in regulating insulin-associated cardiovascular and metabolic physiology has been highlighted. However, it is still unclear which CNS site(s) initiate insulin-dependent neural cascades. While some investigations have suggested that circulating insulin can access hypothalamic regions by crossing the blood-brain barrier, other studies point to a necessity of other brain areas upstream of the hypothalamus to initiate central insulin actions. In this context, accumulating evidence points to a possible involvement of the sensory circumventricular organs (CVOs), unique areas located outside of the blood-brain barrier, in insulin-dependent cardiometabolic homeostasis. Here, the multifaceted roles for the sensory CVOs in cardiovascular and metabolic regulation, with a special emphasis on insulin receptor pathways, are discussed.

Bile acids (BAs) are amphipathic molecules synthetized in the liver. They are primarily involved in the digestion of nutrients. Apart from their role in dietary lipid absorption, BAs have progressively emerged as key regulators of systemic metabolism and inflammation. In the last decade, it became evident that BAs are particularly important for the regulation of glucose, lipid, and energy metabolism. Indeed, the interest in role of BA in metabolism homeostasis is further increased due to the global public health increase in obesity and related complications and a large number of research postulating that there is a close mutual relationship between BA and metabolic disorders. This strong relationship seems to derive from the role of BAs as signaling molecules involved in the regulation of a wide spectrum of metabolic pathways. These actions are mediated by different receptors, particularly nuclear farnesoid X receptor (FXR) and Takeda G protein coupled receptor 5 (TGR5), which are probably the major effectors of BA actions. These receptors activate transcriptional networks and signaling cascades controlling the expression and activity of genes involved in BA, lipid and carbohydrate metabolism, energy expenditure, and inflammation. The large correlation between BAs and metabolic disorders offers the possibility that modulation of BAs could be used as a therapeutic approach for the treatment of metabolic diseases, including obesity itself. The aim of this review is to describe the main physiological and metabolic actions of BA, focusing on its signaling pathways, which are important in the regulation of metabolism and might provide new BA -based treatments for metabolic diseases.

Emerging research underscores the pivotal role of adipose tissue in regulating systemic aging processes, particularly when viewed through the lens of the endocrine hypotheses of aging. This study delves into the unique adipose characteristics in an important animal model of aging - the long-lived Ames dwarf (df/df) mice. Characterized by a Prop1df gene mutation, these mice exhibit a deficiency in growth hormone (GH), prolactin, and TSH, alongside extremely low circulating IGF-1 levels. Intriguingly, while surgical removal of visceral fat (VFR) enhances insulin sensitivity in normal mice, it paradoxically increases insulin resistance in Ames dwarfs. This suggests an altered profile of factors produced in visceral fat in the absence of GH, indicating a unique interplay between adipose tissue function and hormonal influences in these models. Our aim was to analyze the gene expression related to lipid and glucose metabolism, insulin pathways, inflammation, thermoregulation, mitochondrial biogenesis, and epigenetic regulation in the visceral (perirenal and epididymal) adipose tissue of Ames dwarf and normal mice. Our findings reveal an upregulation in the expression of key genes such as Lpl, Adrβ3, Rstn, Foxo1, Foxo3a, Irs1, Cfd, Aldh2, Il6, Tnfα, Pgc1α, Ucp2, and Ezh2 in perirenal and Akt1, Foxo3a, PI3k, Ir, Acly, Il6, Ring1a, and Ring 1b in epididymal fat in df/df mice. These results suggest that the longevity phenotype in Ames dwarfs, which is determined by peripubertal GH/IGF-1 levels, may also involve epigenetic reprogramming of adipose tissue influenced by hormonal changes. The increased expression of genes involved in metabolic regulation, tumor suppression, mitochondrial biogenesis, and insulin pathways in Ames dwarf mice highlights potentially beneficial aspects of this model, opening new avenues for understanding the molecular underpinnings of longevity and aging.

Prostate cancer (PCa) malignant progression is accompanied with the reprogramming of glucose metabolism. However, the genes involved in the regulation of glucose metabolism in PCa are not fully understood. Here, we propose a new method, DMRG, which constructs a weighted differential network (W-K-DN) to define the important metabolism-related genes. Based on biological knowledge and prostate cancer transcriptome data, a tripartite motif-containing 25 (TRIM25) was defined using DMRG; TRIM25 was involved in the regulation of glucose metabolism, which was verified by overexpressing or knocking down TRIM25 in PCa cell lines. Differential expression analysis of TCA cycle enzymes revealed that TRIM25 regulated isocitrate dehydrogenase 1 (IDH1) and fumarate hydratase (FH) expression. Moreover, a protein–RNA interaction network of TRIM25 revealed that TRIM25 interacted with RNA-binding proteins, including DExH-box helicase 9 and DEAD-box helicase 5, to play a role in regulating the RNA processing of metabolic enzymes, including IDH1 and FH. Furthermore, TRIM25 expression level was found to be positively correlated with Gleason scores in PCa patient tissues. In conclusion, this study provides a new method to define genes influencing tumor progression, and sheds light on the role of the defined TRIM25 in regulating glucose metabolism and promoting PCa malignancy.

Multiple signals have been shown to be involved in regulation of fatty acid (FA) and glucose metabolism in contracting skeletal muscle. This study aimed to determine whether a Ca(2+)-stimulated kinase, CaMKK, is involved in regulation of contraction-induced substrate metabolism and whether it does so in an AMP-activated protein kinase (AMPK)-dependent manner. Rat hindlimbs were perfused at rest (n = 16), with 3 mM caffeine (n = 15), with 2 mM 5-aminoimidazole-4-carboxamide 1-beta-d-ribofuranoside (AICAR; n = 16), or during moderate-intensity muscle contraction (MC; n = 14) and with or without 5 microM STO-609, a CaMKK inhibitor. FA uptake and oxidation increased (P < 0.05) 64% and 71% by caffeine, 42% and 93% by AICAR, and 65% and 143% by MC. STO-609 abolished (P < 0.05) caffeine- and MC-induced FA uptake and oxidation but had no effect with AICAR treatment. Glucose uptake increased (P < 0.05) 104% by caffeine, 85% by AICAR, and 130% by MC, and STO-609 prevented the increase in glucose uptake in caffeine and muscle contraction groups. CaMKKbeta activity increased (P < 0.05) 113% by caffeine treatment and 145% by MC but was not affected by AICAR treatment. STO-609 prevented the caffeine- and MC-induced increase in CaMKKbeta activity. Caffeine, AICAR, and MC increased (P < 0.05) AMPKalpha2 activity by 295%, 11-fold, and 7-fold but did not affect AMPKalpha1 activity. STO-609 decreased (P < 0.05) AMPKalpha2 activity induced by caffeine treatment and MC by 60% and 61% but did not affect AICAR-induced activity. Plasma membrane transport protein content of CD36 and glucose transporter 4 (GLUT4) increased (P < 0.05) with caffeine, AICAR, and MC, and STO-609 prevented caffeine- and MC-induced increases in protein content. These results show the importance of Ca(2+)-dependent signaling via CaMKK activation in the regulation of substrate uptake and FA oxidation in contracting rat skeletal muscle and agree with the notion that CaMKK is an upstream kinase of AMPK in the regulation of substrate metabolism in skeletal muscle.

&lt;div&gt;Abstract&lt;p&gt;Wnt signaling plays a critical role in embryonic development, and its deregulation is closely linked to the occurrence of a number of malignant tumors, including breast and colon cancer. The pathway also induces Snail-dependent epithelial-to-mesenchymal transition (EMT), which is responsible for tumor invasion and metastasis. In this study, we show that Wnt suppresses mitochondrial respiration and cytochrome C oxidase (COX) activity by inhibiting the expression of 3 COX subunits, namely, COXVIc, COXVIIa, and COXVIIc. We found that Wnt induced a glycolytic switch via increased glucose consumption and lactate production, with induction of pyruvate carboxylase (PC), a key enzyme of anaplerosis. In addition, Wnt-induced mitochondrial repression and glycolytic switching occurred through the canonical β-catenin/T-cell factor 4/Snail pathway. Short hairpin RNA–mediated knockdown of E-cadherin, a regulator of EMT, repressed mitochondrial respiration and induced a glycolytic switch via Snail activation, indicating that EMT may contribute to Wnt/Snail regulation of mitochondrial respiration and glucose metabolism. Together, our findings provide a new function for Wnt/Snail signaling in the regulation of mitochondrial respiration (via COX gene expression) and glucose metabolism (via PC gene expression) in tumor growth and progression. &lt;i&gt;Cancer Res; 72(14); 3607–17. ©2012 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;

&lt;div&gt;Abstract&lt;p&gt;Wnt signaling plays a critical role in embryonic development, and its deregulation is closely linked to the occurrence of a number of malignant tumors, including breast and colon cancer. The pathway also induces Snail-dependent epithelial-to-mesenchymal transition (EMT), which is responsible for tumor invasion and metastasis. In this study, we show that Wnt suppresses mitochondrial respiration and cytochrome C oxidase (COX) activity by inhibiting the expression of 3 COX subunits, namely, COXVIc, COXVIIa, and COXVIIc. We found that Wnt induced a glycolytic switch via increased glucose consumption and lactate production, with induction of pyruvate carboxylase (PC), a key enzyme of anaplerosis. In addition, Wnt-induced mitochondrial repression and glycolytic switching occurred through the canonical β-catenin/T-cell factor 4/Snail pathway. Short hairpin RNA–mediated knockdown of E-cadherin, a regulator of EMT, repressed mitochondrial respiration and induced a glycolytic switch via Snail activation, indicating that EMT may contribute to Wnt/Snail regulation of mitochondrial respiration and glucose metabolism. Together, our findings provide a new function for Wnt/Snail signaling in the regulation of mitochondrial respiration (via COX gene expression) and glucose metabolism (via PC gene expression) in tumor growth and progression. &lt;i&gt;Cancer Res; 72(14); 3607–17. ©2012 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;

Branched chain amino acids and metabolic regulation

The tight regulation of glucose and lipid metabolism is crucial for maintaining metabolic health. Dysregulation of these processes can lead to the development of metabolic diseases. Secreted factors, or hormones, play an essential role in the regulation of glucose and lipid metabolism, thus also playing an important role in the development of metabolic diseases such as type 2 diabetes and obesity. Given the important roles of secreted factors, there has been significant interest in identifying new secreted factors and new functions for existing secreted factors that control glucose and lipid metabolism. In this review, we evaluate novel secreted factors or novel functions of existing factors that regulate glucose and lipid metabolism discovered in the last decade, including secreted isoform of endoplasmic reticulum membrane complex subunit 10, vimentin, cartilage intermediate layer protein 2, isthmin-1, lipocalin-2, neuregulin-1 and neuregulin-4. We discuss their discovery, tissues of origin, mechanisms of action and sex differences, emphasising their potential to regulate metabolic processes central to diabetes. Additionally, we discuss the translational barriers, particularly the absence of identified receptors, that hamper their functional characterisation and further therapeutic development. Ultimately, the identification of new secreted factors may give insights into previously unidentified pathways of disease progression and mechanisms of glucose and lipid homeostasis.

Conference Article| May 01 1995 Regulation of glucose metabolism in cardiac muscle L. Hue; L. Hue * 1Hormone and Metabolic Research Unit, International Institute of Cellular and Molecular Pathology, and Louvain University Medical School, avenue Hippocrate 75, B-1200 Brussels, Belgium *To whom correspondence should be addressed. Search for other works by this author on: This Site PubMed Google Scholar C. Depre; C. Depre 1Hormone and Metabolic Research Unit, International Institute of Cellular and Molecular Pathology, and Louvain University Medical School, avenue Hippocrate 75, B-1200 Brussels, Belgium Search for other works by this author on: This Site PubMed Google Scholar V. Lefebvre; V. Lefebvre 1Hormone and Metabolic Research Unit, International Institute of Cellular and Molecular Pathology, and Louvain University Medical School, avenue Hippocrate 75, B-1200 Brussels, Belgium Search for other works by this author on: This Site PubMed Google Scholar M. H. Rider; M. H. Rider 1Hormone and Metabolic Research Unit, International Institute of Cellular and Molecular Pathology, and Louvain University Medical School, avenue Hippocrate 75, B-1200 Brussels, Belgium Search for other works by this author on: This Site PubMed Google Scholar K. Veitch K. Veitch 1Hormone and Metabolic Research Unit, International Institute of Cellular and Molecular Pathology, and Louvain University Medical School, avenue Hippocrate 75, B-1200 Brussels, Belgium Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (1995) 23 (2): 311–314. https://doi.org/10.1042/bst0230311 Article history Received: December 16 1994 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Citation L. Hue, C. Depre, V. Lefebvre, M. H. Rider, K. Veitch; Regulation of glucose metabolism in cardiac muscle. Biochem Soc Trans 1 May 1995; 23 (2): 311–314. doi: https://doi.org/10.1042/bst0230311 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search Keywords: Ca/CAMK, calcium- and calmodulin-dependent protein kinase, FBPase-2, fructose-2,6-bisphosphatase, Fru-2,6-P2, fructose 2,6-bisphosphate, NO, nitric oxide, PFK-1, 6-phosphofructo-1-kinase, PFK-2, 6-phosphofructo-2-kinase, PKA, cyclic AMP-dependent protein kinase, PI-3-kinase, phosphatidylinositol-3-kinase This content is only available as a PDF. © 1995 Biochemical Society1995 Article PDF first page preview Close Modal You do not currently have access to this content.

Metabolic disorders are major global health concerns with increasing prevalence worldwide. Experimental evidence suggests the role of tachykinins and their receptors in metabolic regulation, neuroendocrine control, and inflammatory responses. This review aims to explore the implications of tachykinin receptors and their antagonists in the management of metabolic disorders. A comprehensive literature search was performed across major scientific databases to identify and analyze preclinical and clinical studies on tachykinin receptors and their antagonists in the context of metabolic disorders. The key mechanisms of action of drugs, important therapeutic outcomes, and challenges associated with drug development were covered. The reported experimental and clinical studies suggest that the antagonists of NK1R, NK2R, and NK3R could influence glucose metabolism, lipid homeostasis, and appetite regulation. While NK1R antagonists, such as aprepitant, demonstrated anti-inflammatory and neuroprotective effects, NK3R antagonists, including fezolinetant, showed promise in modulating energy balance and thermoregulation. These studies emphasized the emerging potential of tachykinin receptors and their antagonists in the management of metabolic dysfunctions. However, the challenges associated with its clinical translation, including receptor redundancy, limited biomarker-based patient stratification, and variations in receptor expression across species, are still relevant and need to be addressed to improve therapeutic outcomes. Tachykinin receptor antagonists hold significant potential as therapeutic agents in the management of metabolic disorders. Further studies are warranted to overcome translational barriers, address safety issues, validate biomarkers, and refine receptor selectivity to achieve maximum therapeutic benefits.

BackgroundAmino acids have been reported to act as modulators of various regulatory processes and to provide new therapeutic applications for either the prevention or treatment of metabolic disorders. The purpose of the present study is to investigate the effects of single oral dose administration and a continuous treatment of L-tryptophan (L-Trp) on the regulation of blood pressure and glucose metabolism in stroke-prone spontaneously hypertensive rats (SHRSP).MethodsFirst, male 9-week-old SHRSP were administered 100 mg L-Trp·kg-1 body weight in saline to the L-Trp group and 0.9% saline to the control group via a gastric tube as a single oral dose of L-Trp. Second, three groups of SHRSP were fed an AIN-93M-based diet supplemented with L-tryptophan (L-Trp) (0, 200, or 1000 mg·kg-1 diet) for 3 weeks as continuous treatment of L-Trp.ResultsSingle oral dose administration of L-Trp improved blood pressure, blood glucose, and insulin levels. Blood pressure, blood glucose, and insulin levels improved significantly in the L-Trp treatment groups. The administration of L-Trp also significantly increased plasma nitric oxide and serotonin levels.ConclusionL-Trp by both single oral dose administration and continuous treatment improves glucose metabolism and blood pressure in SHRSP.

Increased levels of neuropeptide Y have been reported in transthyretin-null mice. This effect might be related to transthyretin ligands (retinol and thyroxine) since, through binding to nuclear receptors, they modulate the expression of genes that control cellular metabolism. The retinoic X receptors form obligatory heterodimers with peroxisome proliferator-activated receptors and liver X receptors - potent regulators of fat, glucose and cholesterol homeostasis. We used transthyretin-null mice to investigate whether the absence of transthyretin influences metabolism. Transthyretin-null mice do not differ from controls in body weight and white adipose tissue morphology, nor in basal or fast-induced circulating levels of glucose, lipids, and leptin. Glucose tolerance tests show that transthyretin-null mice have normal capacity to remove and metabolize energy substrates. Expression of genes encoding lipid transporters and nuclear receptors are also similar in transthyretin-null and control mice. Therefore, the absence of transthyretin does not seem to influence the regulation of lipid and glucose metabolism.

A crucial aspect of carcinogenesis is the adaptation of cells to the changing environmental conditions of the tumor mass. To grow and proliferate, the cells need nutrients that have to be delivered by surrounding vessels. In addition, they have to cope with a gradient of oxygen tension as the tumor mass grows. Hypoxia inducible factor 1 (HIF-1) mediates important responses to physiologic and pathologic processes that allow angiogenesis, erythropoiesis, cell proliferation and survival, and metabolic changes to take place. It is a heterodimeric transcription factor regulated by a complex network. Among the major metabolic changes evident in cancer cells is the activation of the glycolytic pathway, even in the presence of oxygen. HIF-1 regulates glucose and energy metabolism by directly activating the gene expression of glycolytic enzymes, regulatory enzymes, and glucose transporters. HIF-1α (the regulated subunit of the HIF-1 complex) is regulated mainly at the posttranscriptional level through mechanisms that block its proteasomal degradation depending on the oxygen concentration. HIF-1 is overexpressed in many tumors, and evidence is mounting that HIF-1 regulation of glucose and energy metabolism is important in carcinogenesis and tumor progression.

The metabolic syndrome has become one of the major public health challenges in the world, and adjusting glucose and lipid levels to their normal values is crucial for treating the metabolic syndrome. Olfactory receptors (ORs) expressed in extra-nasal tissues participate in diverse biological processes, including the regulation of glucose and lipid metabolism. Ectopic ORs can regulate a variety of metabolic events including insulin secretion, glucagon secretion, fatty acid oxidation, lipogenesis and thermogenesis. Understanding the physiological function and deciphering the olfactory recognition code by suitable ligands make ectopic ORs potential targets for the treatment of the metabolic syndrome. In this review, we delineate the roles and mechanisms of ectopic ORs in the regulation of glucose and lipid metabolism, summarize the corresponding natural ligands, and discuss existing problems and the therapeutic potential of targeting ORs in the metabolic syndrome.