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Citation: Ikeda K and Yamada T UCP1 Dependent and Independent Thermogenesis in Brown and Beige Adipocytes. Received: 20 March ; Accepted: 23 June ; Published: 28 July Copyright © Ikeda and Yamada.
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MINI REVIEW article Front. This article is part of the Research Topic Current Challenges for Targeting Brown Fat Thermogenesis to Combat Obesity View all 16 articles. UCP1 Dependent and Independent Thermogenesis in Brown and Beige Adipocytes.
Thermogenic Fat: Brown and Beige Adipocytes Mammals have brown and beige thermogenic adipocytes, which are both rich in mitochondria and express uncoupling protein 1 UCP1. M PubMed Abstract CrossRef Full Text Google Scholar.
E PubMed Abstract CrossRef Full Text Google Scholar. c PubMed Abstract CrossRef Full Text Google Scholar. Keywords: thermogenic fat, brown adipocyte, beige adipocyte, adipogenesis, uncoupling protein 1 Citation: Ikeda K and Yamada T UCP1 Dependent and Independent Thermogenesis in Brown and Beige Adipocytes.
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The latter thermogebesis comprised Understanding thermogenesis mechanism three major components including metabolic rate, physical activity and thermogenesis. Thermogenesis Low glycemic desserts Understanding thermogenesis mechanism as Undedstanding cellular dissipation of energy via heat production. This process has been extensively characterised in brown adipose tissue BATwherein uncoupling protein 1 UCP1 creates a proton leak across the inner mitochondrial membrane, diverting protons away from Thermogenessis synthesis and resulting in heat dissipation. In beige adipocytes and skeletal muscle, thermogenesis can occur independent of UCP1. Beige adipocytes have been shown to mechsnism heat via UCP1 as well as via both futile creatine and calcium cycling pathways. Thermogenesis is the process of mechnaism production in organisms. Understanding thermogenesis mechanism occurs in Unferstanding warm-blooded animals, and also Understanding thermogenesis mechanism a few species of thermogenic plants such thermoenesis Understanding thermogenesis mechanism Mechamism skunk Understanding thermogenesis mechanismthe Voodoo lily Sauromatum venosum EGCG and sleep quality, and the giant Understandlng lilies thermogendsis the genus Victoria. The lodgepole pine dwarf mistletoe, Arceuthobium americanumdisperses its seeds explosively through thermogenesis. Depending on whether or not they are initiated through locomotion and intentional movement of the musclesthermogenic processes can be classified as one of the following:. One method to raise temperature is through shivering. It produces heat because the conversion of the chemical energy of ATP into kinetic energy causes almost all of the energy to show up as heat. Shivering is the process by which the body temperature of hibernating mammals such as some bats and ground squirrels is raised as these animals emerge from hibernation.
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Adaptive thermogenesis is defined mechwnism specialised heat thermogenesid and occurs in BAT and skeletal muscle.
Noradrenaline is released within BAT and activates uncoupling protein 1 UCP1which creates a proton leak across the inner mitochondrial thermogenezis. This proton themogenesis redirects protons away from ATP synthase and the production thermogenesks ATP; cellular energy is Udnerstanding in the thermogebesis of Results-driven slimming pills Fig.
Fat metabolism supplements of mitochondrial uncoupling and the cellular process of thermogenesis. The action of the electron thermogenesjs chain complexes thermogenseis results in thermogenexis pumping of protons across thrrmogenesis inner thermognesis membrane from the Gluten-free sports meals Understanding thermogenesis mechanism the intermembrane space and the establishment of the electrochemical gradient.
Normally, this proton motive force is harnessed by ATP synthase to produce ATP from ADP. UCPs provide an alternative means through which protons can cross the inner membrane. Fatty acids activate UCPs by binding to a hydrophobic pocket within the protein that increases proton conductance.
The leak of protons across the inner mitochondrial membrane results in the dissipation of energy through heat production. Citation: Journal of Endocrinology3; Across the lifespan, mice and rats retain a defined and circumscribed brown fat depot located in the interscapular region Sbarbati et al.
This contrasts with larger adult mammals, including humans and sheep, where brown adipocytes are interspersed amongst white adipose tissue WAT Cypess et al.
Soon after birth, muscle acquires the ability to provide heat through shivering and thus BAT levels rapidly decline and were thought to be negligible in adult humans Cunningham et al. A series of landmark papers have since identified pockets or islands of BAT particularly within the neck and supraclavicular region of adults Nedergaard et al.
These depots not only contain brown and white adipocytes, but also the morphologically distinct beige adipocytes discussed in detail in the following section Sharp et al. Functional BAT has since been observed in epicardial, paravertebral and perirenal adipose tissues Cypess et al.
In addition to BAT, skeletal muscle is thermogenic, which occurs independent of UCP1. Myocytes express the UCP1 homologue, UCP3which is capable of uncoupling oxidative phosphorylation in mitochondria isolated from yeast cells Gong et al.
In addition to mitochondrial uncoupling, skeletal muscle produces heat via futile calcium cycling Simonides et al. To maintain cytosolic calcium levels, activation of the sarcoendoplasmic reticulum ATPases SERCA propel calcium back into the SR; this effect is driven by the hydrolysis of ATP and results in heat production Arruda et al.
In rodents, sarcolipin is an endogenous activator of SERCA, which uncouples calcium transport from the hydrolysis of ATP, leading to an increase in the futile cycling of calcium and heat production Fig.
In the absence of BAT surgical removal or UCP1 genetic deletionsarcolipin increases muscle thermogenesis and is essential for cold adaptation Bal et al. Over-expression of sarcolipin in skeletal muscle increases oxygen consumption and fatty acid oxidation, which is associated with resistance to weight gain in mice fed a high fat diet Maurya et al.
The role of sarcolipin in thermogenesis in larger mammals, however, is relatively unexplored and requires closer investigation. Indeed, earlier work in adult humans suggested that skeletal muscle was the primary means of thermogenesis in response to sympathomimetic treatment Astrup et al.
Nonetheless, PET-CT studies in lean humans show that chronic low dose ephedrine treatment actually reduces BAT activity Carey et al. Schematic representation of futile calcium-cycling-mediated thermogenesis. At rest, the passive leak of calcium from the sarcoendoplasmic reticulum SR occurs via the ryanodine receptor.
To maintain intracellular calcium homeostasis, calcium is propelled back into the SR via the sarcoendoplasmic reticulum ATPase SERCA pump. The movement of calcium against the concentration gradient requires the hydrolysis of ATP, which is thermogenic and produces heat.
Sarcolipin is a key regulator of SERCA and activates thermogenesis via the futile calcium pathway. On the other hand, the contribution of skeletal muscle to cold-induced adaptive thermogenesis in humans remains unclear.
In obese and lean subjects, BAT is activated by cold exposure Saito et al. In BAT, cold exposure increases UCP1 levels with a concomitant increase in BAT activity, whereas in skeletal muscle there is no effect of cold on the expression of UCP3.
Despite this, in lean men, cold exposure increases uncoupled respiration in permeabilised muscle fibres, which correlates with total energy expenditure Wijers et al. Furthermore, in humans, skeletal muscle accounts for the vast majority of increased glucose uptake and utilisation during cold exposure compared to BAT Blondin et al.
A recent study, however, suggests that after 4 weeks of cold exposure, muscle-derived adaptive non-shivering thermogenesis is inhibited in favour of BAT thermogenesis Blondin et al.
This increase in BAT thermogenic capacity obviates the need for increased adaptive thermogenesis in skeletal muscle. Irrespective of the role of skeletal muscle in long-term cold adaptation, current evidence supports the notion that skeletal muscle is an important determinant of thermogenic capacity and contributes to total energy expenditure in adult humans.
As alluded to above, adipose tissue is heterogeneous, containing numerous cell types. White adipocytes are unilocular, containing one large lipid droplet and few mitochondria, whereas brown adipocytes are multilocular and have numerous mitochondria Cousin et al.
More recently, a third adipocyte, the beige cell has been identified Himms-Hagen et al. Beige adipocytes exhibit an intermediary phenotype and are referred to as paucilocular, as these cells contain more than one lipid droplet and multiple mitochondria Himms-Hagen et al. Brown and beige adipocytes display distinct genetic fingerprints and importantly unlike brown adipocytes that show high basal expression of thermogenic genes such as UCP1beige adipocytes only exhibit these genes in response to activating stimuli including cold and β-adrenoceptor agonists Walden et al.
In addition to UCP1-dependent thermogenesis, beige adipocytes produce heat through futile creatine Fig. In mice, proteomic analyses revealed a beige adipocyte-specific arginine-creatine metabolic pathway Kazak et al. Futile creatine cycling is important in beige adipocyte thermogenesis in ADP-depleted states, wherein this pathway drives the hydrolysis of ATP and thus increases oxygen consumption Kazak et al.
Cold exposure for 1 week increased the expression of both creatine kinase U-type, mitochondrial Ckmt1 and creatine kinase S-type, mitochondrial Ckmt2 in inguinal beige adipocytes, indicative of an upregulation in creatine cycling.
Furthermore, treatment with the β3-adrenoceptor agonist, CLinduced Ucp1 -expressing beige adipocytes in the inguinal fat depot, as well as Ucp1 -negative, Ckmt2 -positive beige adipocytes in epididymal fat Bertholet et al.
Murine beige adipocytes also produce heat via futile calcium cycling and the activation of SERCA2b Ikeda et al. Inhibition or downregulation of SERCA2b in inguinal adipose tissue attenuates the noradrenaline-induced increase in oxygen consumption Ikeda et al.
To date, the vast majority of studies have utilised UCP1 protein or mRNA expression as a marker for beige adipocytes, and thus the abundance and importance of these cells have likely been underestimated.
It is now apparent that multiple pathways contribute to thermogenesis in these unique beige cells. The role of beige adipocytes in determining thermogenesis and energy expenditure in larger mammals including sheep and pigs, however, requires further interrogation.
Schematic diagram depicting the futile creatine cycle. Within mitochondria, thermogenesis can occur in the ADP-depleted state via creatine cycling.
Creatine is phosphorylated by creatine kinase CK and then dephosphorylated. The responsible phosphatase is currently unidentified. The process of creatine dephosphorylation is thermogenic via the hydrolysis of ATP. Control of adaptive thermogenesis is mediated by the hypothalamus, and while only explained briefly here, has been well detailed by Morrison Morrison In rodents, when exposed to cold, thermosensory inputs act via the median preoptic area to stimulate the dorsomedial hypothalamus DMH to increase sympathetic nerve activity to BAT through the rostral raphe pallidus rRPa Hermann et al.
Development of Designer Receptor Exclusivity Activated by Designer Drugs DREADD technology has allowed for further characterisation of these temperature-sensitive neurons. Use of DREADDS suggests that activation of GABA neurons in the preoptic area has little effect on body temperature or energy expenditure Yu et al.
Indeed, these studies show that leptin-receptor-expressing neurons in the preoptic area are integral to ambient temperature-induced metabolic food intake and energy expenditure adaptations Yu et al. Within the preoptic area, there is clearly topographical neuronal organisation as cold exposure increases c-Fos levels in GABA neurons within the ventral part of the lateral preoptic area Zhao et al.
Optogenetic inhibition of this subset of GABA neurons causes hyperthermia, whereas activation of the same reduces body temperature Zhao et al. Thus, within the preoptic area, there is an integrated network of neurons, including both GABA-ergic and leptin responsive cells, capable of sensing changes in skin temperature and modifying thermogenic output.
In addition to the aforementioned temperature-sensitive pathway, metabolic factors such as leptin, insulin and ghrelin modulate thermogenic activity via hypothalamic appetite-regulating peptides.
Blood-borne factors can diffuse across the blood brain barrier via fenestrated capillaries and act directly on neurons in the arcuate nucleus Banks Importantly, two distinct sets of neurons are found in the arcuate nucleus, being either orexigenic or those that elicit satiety.
The POMC neurons are activated by leptin Elias et al. A second population of neurons contain neuropeptide Y NPY and agouti-related protein AgRPwhich stimulate food intake in response to direct stimulation by ghrelin Kamegai et al.
NPY exerts an immediate effect to stimulate food intake, primarily via action at Y1 receptors in the PVN Kask et al.
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| Molecular mechanisms of thermogenesis - Edward Mills | As these tools are developed and applied in tandem, they will expand our depth of understanding for the importance of lipid metabolism in thermogenic adipose tissue. In Current Protocols in Pharmacology, chapter 5, unit 5. Periasamy M, Maurya SK, Sahoo SK, Singh S, Sahoo SK, Reis FCG, et al. J Lipid Res. McCullagh KJ, Calabria E, Pallafacchina G, Ciciliot S, Serrano AL, Argentini C, et al. |
| Thermogenesis - Wikipedia | In Encyclopedia. Copy Citation. Home Entry Topic Review Current: Thermogenesis. This entry is adapted from the peer-reviewed paper brown adipose tissue thermogenesis mitochondria lipids. Introduction Body temperature regulation is a selective advantage that has allowed endotherms to thrive in diverse climates. Mitochondrial Lipid Signaling and Adaptive Thermogenesis Thermogenesis in brown and beige adipocytes is dependent on mitochondrial lipid processing. References Kajimura, S. Brown and Beige Fat: Physiological Roles beyond Heat Generation. Cell Metab. Cannon, B. Brown adipose tissue: Function and physiological significance. Roesler, A. UCP1-independent thermogenesis. Rosen, E. Adipocytes as regulators of energy balance and glucose homeostasis. Nature , , — Park, H. Lipid Regulators of Thermogenic Fat Activation. Trends Endocrinol. TEM , 30, — Lynes, M. Lipokines and Thermogenesis. Endocrinology , , — Wikstrom, J. Hormone-induced mitochondrial fission is utilized by brown adipocytes as an amplification pathway for energy expenditure. Embo J. Bartelt, A. Brown adipose tissue activity controls triglyceride clearance. Global Analysis of Plasma Lipids Identifies Liver-Derived Acylcarnitines as a Fuel Source for Brown Fat Thermogenesis. Cold-Activated Lipid Dynamics in Adipose Tissue Highlights a Role for Cardiolipin in Thermogenic Metabolism. Cell Rep. Chaurasia, B. Adipocyte Ceramides Regulate Subcutaneous Adipose Browning, Inflammation, and Metabolism. Gohlke, S. Identification of functional lipid metabolism biomarkers of brown adipose tissue aging. Leiria, L. Ceramides are necessary and sufficient for diet-induced impairment of thermogenic adipocytes. Hoene, M. The lipid profile of brown adipose tissue is sex-specific in mice. Acta , , — Justo, R. Brown adipose tissue mitochondrial subpopulations show different morphological and thermogenic characteristics. Mitochondrion , 5, 45— Tajima, K. Mitochondrial lipoylation integrates age-associated decline in brown fat thermogenesis. Berry, D. Mouse strains to study cold-inducible beige progenitors and beige adipocyte formation and function. Chen, Y. Thermal stress induces glycolytic beige fat formation via a myogenic state. Rajbhandari, P. Single cell analysis reveals immune cell-adipocyte crosstalk regulating the transcription of thermogenic adipocytes. eLife , 8, e Ramirez, A. Single-cell transcriptional networks in differentiating preadipocytes suggest drivers associated with tissue heterogeneity. Burl, R. Deconstructing Adipogenesis Induced by β3-Adrenergic Receptor Activation with Single-Cell Expression Profiling. Henriques, F. Single-Cell RNA Profiling Reveals Adipocyte to Macrophage Signaling Sufficient to Enhance Thermogenesis. Kumar, R. Single Cell Metabolomics: A Future Tool to Unmask Cellular Heterogeneity and Virus-Host Interaction in Context of Emerging Viral Diseases. Linke, V. A large-scale genome-lipid association map guides lipid identification. Yore, M. Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell , , — Morstein, J. Photoswitchable Lipids. Chembiochem Eur. Daemen, S. Microscopy tools for the investigation of intracellular lipid storage and dynamics. Mechler, A. Labeling phospholipid membranes with lipid mimetic luminescent metal complexes. Acta Bba Biomembr. Schütz, G. Properties of lipid microdomains in a muscle cell membrane visualized by single molecule microscopy. Hui, S. Quantitative Fluxomics of Circulating Metabolites. Wang, Y. Utilizing tandem mass spectrometry for metabolic flux analysis. By using this site, you agree to the Terms and Conditions and Privacy Policy. Upload a video for this entry. Contributor MDPI registered users' name will be linked to their SciProfiles pages. View Times: Revisions: 3 times View History. Finally, we show that skeletal muscle-specific UCP3 expression rescues drug- induced thermogenesis a response that requires fatty acids in global UCP3 knockout mice, showing that muscle may be a novel site of UCP3 thermogenesis. The overall working hypothesis of this proposal is that UCP3 coordinates the maximal capacity for skeletal muscle thermogenesis and fat oxidation through the control of mitochondrial malate and potentially other C4 metabolite mitochondrial import anaplerotic flux of malate and likely aspartate, among others. We will test this in the following Aims: 1 Define the role of UCP3 in C4 metabolite mitochondrial transport and the molecular mechanisms involved. Significance summary: This work will provide fundamental and novel insights into the molecular mechanisms regulating UCP3 and likely UCP1 , and will identify novel UCP-modulating? targets and mechanisms. Work in this proposal aims to determine the molecular mechanisms by which mitochondrial uncoupling protein 3 UCP3 increases fat oxidation and thermogenesis, especially in skeletal muscle based on our team's recent discoveries that UCP3 has a novel anaplerotic function to import malate into mitochondria and that is controls not only drug-induced but also physiologically mediated thermogenesis. Experiments are designed to identify the repertoire of solutes that UCP3 transports, and they will also characterize a novel interaction between UCP3 and mitochondrial malate dehydrogenase 2 mMDH2 and its functional importance for UCP3 function, malate transport, and thermogenesis. A greater mechanistic understanding of the regulation and functions of UCP3 as well as other thermogenic uncoupling proteins is greatly needed if we are to exploit these promising energy-expending proteins therapeutically, therefore this work will lay a foundation for the development of anti-obesity drugs that target UCP3-induced energy wasting and fat metabolism in muscle. Toggle navigation. Home Search Services Blog Contact About. Molecular mechanisms of thermogenesis Mills, Edward M. University of Texas Austin, Austin, TX, United States. Share this grant: : :. Abstract Funding Institution Related projects Publications Comments. Recent in Grantomics:. Recently viewed grants:. Recently added grants:. Funding Agency. Agency National Institute of Health NIH Institute National Institute of Diabetes and Digestive and Kidney Diseases NIDDK Type Research Project R Project Start Project End Budget Start Budget End Support Year 6 Fiscal Year Total Cost Indirect Cost. Name University of Texas Austin. City Austin State TX Country United States Zip Code Related projects. Nowinski, Sara M; Solmonson, Ashley; Mills, Edward M Chewing the fat for Akt1 inhibition and oncosuppression. Mol Cell Oncol 3:e Hirasaka, Katsuya; Mills, Edward M; Haruna, Marie et al. |
| Thermogenesis | Encyclopedia MDPI | Temperature-acclimated brown adipose tissue modulates insulin sensitivity in humans. Similarly, creatine enzyme Ckmt1 and Ckb double KO mice showed cold intolerance and reduced norepinephrine responses to activate thermogenic respiration The G3P shuttle is a predominant metabolic pathway in skeletal muscle and BAT and is stimulated by TH 1. Barbe P , Larrouy D , Boulanger C , et al. Fatty acids activate UCPs by binding to a hydrophobic pocket within the protein that increases proton conductance. Jimenez M , Léger B , Canola K , et al. |
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