Enhanced thermogenesis -
These beneficial effects originate from peripheral tissues or cells such as the liver and macrophages. Here, we found that miR in the brain affects whole-body metabolism by modulating the sympathetic nerve tone.
To the best of our knowledge, this is the first study to demonstrate that a certain miRNA in the central nervous system has substantial effects on metabolism by altering sympathetic nerve activity, and we identify crosstalk between miR, metabolic miRNA, and the central nervous system.
Because increased sympathetic nerve activity is known to accelerate atherosclerosis by several mechanisms 51 , 52 , 53 , 54 , its reduction via deletion or inhibition of miR can contribute to the amelioration of atherosclerosis. Rodents have only one miR in an intron of the Srebf2 gene, while humans have another, miRb, in an intron of the SREBF1 gene.
miRa and miRb have been shown to share the same genes as their targets by comprehensive transcriptome and bioinformatics analysis 55 , therefore, the copy number of miR is most likely to be important for these phenotypic changes.
In this study, Srebf2 expression was induced by cold stress, HFD feeding, and thapsigargin treatment, while Srebf1 was induced only by cold stress. Since there may be different pathways for inducing Srebf1 expression other than ER stress 56 , further analyses are needed.
Diet-induced thermogenesis is another form of adaptive thermogenesis that limits weight gain in response to caloric excess such as HFD feeding. As discussed above, HFD feeding is known to induce ER stress in the hypothalamus We found that HFD feeding also up-regulated miR in the hypothalamus.
ER, stress-induced miR can enhance sympathetic nerve activity by suppressing the GABA A receptor-mediated mechanism, leading to increased BAT thermogenesis.
Thus, diet-induced thermogenesis probably shares the same pathway as cold-induced thermogenesis from the viewpoint of miR and the GABA A receptors. A recent report showed that hunger signal stimulates GABAergic neurons in medullary reticular nuclei, which innervate the rRPa and inhibit BAT thermogenesis to reduce energy expenditure 57 , which is compatible with and supports our findings.
Accumulating evidence indicates that beige adipose tissue, which differentiates from WAT and functions similarly to BAT, is also important for whole-body metabolism and is expected to have clinical implications Because WAT is also under the control of the sympathetic nerve tone, we evaluated the extent of browning of WAT in this study.
Previous reports have shown that miR deficiency or long-term inhibition of miR can lead to obesity with HFD feeding 20 , 21 , Therefore, miR deficiency or long-term inhibition of miR may fail to induce HFD-induced thermogenesis and browning of WAT, which in part contributes to obesity with HFD feeding.
Further analysis is needed to elucidate this mechanism. In conclusion, we identified a neural mechanism for the regulation of adaptive thermogenesis via miR During cold stress, miR in the brain Dbh -positive neurons in particular contributes to the maintenance of BAT thermogenesis and whole-body metabolism through increased sympathetic nerve activity by suppressing GABA A inhibitory neuronal transmission.
This neural machinery may serve as an adaptive defense mechanism against cold stress and other stresses such as fear conditioning or behavior stress. DBH -Cre mice were generated by Dr. Kazuto Kobayashi and provided by the RIKEN BRC through the National Bio-Resource Project of the MEXT, Japan Mice were weaned at the age of 4 weeks and fed normal chow NC containing 4.
All of the experimental protocols were approved by the Ethics Committee for Animal Experiments of Kyoto University. All animal experiments were performed in accordance with the ethical guidelines of the Animal Experimentation Committee of Kyoto University. Primers for genotyping and product size are listed in Supplementary Table 1.
Antibodies used in this study comprised: anti-ABCA1 antibody NB; Novus Biologicals, CO , anti-UCP1 antibody U , anti-β-actin antibody A Sigma-Aldrich, MO , anti-TH antibody AB , anti-goat-IgG biotin-conjugated antibody APB , anti-rabbit-IgG biotin-conjugated antibody APB Millipore, MA , anti-c-fos antibody sc , anti-PGC1α antibody H , anti-CHOP antibody sc Santa Cruz Biotechnology, CA , anti-GAPDH antibody , anti-BIP antibody , anti-cleaved-caspase 3 antibody Cell Signaling Technology, MA , and anti-rabbit, anti-mouse, and anti-goat IgG HRP-linked antibodies GE Healthcare, Inc.
NE, AMPT methyl ester hydrochloride, and thapsigargin were purchased from Sigma-Aldrich. Total RNA was isolated using TriPure reagent Sigma-Aldrich from organs or cells. Expression levels were normalized using β-actin expression levels. miRa and miRb were measured using TaqMan MicroRNA Assays Applied Biosystems, Inc.
Expression levels were normalized using U6 snRNA expression. Human Total RNA Master Panel II Clontech, CA and human adipose tissue RNA Biochain, CA were used for the distribution of genes in human organs.
All analyses were performed using a StepOnePlus real-time PCR system and StepOne Software v2. Primers used for quantitative real-time PCR in this study are listed in Supplementary Table 2. Western blotting was performed using standard procedures.
After a washing step in PBS containing 0. The membrane was then washed in 0. Densitometry was performed using ImageJ software 1. Anesthetized mice were placed on ice, and BAT and rectal temperature were recorded simultaneously every minute.
Male mice at 8 weeks old were kept in separate chambers at the indicated temperature for 3 days, and oxygen consumption rates were measured using an Oxymax indirect calorimetric system and analyzed by CLAX software v2. The measurement is based on the oxidation of octanoyl-CoA, which is coupled to NADH-dependent reduction of INT to INT-formazan.
The formazan production from the same amount of BAT homogenates with or without octanoyl-CoA was measured by an ARVO X 3 microplate reader at O. The subtracted O.
values presented here are proportional to the FAO activity. NETO was measured using AMPT as follows 25 , Mice were euthanized by decapitation without anesthesia in order to prevent NE release from sympathetic terminals. BAT was homogenized, and then NE concentrations were measured for the pre- and post-AMPT treatment groups.
Values were calculated as NE content per gram of BAT. Surgical denervation of nerves that innervate iBAT was performed as follows Under anesthesia with isoflurane, a midline incision in the skin along the upper dorsal surface was made.
The medial, ventral surface of iBAT was exposed to visualize nerves beneath the pad. There are five intercostal nerves that unilaterally innervate each iBAT lobe and these nerves appear in bundles of two to three.
The left side of BAT was denervated and the right side of BAT was sham-operated. Mice were analyzed 1 week after the operation. Successful denervation was confirmed by NE content in BAT. After anesthetization, mice were perfused transcardially with ice-cold PBS pH 7. The brain tissues were embedded in O.
The slices were treated with methanol supplemented with 0. After washing with T-PBS, slices were embedded and coverslipped. c-fos-positive cells in the rRPa were counted.
The mean number of c-fos-positive cells from six sequential sections are presented here. Data were obtained by Axio Observer 7 and Zen 2 pro software Carl Zeiss, Inc. This cycle was repeated for 7 consecutive days.
Blood pressure and heart rate were measured using a noninvasive tail-cuff system BPA, Softron. The mean of 8 measurements per mouse was used as values for blood pressure and heart rate. The human iPS cells used in this study were B7, which were generated by Dr.
Shinya Yamanaka 61 from dermal fibroblasts Cell Applications, Inc. obtained from a healthy donor who gave informed consent.
The iPS cell line is widely used for research and ethical approval is not required in Japan. These human iPS cells, including controls, were differentiated into cortical neurons using the quick embryoid body-like aggregate SFEBq method The use of human iPS cells was approved by the Ethics Committee of Kyoto University.
A plasmid with AAV capsid serotype 9 pAAV-RC9 was obtained from Penn Vector Core at the University of Pennsylvania. A plasmid with AAV conditional shRNA pAAV-dsRed-Sico-shRNA , in which the shRNA was expressed only when regulated by Cre recombinase was kindly provided by Dr.
Marina Picciotto, Yale University The purification method was performed with slight modifications Briefly, AAV cells Agilent Technologies, CA were transfected with pAAV-GFP or pAAV-conditional shRNA, pHelper, and pAAV-RC9 vector plasmids using a standard PEI Polysciences, Inc.
PA -mediated transfection method. The supernatant was used as the virus-containing solution. Quantitative real-time PCR was performed to measure the titer of the purified virus. Two to three kinds of shRNA sequence against indicated genes were cloned into pAAV-conditional shRNA pAAV-dsRed-Sico-shRNA.
The sequences were confirmed by xl Genetic Analyzer, Foundation Data Collection v3. These plasmids are co-transfected with Cre-expression vectors into Neuro2a cells.
The most-effective sequence was selected for in vivo experiments. Sequences for shRNA used for the in vivo study are listed in Supplementary Table 3. An AAV9 viral vector was injected into neonatal brains by icv injection as reported previously In brief, P0 neonatal mice were placed on a cold aluminum plate on ice to induce hypothermia anesthesia.
The same procedure was performed with the contralateral ventricle. After completing viral injections into both hemispheres, the pup was placed back on a warming pad.
AAV9 vector-injected mice were analyzed at 8 weeks of age. fdANOVA was used for the analysis of the oxygen consumption curves. Exact p values are provided in a Source Data file. Statistical and data analyses were performed using ImageJ 1. Further information on research design is available in the Nature Research Reporting Summary linked to this article.
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Download references. We would like to thank Dr. Kazuto Kobayashi and RIKEN BRC for providing DBH-Cre mice. This work was supported by the Ministry of Education, Culture, Sports, Science, and Technology MEXT and Japan Society for the Promotion of Science JSPS KAKENHI Grants 17K and 20K T.
This work was also supported by AMED under grant JP19fk K. Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Laboratory of Physiological Functions of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan.
Department of Biological Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Department of Psychiatry and Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, CT, USA.
Center for iPS Cell Research and Application CiRA , Kyoto University, Kyoto, Japan. iPSC-based Drug Discovery and Development Team, RIKEN BioResource Research Center BRC , Kyoto, Japan.
Medical-risk Avoidance based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project AIP , Kyoto, Japan. Department of Integrative Physiology, Nagoya University Graduate School of Medicine, Nagoya, Japan. Laboratory of Nutrition Chemistry, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan.
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Skip to main content. Actions for this page Listen Print. Summary Read the full fact sheet. On this page. What is metabolism? Two processes of metabolism Metabolic rate Metabolism and age-related weight gain Hormonal disorders of metabolism Genetic disorders of metabolism Where to get help.
Two processes of metabolism Our metabolism is complex — put simply it has 2 parts, which are carefully regulated by the body to make sure they remain in balance.
They are: Catabolism — the breakdown of food components such as carbohydrates , proteins and dietary fats into their simpler forms, which can then be used to provide energy and the basic building blocks needed for growth and repair.
Anabolism — the part of metabolism in which our body is built or repaired. Anabolism requires energy that ultimately comes from our food. When we eat more than we need for daily anabolism, the excess nutrients are typically stored in our body as fat.
Thermic effect of food also known as thermogenesis — your body uses energy to digest the foods and drinks you consume and also absorbs, transports and stores their nutrients.
Energy used during physical activity — this is the energy used by physical movement and it varies the most depending on how much energy you use each day.
Physical activity includes planned exercise like going for a run or playing sport but also includes all incidental activity such as hanging out the washing, playing with the dog or even fidgeting! Basal metabolic rate BMR The BMR refers to the amount of energy your body needs to maintain homeostasis.
Factors that affect our BMR Your BMR is influenced by multiple factors working in combination, including: Body size — larger adult bodies have more metabolising tissue and a larger BMR. Amount of lean muscle tissue — muscle burns kilojoules rapidly. Crash dieting, starving or fasting — eating too few kilojoules encourages the body to slow the metabolism to conserve energy.
Age — metabolism slows with age due to loss of muscle tissue, but also due to hormonal and neurological changes. Growth — infants and children have higher energy demands per unit of body weight due to the energy demands of growth and the extra energy needed to maintain their body temperature.
Gender — generally, men have faster metabolisms because they tend to be larger. Genetic predisposition — your metabolic rate may be partly decided by your genes. Hormonal and nervous controls — BMR is controlled by the nervous and hormonal systems.
Hormonal imbalances can influence how quickly or slowly the body burns kilojoules. Environmental temperature — if temperature is very low or very high, the body has to work harder to maintain its normal body temperature, which increases the BMR. Infection or illness — BMR increases because the body has to work harder to build new tissues and to create an immune response.
Amount of physical activity — hard-working muscles need plenty of energy to burn. Regular exercise increases muscle mass and teaches the body to burn kilojoules at a faster rate, even when at rest. Drugs — like caffeine or nicotine , can increase the BMR. Dietary deficiencies — for example, a diet low in iodine reduces thyroid function and slows the metabolism.
Thermic effect of food Your BMR rises after you eat because you use energy to eat, digest and metabolise the food you have just eaten. Hot spicy foods for example, foods containing chilli, horseradish and mustard can have a significant thermic effect. Energy used during physical activity During strenuous or vigorous physical activity, our muscles may burn through as much as 3, kJ per hour.
Metabolism and age-related weight gain Muscle tissue has a large appetite for kilojoules. Hormonal disorders of metabolism Hormones help regulate our metabolism.
Thyroid disorders include: Hypothyroidism underactive thyroid — the metabolism slows because the thyroid gland does not release enough hormones. Some of the symptoms of hypothyroidism include unusual weight gain, lethargy, depression and constipation.
Hyperthyroidism overactive thyroid — the gland releases larger quantities of hormones than necessary and speeds the metabolism. Some of the symptoms of hyperthyroidism include increased appetite, weight loss, nervousness and diarrhoea. Genetic disorders of metabolism Our genes are the blueprints for the proteins in our body, and our proteins are responsible for the digestion and metabolism of our food.
Some genetic disorders of metabolism include: Fructose intolerance — the inability to break down fructose, which is a type of sugar found in fruit, fruit juices, sugar for example, cane sugar , honey and certain vegetables.
Galactosaemia — the inability to convert the carbohydrate galactose into glucose. Galactose is not found by itself in nature.
It is produced when lactose is broken down by the digestive system into glucose and galactose. Sources of lactose include milk and milk products, such as yoghurt and cheese. Phenylketonuria PKU — the inability to convert the amino acid phenylalanine into tyrosine.
High levels of phenylalanine in the blood can cause brain damage. High-protein foods and those containing the artificial sweetener aspartame must be avoided. Where to get help Your GP doctor Dietitians Australia External Link Tel. Metabolic disorders External Link , MedlinePlus, National Library of Medicine, National Institutes of Health, USA.
Rolfes S, Pinna K, Whitney E , 'Understanding normal and clinical nutrition' External Link , Cengage Learning, USA. Dietary energy External Link , National Health and Medical Research Council NHMRC and Department of Health and Aged Care, Australian Government.
Healthy weight and cancer risk External Link , Cancer Council NSW. Physical activity and exercise guidelines for all Australians External Link , Department of Health and Aged Care, Australian Government. Give feedback about this page.
CHUL-HONG PARKHELIA CHENG therrmogenesis, SANG R. LEEKENNETH Enhanced thermogenesisJI SUK CHANG; LB: Overexpression of GOT1 in Brown Adipose Tissue Tnermogenesis Thermogenesis thetmogenesis Glucose Metabolism Muscle recovery for martial artists Activating the Malate-Aspartate Shuttle. Brown adipose tissue BAT is characterized by thermogenic and glucose-consuming properties. BAT takes up large amounts of circulating glucose during cold exposure or pharmacological stimulation of β 3 -adrenergic receptors β 3 ARbut glucose oxidation in mitochondria only modestly contributes as a fuel source for thermogenesis. How glucose metabolism supports thermogenesis is incompletely understood. Here, we identify a novel role of the malate-aspartate shuttle MAS in enhancing thermogenesis, glucose uptake and glycolysis in brown adipose tissue. Commentary Open Access Division of Endocrinology, Diabetes and Metabolism, Flavonoids and blood sugar control Thhermogenesis Deaconess Medical Enhajced and Harvard Medical School, Boston, Massachusetts, USA. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA. Address correspondence to: Shingo Kajimura, Center for Life Sciences, 3 Blackfan Circle, Room CLS, Boston, MassachusettsUSA. Phone: Find articles by Yook, J.
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